Oltre la pseudoiponatriemia: disordini del sodio nel mieloma multiplo, implicazioni cliniche e meccanismi patogenetici

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Elena Tanzarella

DOI: 10.69097/43-02-2026-08

Elena Tanzarella1, Michele Paolisi1, Martina Catania1, Francesca Tunesi1, Liliana Italia De Rosa1, Pierpaolo Bianca1, Kristiana Kola1, Alessandro Barruscotti2, Rodolfo Fernando Rivera3, Paolo Manunta1,2, Giuseppe Vezzoli1,2, Maria Teresa Sciarrone Alibrandi2

1 Vita Salute San Raffaele University, 20132 Milan, Italy
2 O.U. Nephrology and Dialysis, San Raffaele Scientific Institute, 20132 Milan, Italy
3 Nephrology and Dialysis Unit, Pio XI Hospital, ASST Brianza, Via Mazzini 1, Desio (MB)

Corrispondenza a:
Liliana Italia De Rosa
UO Operativa Nefrologia e Dialisi Ospedale IRCCS San Raffaele Milano
Via Olgettina 60 20132 Milano
Tel 0226435330 Fax 0226432384
E-mail: derosa.liliana@hsr.it

 

Abstract

L’iponatriemia è un reperto relativamente frequente nel mieloma multiplo (MM) e può derivare da pseudoiponatriemia, conseguente a marcata iperproteinemia, oppure da iponatriemia vera, espressione di un’alterazione reale dell’omeostasi sodio-acqua. La distinzione è cruciale, poiché le due condizioni differiscono per meccanismi fisiopatologici, implicazioni cliniche e strategie terapeutiche.
La pseudoiponatriemia, osservata nel 15–20% dei pazienti con MM, rappresenta un artefatto analitico tipico della misurazione mediante potenziometria indiretta, in cui l’elevata concentrazione di proteina M riduce la frazione acquosa plasmatica. In tali casi, l’osmolarità sierica è normale e non è indicata alcuna correzione della natriemia.
La iponatriemia vera (<135 mEq/L con ipo-osmolarità plasmatica) è meno comune ma clinicamente più rilevante, associandosi a prognosi sfavorevole e possibile sintomatologia significativa. Le cause comprendono: danno renale (nefropatia da cilindri, sindrome di Fanconi, deposizione interstiziale di catene leggere), ipervolemia da insufficienza renale avanzata, ipovolemia per perdite gastrointestinali o diuretici, farmaci (bortezomib, ciclofosfamide), SIADH paraneoplastica e alterazioni dell’elettroneutralità da proteine M cationiche, responsabili di riduzioni addizionali, ma modeste della natriemia. Il trattamento della pseudoiponatriemia mira al controllo della malattia e alla riduzione della paraproteinemia. La iponatriemia vera richiede invece un approccio etiologico: espansione volemica con soluzione salina isotonica nell’ipovolemia, restrizione idrica con o senza supplementi nella SIADH, modulazione della terapia diuretica nell’ipervolemia e sospensione dei farmaci implicati. Il controllo del clone plasmacellulare con schemi tripli o quadrupli è fondamentale per prevenire recidive. Un percorso diagnostico strutturato, integrando valutazione volemica, indagini mirate e revisione terapeutica, è fondamentale per distinguere le forme di iponatriemia e guidarne la gestione. Parole chiave: mieloma multiplo, iponatriemia, pseudoiponatriemia

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

Multiple myeloma (MM) is a malignant plasma cell disorder characterized by clonal proliferation within the bone marrow and overproduction of a monoclonal immunoglobulin, commonly referred to as M protein. This abnormal protein production and the associated tumor burden contribute to a wide range of clinical manifestations and complications [1, 2].

Epidemiology

Globally, MM accounts for an estimated 160,000 new cases and over 100,000 deaths annually. In the United States, it represents approximately 1.8% of all newly diagnosed cancers. The median age at diagnosis is around 70 years, with a slightly higher incidence in men than in women. African American individuals have an increased risk compared with other ethnic groups [1–3].

Pathogenesis and Risk Factors

The pathogenesis of MM is multifactorial and incompletely understood. Established risk factors include advanced age, male sex, African ancestry, and family history of plasma cell disorders. Environmental and occupational exposures, such as to benzene and certain pesticides, have been suggested as possible contributors [1, 4–6].

M Protein Characteristics

M protein is most frequently of the IgG subtype (~55% of cases) or IgA (~20%), and 40% of patients present with Bence Jones proteinuria due to excess free monoclonal κ or λ light chains in the urine. A subset (15–20%) secrete only Bence Jones protein without detectable serum M protein. Rare variants include IgM, IgD, and IgE myeloma, as well as non-secretory forms detected only by serum free light chain assays [1, 4, 7].

Clinical Features and Complications

MM can present insidiously, with fatigue, bone pain, recurrent infections, or biochemical abnormalities. Major complications include [1, 4, 7, 8]:

  • Osteolytic lesions and fractures – due to osteoclast activation and osteoblast inhibition
  • Hypercalcemia – present in ~30% of newly diagnosed cases, resulting from bone resorption, increased osteoclast-activating cytokines, and reduced renal calcium excretion
  • Renal impairment – caused by light chain deposition, hypercalcemia, amyloidosis, or nephrotoxic agents
  • Amyloidosis (AL) – develops in 10–20% of patients due to light chain deposition in organs such as kidney, heart, and liver
  • Anemia – from bone marrow infiltration, renal dysfunction, or nutritional deficiencies
  • Infections – secondary to immunoparesis and treatment-related immune suppression.

Therapeutic Approach

Treatment of MM is tailored to patient age, comorbidities, cytogenetic risk, and transplant eligibility. Modern regimens integrate multiple drug classes [9–11]:

  • Proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib)
  • Immunomodulatory and anti-angiogenic drugs (e.g., lenalidomide, pomalidomide). Monoclonal antibodies – notably daratumumab (anti-CD38), which has significantly improved response depth and survival in both transplant-eligible and -ineligible patients, and is used in induction, consolidation, and relapse settings, often in triplet or quadruplet combinations
  • Corticosteroids (e.g., dexamethasone)
  • Alkylating agents (e.g., cyclophosphamide, melphalan), especially in conditioning before autologous stem cell transplantation.

For transplant-eligible patients, induction regimens such as D-VTd (daratumumab, bortezomib, thalidomide, dexamethasone) or D-VRd (daratumumab, bortezomib, lenalidomide, dexamethasone) are now widely adopted, followed by high-dose melphalan and autologous stem cell transplantation. Maintenance therapy, typically with lenalidomide, prolongs progression-free survival [11].

 

Hyponatremia in multiple myeloma

Hyponatremia, defined as a serum sodium concentration <135 mEq/L, is a relatively frequent laboratory abnormality in patients with multiple myeloma (MM) and may occur as pseudohyponatremia or true hyponatremia. Correct classification is critical, as these conditions differ substantially in their pathogenesis, clinical significance, and management strategies [12–14].

Pseudohyponatremia

Pseudohyponatremia is the artifactual lowering of measured serum sodium in the presence of normal serum osmolality (275–295 mOsm/kg). Pseudohyponatremia can also occur with increased serum OSM (e.g., in hyperglycemia). In MM, this occurs due to marked hyperproteinemia from excess monoclonal immunoglobulin (M protein) production. The high protein content increases the non-aqueous fraction of plasma, thereby reducing the proportion of plasma water, the compartment in which sodium resides [15, 16].

When sodium is measured by indirect ion-selective electrode (ISE), which requires sample dilution, the reduced water fraction leads to underestimation of sodium concentration, despite normal osmotic activity. Direct ISE, performed on undiluted serum or plasma, avoids this artifact.

Pseudohyponatremia is not an uncommon finding in patients with multiple myeloma. Several studies have documented its occurrence in approximately 15–20% of cases (Figure 1). This prevalence highlights how frequently the condition can be encountered in clinical practice, particularly in patients with markedly elevated levels of monoclonal protein [17–19].

From a clinical standpoint, pseudohyponatremia has no osmotic consequences, as the actual sodium concentration in the plasma water compartment remains normal. Therefore, no corrective measures targeting sodium levels are required. The key lies in recognizing the condition promptly, in order to avoid inappropriate therapeutic interventions and to focus instead on managing the underlying myeloma and reducing paraproteinemia.

True Hyponatremia

True hyponatremia in MM is defined by:

  • Serum sodium <135 mEq/L
  • Hypo-osmolality (<275 mOsm/kg)

Although less common than pseudohyponatremia, the estimates remain uncertain, although more data indicate that its prevalence is around 8% (Figure 1), it carries greater clinical significance, as it may contribute to neurological symptoms ranging from mild confusion to seizures and coma, and it is associated with worse overall prognosis. The pathogenesis of true hyponatremia in MM is multifactorial, with several mechanisms often coexisting in the same patient [13, 14, 20] (Figure 2).

Hyponatremia in MM – Pseudo vs True.
Figure 1. Hyponatremia in MM – Pseudo vs True.
Figure 2. Causes of true hyponatremia in MM.
Figure 2. Causes of true hyponatremia in MM.

 

Pathophysiological Mechanisms of True Hyponatremia in Multiple Myeloma According to Volume Status

Hypovolemic Hyponatremia

a. Gastrointestinal and Extrarenal Losses

Gastrointestinal sodium and water losses are frequent in MM patients due to chemotherapy-induced vomiting and diarrhea, poor oral intake, or infections. The ensuing extracellular fluid volume depletion activates baroreceptor-mediated ADH release, promoting renal water reabsorption. Since water is retained in excess of sodium, serum sodium concentration declines further. In these cases, the urine sodium is typically low (<20 mmol/L) because the kidneys avidly retain sodium to defend effective arterial blood volume [21].

b. Renal Salt-Wasting: Fanconi Syndrome and Tubular Injury

Excess light chains are taken up by proximal tubular cells via endocytosis. Inside the cells, they may precipitate and cause lysosomal rupture, leading to cellular injury. This impairs the reabsorption of bicarbonate, phosphate, glucose, uric acid, amino acids, and sodium. The resultant bicarbonate loss produces a normal anion gap metabolic acidosis, while chronic proximal tubular injury leads to natriuresis and mild to moderate volume depletion, both of which may exacerbate hypovolemic hyponatremia [22–25].

Loop and thiazide diuretics, frequently used in MM to manage hypercalcemia or fluid overload, can further promote renal sodium loss and worsen hypovolemia. Thiazides, in particular, impair urinary dilution in the distal tubule, creating a setting in which ADH-induced water retention can more easily cause hyponatremia [26].

In summary, when sodium loss (gastrointestinal or renal) exceeds water loss and stimulates non-osmotic ADH release, true hypovolemic hyponatremia ensues.

Euvolemic Hyponatremia

a. Paraneoplastic SIADH

Although rare, MM may be associated with ectopic ADH production by malignant plasma cells or cells in the tumor microenvironment. More commonly, cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) – produced in abundance in MM – can potentiate the renal tubular response to ADH, lowering the threshold for water reabsorption. This leads to water retention, low serum osmolality, and high urine osmolality despite hyponatremia, in the absence of overt edema or signs of volume depletion, i.e. a euvolemic state [13, 27].

b. Drug-Induced SIADH (Bortezomib and Cyclophosphamide)

Bortezomib and cyclophosphamide have both been implicated in the development of SIADH. Potential mechanisms include direct stimulation of hypothalamic ADH release, increased sensitivity of renal collecting ducts to ADH, and indirect effects through inflammatory cytokine release or oxidative stress (Figure 3). In these cases, urine sodium is typically elevated (>20 mmol/L) and urine osmolality is inappropriately high for the degree of hyponatremia, while the patient appears clinically euvolemic [28–31].

Mechanism by which bortezomib induces hyponatremia.
Figure 3. Mechanism by which bortezomib induces hyponatremia.

c. Electroneutrality and Strong Ion Difference Alterations

According to Stewart’s physicochemical model of acid–base balance, plasma sodium concentration is not only a reflection of sodium intake and excretion but also depends on the Strong Ion Difference (SID) – the net balance between fully dissociated cations (Na⁺, K⁺, Ca²⁺, Mg²⁺) and anions (Cl⁻, lactate, sulfate) [32, 33].

M protein, especially when highly cationic, contributes to the pool of strong cations in plasma. To maintain electroneutrality, a compensatory reduction in sodium (and sometimes potassium) may occur, often accompanied by an increase in chloride concentration. This can lead to a lower anion gap, which, if unrecognized, may be mistakenly attributed to other causes [20, 33]. When SID alterations predominate in otherwise hemodynamically stable patients, the resulting hyponatremia is usually mild and euvolemic, but it may compound other mechanisms such as SIADH.

Unlike pseudohyponatremia, this is not a laboratory artifact – serum osmolality is genuinely reduced because the decrease in plasma sodium within the aqueous compartment is real.

Hypervolemic Hyponatremia

MM-Related Advanced Renal Failure

In multiple myeloma, monoclonal free light chains are freely filtered by the glomerulus. In the distal tubules, they interact with Tamm–Horsfall protein to form obstructive casts. These casts block tubular flow, trigger local inflammation, and damage the tubular epithelium. Beyond cast formation, free light chains may deposit within the renal interstitium, provoking inflammation, fibrosis, and even acute tubular necrosis. The cumulative effect of these lesions is a progressive fall in glomerular filtration rate (GFR) with impaired sodium and water handling. As GFR declines, the kidney progressively loses its ability to excrete electrolyte-free water, so that even modest fluid intakes cannot be fully eliminated. In parallel, activation of neurohormonal systems (renin–angiotensin–aldosterone system, sympathetic nervous system, and non-osmotic ADH release) promotes renal retention of sodium and water to defend effective arterial blood volume. However, the defect in free water clearance is relatively greater than the defect in sodium excretion, resulting in a disproportionate accumulation of water over sodium. The net effect is expansion of the extracellular fluid volume with edema and congestion, but a fall in serum sodium concentration due to dilution – the typical picture of hypervolemic hyponatremia in advanced MM-related kidney disease [20, 22, 34–36].

Table 1 outlines the pathogenetic mechanisms underlying true hyponatremia.

Volume status Main causes in MM Predominant mechanism
Hypovolemic Chemotherapy-related vomiting and diarrhea; infections; poor oral intake; Fanconi syndrome; loop or thiazide diuretics; other tubular salt-wasting lesions Loss of sodium and water with relatively greater sodium loss → reduced effective arterial blood volume, non-osmotic ADH release, impaired free water excretion
Euvolemic Paraneoplastic SIADH; bortezomib- or cyclophosphamide-induced SIADH; predominant SID/electroneutrality changes from highly cationic M protein Inappropriate ADH secretion or increased renal sensitivity to ADH; in selected cases dominant physicochemical (SID) effects → water retention without overt edema
Hypervolemic Advanced MM-related renal failure due to cast nephropathy, light chain interstitial deposition, and chronic tubulointerstitial damage Impaired free water clearance with retention of sodium and water, but proportionally greater water retention → edema and dilutional hyponatremia
Table 1. Pathogenesis of true Hyponatremia in MM.

 

Clinical Approach

Step 1 – History and Physical Examination

Document disease status, renal function history, fluid intake, medications, and gastrointestinal losses.

Assess neurological symptoms (confusion, seizures, coma) and volume status:

  • Hypovolemia: dry mucous membranes, orthostatic hypotension, tachycardia;
  • Hypervolemia: edema, ascites, jugular venous distension.

Step 2 – Laboratory Work-Up

Serum Sodium concentration

Serum osmolality (distinguish true vs pseudo)

Renal function (urea, creatinine)

Serum protein electrophoresis and M protein quantification

Free light chain assay

Thyroid and adrenal function (TSH, cortisol)

Urine

Urinary sodium:

  • <20 mmol/L → hypovolemia with sodium retention
  • >20 mmol/L → SIADH or renal salt wasting

Urine osmolality:

High in SIADH despite hyponatremia

Diagnostic Key Points

Always confirm hypo-osmolality to classify true hyponatremia.

In MM, pseudohyponatremia is more frequent, but true hyponatremia requires cause-specific intervention.

Avoid sodium correction in pseudohyponatremia – focus on treating the underlying myeloma and reducing paraproteinemia.

In true hyponatremia, tailored therapy to the mechanism: volume repletion for hypovolemia, fluid restriction for SIADH, careful diuretic management in hypervolemia, and drug review.

Figure 4 depicts the diagnostic algorithm for differentiating pseudohyponatremia from true hyponatremia in multiple myeloma.

Pseudohyponatremia vs true Hyponatremia.
Figure 4. Pseudohyponatremia vs true Hyponatremia.

 

Therapeutic Considerations

The treatment of hyponatremia in multiple myeloma (MM) hinges on two critical steps: accurate classification into pseudohyponatremia or true hyponatremia, and precise identification of the underlying mechanism in the latter.

Pseudohyponatremia

Because pseudohyponatremia represents a measurement artifact rather than a genuine disturbance in sodium-water balance, no specific sodium correction is warranted. In fact, attempts to raise serum sodium in this setting may be not only unnecessary but also potentially harmful, especially if hypertonic saline is used. The therapeutic focus must instead be directed at controlling the myeloma itself – through reduction of the M protein burden – thereby normalizing plasma water content and resolving the laboratory abnormality. Transitioning to direct ion-selective electrode measurement can prevent repeated misclassification.

True Hyponatremia

Management must be individualized, as multiple pathophysiological processes may coexist [37]. In addition to classifying true hyponatremia according to volume status (hypovolemic, euvolemic, or hypervolemic), treatment should be guided by an assessment of effective osmolality and osmotic load. Measurement of urine osmolality together with urinary sodium and potassium concentrations allows an approximate estimation of daily osmolar excretion and electrolyte-free water clearance. When urinary osmolality is high and osmolar excretion is low (e.g., in patients with poor oral solute intake), even relatively small amounts of hypotonic fluids may worsen hyponatremia. In this setting, the correction strategy must balance fluid restriction with an increase in osmotic load (oral sodium chloride or urea), as emphasized in onconephrology literature on hyponatremia and electrolyte disorders in cancer patients [38].

Hypovolemic hyponatremia (e.g., from gastrointestinal losses or renal salt-wasting due to Fanconi syndrome or diuretics) requires cautious volume repletion, ideally with isotonic saline, correcting sodium gradually to avoid osmotic demyelination [37]. In these patients, low urine sodium (<20 mmol/L) indicates appropriate renal sodium conservation, whereas higher values suggest ongoing renal losses (e.g., diuretics, tubular injury). Restoration of effective arterial blood volume downregulates non-osmotic ADH release, increases electrolyte-free water clearance, and allows serum sodium to normalize.

Hypervolemic hyponatremia from advanced MM-related renal failure benefits from sodium and fluid restriction, judicious diuretic use, and optimization of renal support; dialysis may be necessary in refractory cases [37]. In this context, total body sodium and water are both increased, but water retention is relatively greater because of impaired free water clearance and persistent ADH activity. Estimating osmolar excretion helps to define how stringent fluid restriction must be and whether additional osmotic load (e.g., hypertonic dialysis baths or carefully titrated loop diuretics combined with salt and albumin, when appropriate) is needed to enhance aquaresis without further worsening congestion.

In euvolemic, SIADH-related hyponatremia – whether paraneoplastic or drug-induced (e.g., bortezomib, cyclophosphamide) – the cornerstone of treatment is reduction of effective water intake relative to the patient’s osmolar output. Fluid restriction, increased solute intake (oral salt or urea), and in selected cases vasopressin receptor antagonists are used to raise sodium by enhancing electrolyte-free water excretion [37–39]. The required degree of fluid restriction can be estimated from urine osmolality: when urine is highly concentrated and osmolar excretion is low, very strict fluid restriction may be necessary unless osmotic load is increased. Discontinuation or dose adjustment of the offending drug should be considered whenever feasible, balancing oncologic efficacy with electrolyte stability [37–39].

Drug-induced natriuresis from thiazide or loop diuretics, when it presents as hypovolemic hyponatremia, warrants withdrawal or dose reduction, along with electrolyte repletion [37]. In contrast, in hypervolemic patients with advanced renal failure, loop diuretics may be used strategically to increase sodium and water excretion and thereby improve congestion and serum sodium, provided that blood pressure and renal perfusion are carefully monitored.

Electroneutrality-related sodium depression from highly cationic M protein is generally mild; here, management focuses on myeloma-directed therapy, as sodium levels typically normalize with paraprotein reduction [20]. In these patients, hyponatremia often coexists with other mechanisms (e.g., SIADH or renal failure), and the same principles of osmolality-based management and volume-status–oriented therapy apply.

Figure 5 outlines the treatment approach to hyponatremia in multiple myeloma.

Treatment of Hyponatremia in Multiple Myeloma
Figure 5. Treatment of Hyponatremia in Multiple Myeloma

 

Conclusions

Hyponatremia in MM is a multifaceted clinical problem that may arise from either laboratory artifact (pseudohyponatremia) or genuine disturbances in sodium and water homeostasis (true hyponatremia). Pseudohyponatremia – driven by marked hyperproteinemia from excessive monoclonal immunoglobulin production – is common, occurring in up to one fifth of patients, and requires recognition to avoid unnecessary and potentially harmful sodium correction. In contrast, true hyponatremia, although less frequent, carries important prognostic implications and is typically the result of overlapping mechanisms including renal impairment, hypovolemia, drug-induced effects, and, in rare cases, paraneoplastic SIADH. Additional contributions from physicochemical alterations, such as strong ion difference shifts due to cationic M protein, may further modulate sodium balance.

A structured diagnostic approach – integrating volume status assessment, serum and urine studies, and careful medication review – is essential to differentiate between pseudo and true hyponatremia and to guide targeted interventions. Ultimately, optimal management hinges on addressing the underlying myeloma, correcting reversible contributors, and individualizing fluid and electrolyte therapy to the patient’s pathophysiological profile.

 

KEY CLINICAL MESSAGES

  • Differentiate pseudo from true hyponatremia – confirm serum hypo-osmolality before initiating sodium correction; pseudohyponatremia is common in MM and should not be treated with sodium supplementation.
  • Recognize high prevalence – pseudohyponatremia occurs in up to 15–20% of MM patients, often in the setting of marked hyperproteinemia from monoclonal immunoglobulin excess.
  • Identify overlapping mechanisms in true hyponatremia – renal impairment, hypovolemia, drug effects (diuretics, bortezomib, cyclophosphamide), and paraneoplastic SIADH can coexist, amplifying severity.
  • Consider physicochemical factors – cationic M protein may alter the strong ion difference, subtly lowering sodium concentration and reducing the anion gap.
  • Tailor treatment to etiology – volume repletion for hypovolemia, fluid restriction for SIADH, cautious diuretic use in hypervolemia, and always address the underlying myeloma to reverse contributing factors.

 

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Danno renale acuto e biomarcatori diagnostici precoci: una revisione narrativa della letteratura

Pubblicato il Scarica PDF

Gerasopoulos Georgios

DOI: 10.69097/43-02-2026-07

Georgios Gerasopoulos1, Andreas Kapellakis-Malliaras2, Achilleia-Maria Pavlou3

1 First Department of Surgery, General Hospital Papageorgiou, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece
2 Department of Nephrology, General Hospital of Katerini, Katerini, Greece
3 Department of Rheumatology, University General Hospital of Ioannina, Ioannina, Greece

Corrispondenza a:
Gerasopoulos Georgios
First Department of Surgery, General Hospital Papageorgiou, Aristotle University of Thessaloniki
Ring road, N. Evkarpia
56403 Thessaloniki, Greece
Tel. 00306955672369
E-mail: ggerasop@gmail.com

 

Abstract

Introduzione. Il danno renale acuto (AKI) è una condizione grave caratterizzata da un’improvvisa compromissione della funzione renale nei pazienti ospedalizzati, in particolare in terapia intensiva, ed è associato a elevata morbilità e mortalità. Gli attuali metodi diagnostici, basati sulle variazioni della creatinina sierica (sCr) e della diuresi, sono influenzati da numerosi fattori confondenti. L’obiettivo di questo studio è indagare il ruolo di biomarcatori specifici, in particolare NGAL, Cistatina C, IL-18 e KIM-1, nella diagnosi di AKI.
Materiali e metodi. In questa revisione della letteratura è stata condotta una ricerca approfondita nelle banche dati PubMed, Scopus e Google Scholar per valutare il potenziale diagnostico precoce di NGAL, Cistatina C, IL-18 e KIM-1 nei pazienti con AKI.
Biomarcatori. La lipocalina associata alla gelatinasi dei neutrofili (NGAL), sia sierica che urinaria, ha mostrato un aumento poco dopo l’insorgenza dell’AKI, diverse ore prima dell’incremento della sCr, permettendo di distinguere l’AKI dalla malattia renale cronica e dall’azotemia prerenale. La Cistatina C (CysC), una proteina prodotta e filtrata costantemente, è stata identificata come un biomarcatore affidabile per l’AKI, sebbene il suo costo elevato ne limiti l’utilizzo. L’interleuchina-18 (IL-18), una citochina pro-infiammatoria, ha mostrato un potenziale diagnostico, in particolare nei pazienti critici e dopo chirurgia cardiovascolare, anche se i risultati sulla sua capacità predittiva sono risultati eterogenei. La Kidney Injury Molecule-1 (KIM-1), una proteina rilasciata nelle urine in seguito a danno tubulare prossimale, ha dimostrato elevata sensibilità e specificità nelle fasi precoci dell’AKI, ed è stata inoltre associata a diverse patologie renali.
Conclusioni. I nuovi biomarcatori (NGAL, CysC, IL-18 e KIM-1) consentono una diagnosi più precoce e accurata dell’AKI rispetto ai metodi tradizionali in diversi contesti clinici. Sono tuttavia necessari ulteriori studi per integrare pienamente queste promettenti molecole nella pratica clinica quotidiana.

Parole chiave: danno renale acuto, biomarcatore, NGAL, cistatina C, IL-18, KIM-1

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

Acute kidney injury (AKI) is a common syndrome affecting up to one third of hospitalized patients with high prevalence among the intensive care unit patients and the older individuals and a high mortality [1, 2]. The term AKI describes a sudden impairment of the renal function and is characterized by increased serum creatinine with or without decreased urine output developing over a period of up to a week [2–4].  Historically, this pathological condition was first mentioned in the early 19th century, while the term acute renal failure was introduced in 1951. For the past two decades, the term acute kidney injury has been used to characterize a wide range of kidney diseases [2].

The first classification system of AKI was the RIFLE system, where R=Risk, I=Injury, F=Failure, L=Loss, E=End-stage disease, using as criteria the respective increase in the levels of serum creatinine and the respective reduction of urine output with or without a decreased GFR (Glomerular Filtration Rate) [5, 6]. As new classifications, AKIN-Acute Kidney Injury Network and KDIGO-Kidney Disease Improving Global Outcomes were developed, GFR was no longer evaluated while the increase of the serum creatinine levels and the decrease of the urine output remained the main criteria for the diagnosis of the acute kidney injury [6–8].

Acute kidney disease is associated with a variety of complications including metabolic abnormalities, pulmonary edema, cardiovascular and long-term renal complications such as the development of chronic kidney disease, while the gastrointestinal, the immune and the nervous systems are also affected [9–12]. Age, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases are not only risk factors for the development of acute kidney injury but also affect the prognosis of these patients along with the duration and severity of the acute kidney disease among others [12].

 

Pathophysiology of AKI

AKI can result from multiple causes, which are classified according to their pathophysiological mechanism into pre-renal, intra-renal, and post-renal. Among pre-renal causes, the most common are those characterized by reduced renal blood flow or renal ischemia; in intra-renal causes, damage to the renal parenchyma is usually observed; post-renal causes are characterized by an obstruction of the urinary system [3, 9, 13–15] (Table 1).

Pre-renal

Decreased renal blood flow

– Sepsis, hypovolemia, shock

– Cardiorenal syndrome

– Hepatorenal syndrome

– Major surgical procedure

– Abdominal compartment syndrome

– Drugs including antihypertensives, contrast media and NSAIDs

– Hypercalcemia
Intra-renal

– Sepsis, systemic infections

– Vascular and blood diseases

– Autoimmune diseases

– Renal diseases including acute interstitial nephritis and rapidly progressive glomerulonephritis

– Rhabdomyolysis

– Tubular necrosis due to ischemia-prolonged low blood pressure

– Acute graft rejection

– Drugs including antibiotics, chemotherapy drugs, contrast media and heavy metals

– Cancer immunotherapy
Post-renal

– Benign prostatic hyperplasia

– Nephrolithiasis, blood clots

– Neoplasms of the genitourinary tract

– Fibrosis (radiation-induced, retroperitoneal)
Table 1. Common causes of AKI.

AKI due to surgery, heart diseases or administration of specific medications (Table 1) is more common in populations with a higher income compared to lower income populations, where kidney injury is mainly caused by dehydration, hypotension, infections including sepsis, venomous animal bites and in relatively rare cases as a complication of pregnancy [16].

In cases associated with acute sepsis, the acute kidney injury can be caused by inflammation, hemodynamic, and metabolic alterations [4, 17]. Of note, these factors, as well as mechanical and various other factors including specific medications and neurohormonal alterations, play a significant role in the development of acute kidney injury following a surgical procedure [8, 18, 19]. Neurohormonal alterations are a significant cause of AKI also in patients with hepatorenal syndrome as well as in patients with cardiorenal syndrome, while hemodynamic changes, inflammation and nephrotoxic drugs combined with chronic kidney disease are implicated as well [14].

Prolonged vasoconstriction and direct renal cellular damage due to iodinated contrast media can lead to acute kidney injury especially in patients suffering from diabetes mellitus and chronic kidney disease. These cases are characterized by a prolonged detection and action of the contrast media within the urinary system resulting in an impaired kidney function [20].

 

Diagnosis of AKI

As mentioned above, the current classifications are based on increased serum creatinine levels and/or a decreased urine output for the diagnosis of acute kidney injury. However, the serum creatinine levels can rise at a slow rate after AKI, and they are also affected by various factors such as diet, age, sex, medication, body muscle volume, hypervolemia, sepsis, rhabdomyolysis, chronic kidney disease, while various technical factors can affect the evaluation of the creatinine levels in the laboratory [6, 13]. Consequently, serum creatinine levels do not always represent accurately the GFR and cannot clarify the cause of the acute kidney injury, while some drugs can affect the prognostic potential of this marker [21].

Specific acute situations, such as surgery, severe pain or hemodynamic instability can result in a decreased urine output which is associated with a lower survival rate, while the duration of this decrease is essential for the prognosis of the patients suffering from acute kidney injury [6, 13, 18].

The management includes fluid administration, vasoactive drugs, withdrawal of the nephrotoxic substances, diuretics, management of the metabolic alterations, while in more severe cases renal replacement therapy may be required [9, 22].

The term biomarker is used to describe a measurable marker that characterizes a biological process as well as a pathological condition or response to treatment [23]. Various biomarkers both in serum and urine have been evaluated to contribute to an earlier diagnosis and as prognostic factors of acute kidney injury [24]. These biomarkers could indicate kidney damage, stress, or an impaired kidney function [22]. In the current literature, the most studied biomarkers for the early diagnosis of AKI are the Neutrophil Gelatinase-associated Lipocalin (NGAL), the Cystatin C, the Interleukin-18 (IL-18), and the Kidney Injury Molecule-1 (KIM-1). To summarize all available data regarding the utilization of the biomarkers mentioned above in early AKI diagnosis, as well as their efficacy compared to conventional biomarkers, we conducted a literature review of all available studies on these molecules. With this report, we aim to draw conclusions from the available literature regarding the use of these biomarkers in early AKI diagnosis.

 

Materials and methods

Study design

To address the research question, we designed and conducted this literature review to investigate any relationship of selected biomarkers to an early diagnosis of AKI onset. The research question was defined using the PICO (Population/Participants, Intervention/Investigation, Comparison/Comparator, Outcomes) framework:

  • Population: All patients diagnosed with Acute Kidney Injury
  • Investigation: Use of diagnostic biomarkers (NGAL, Cystatin C, IL-18, KIM-1)
  • Comparison: No comparator investigation
  • Outcomes: Early diagnosis of Acute Kidney Injury.

Eligibility criteria 

For this literature review, original research articles, reviews including meta-analyses, and clinical trials were included. Only articles in English language and with a full text available were selected.

Search strategy

A thorough search of the MEDLINE database via PubMed, Scopus and Google Scholar was conducted, from January 1990 to the last search date, September 16th, 2024, using the algorithms: ((acute kidney injury) OR (aki)) AND ((diagnostic biomarkers) OR (NGAL) OR (cystatin c) OR (IL-18) OR (KIM-1)). Two independent reviewers (GG, AK) performed the title and abstract screening and then assessed the studies for eligibility through full text evaluation of the articles according to the eligibility criteria mentioned above. Disagreements were addressed by a third independent author (AP).

 

Neutrophil gelatinase-associated lipocalin (NGAL)

Human NGAL, also known as lipocalin-2, is a protein with a specific weight of 25-kDa that is secreted mostly by immune cells such as neutrophils, but it can also be found in numerous human tissues, such as salivary glands, uterus, prostate, trachea, lungs, stomach, colon and kidneys [25, 26].

In the kidneys, NGAL is bound to neutrophil cell gelatinase and is released from the distal tube [27]. The molecule then is filtered through the glomerular membrane and is reabsorbed in the proximal tubule of the kidney while the NGAL quantities observed in urine are caused by proximal tubular damage or originates from their up-regulated synthesis in the distal part of the nephron, especially in the ascending limb and Henle’s loop, and in the collecting duct [28].

NGAL is known to be a siderophoric protein that plays a role in regulating iron activity [29]. NGAL quantities that are not bound to iron can interact with the cell surface receptors resulting in extracellular transfer of intracellular iron [30]. Studies have shown that NGAL interferes in binding iron together with a metabolic product called catechol and creates complexes [31] which enhance microbial growth [32] or mediate oxidative damage [33].

Also, NGAL plays a significant role as an acute phase protein and takes part in various antibacterial immune processes. Inflammatory cytokines induce NGAL expression in neutrophils, epithelial cells, or hepatocytes [34]. The injury of epithelial cells in the intestines [35], stomach, liver [36], or lungs during infections results in an increase in serum NGAL (sNGAL) concentration levels. Additionally, sNGAL levels are higher in patients with septic shock and sepsis-related organ failure compared to those with a milder course of sepsis as shown by a study [37]. Research has shown that NGAL is associated with epithelia and in particular its production increases greatly and sharply when epithelial tissues are damaged, a function investigated by many studies in correlation with early diagnosis of AKI. The previous study [38] also reported that while NGAL is expressed normally at very low concentrations in physiologic conditions, its levels increase sharply after tissue damage, thus categorizing the molecule as a defense protein of the host organism. In the same study, it is reported that NGAL rising above a certain level indicates kidney injury about 24-48 hours before serum creatinine (sCr) does [38]. Serum NGAL can be detected within two hours of AKI onset, with a concentration peak after 6 hours while sNGAL levels remained increased for approximately five days after AKI onset [39].

Another study [31] showed that in 30 patients out of 635 who developed AKI, NGAL in urine was elevated much earlier and in higher levels than sCr. In addition, urinary NGAL (uNGAL) appears as a suitable marker to distinguish AKI from chronic renal failure (CKD) and prerenal azotemia given its acute level increase in AKI compared to CKD and prerenal azotemia, in which no increase was observed [31]. An experimental study in animals suggested that sNGAL can predict early diagnosis of cisplatin-induced AKI accurately but is less useful in later stages compared to blood urea nitrogen (BUN) and sCr [40]. Moreover, another study [41] reported that in 45 patients who developed AKI (out of 77 in the study), uNGAL and urine cystatin C (uCysC) increased rapidly in several cases and remained elevated after the acute phase. The utility of sNGAL had also emerged, contributing positively in diagnosing 100% of patients who developed AKI later [41]. The above three indicators increased approximately 6-24 hours before sCr levels exceeded 0.3mg/dl, while uNGAL in some cases immediately increased significantly and within 24 hours of admission and predicted risk of death or the need for hemodialysis [41]. The NGAL seems to have many prospects to be established as an early biomarker of AKI, as it has been reviewed in various applications including a study in children treated with cardiopulmonary bypass (CPB) [42]. Out of the 196 patients who participated in the research and had gone through CPB, 99 later developed AKI. In this study, high levels of creatinine were reported only 2-3 days after CPB, while NGAL increased 15-fold 2 hours and 25-fold 4-6 hours after the surgical procedure [42].

NGAL has been found to be an independent predictor of CKD progression [43], also demonstrating promise as a marker determining the iron status in CKD instead of serum ferritin, including patients who require renal replacement therapy [44].

NGAL performed significantly in a study linking AKI and cardiac failure [45]. Specifically, in 203 patients, of whom 107 already had chronic renal insufficiency and 96 demonstrated normal renal function, 78 developed AKI. In those with AKI (the threshold for sNGAL was 134 ng/ml) sNGAL increased significantly, while on the same metrics cystatin C (CysC) did not perform adequately. Notably, the performance of natriuretic peptide type B (BNP) was remarkable in all cases of AKI. [45]. As a side note, the previous study indicated the potential usefulness of sNGAL in the early diagnosis of AKI in the setting of heart failure, and showed promise as a marker of renal function in the manifestation of cardiorenal syndrome, while CysC did not contribute to the diagnosis of AKI but showed a relevance with CKD and possibly laid the foundations as an indicator of CKD, as well as of decreased kidney function (impaired GFR) [45]. Promising results for NGAL’s efficiency for the diagnosis and management of AKI and hepatorenal syndrome have also been shown [46, 47].

In a 2023 study by Gupta et al. in trauma patients in ICU, the cut-off values of sNGAL and uNGAL were determined as 122-125 ng/mL and 16 ng/mL, respectively, with sNGAL demonstrating greater prognostic potential in this study [48]. Similarly, Saha et al. in a 2025 study on the diagnosis of AKI in the setting of acute liver failure (ALF), reported that the cut-off values for sNGAL were 129 ng/mL in AKI without ALF, while in patients with ALF and AKI, sNGAL showed a less significant increase [49]. It is also worth mentioning the prospective study by Katz-Greenberg et al. in 2022, where uNGAL was measured in patients with possible admission to the ICU and a diagnosis of AKI. uNGAL increased up to 24-fold depending on the stage of injury, according to the KDIGO staging, where in stage I a mean value of 1255 ng/ml was measured, while a significant increase was also measured in patients needing RRT [50].

Of note, it should be underlined that studies on NGAL in AKI populations are relatively limited in size and may be affected by a number of conditions, such as pre-existing kidney disease and systemic or urinary tract infections [51].

Of course, there are also elements which show that there is still a long way to go from NGAL’s establishment as an indicator for the diagnosis of AKI, such as trials where NGAL had mediocre statistical results and failed at a rate to contribute to diagnosis of AKI [24] or demonstrated limited usefulness, especially when systemic inflammation occurs concurrently with AKI [52].

 

Cystatin C

Cystatin C (CysC) is a 13-kDa cysteine proteinase inhibitor protein with an important role in the catabolism of intracellular peptides and proteins and is produced by all nucleated cells at a constant rate [53]. As blood is filtered by the kidneys, CysC is freely filtered by the glomerulus and like glucose and other substances, is almost completely reabsorbed and catabolized in the proximal tubule [54]. It is not affected by extrarenal factors such as gender, age, race or muscle mass and thus is considered as an independent marker of renal function, compared to sCr [55]. CysC is considered a reliable biomarker of AKI because it is filtered by 99%, is continuously produced and released into plasma and has been found to be more accurate than serum creatinine in many different patient populations [54]. A study showed that in patients with diagnosed AKI, the levels of cystatin C excreted in urine (uCysC) can be used to predispose the need for possible kidney transplantation [56], while another study by the same research team showed that with the fall of estimated GFR score due to AKI, CysC levels increased quite quickly and earlier than sCr. Specifically, in cases of R, I and F from the classic RIFLE ranking system for AKI, CysC increased to a certain level 1.5 days prior to sCr and thus was characterized as not only more sensitive, but also more specific than sCr [56, 57]. Other potential roles for cystatin C include being an earlier marker for acute kidney injury, a superior marker of kidney transplant function, CVD (cardiovascular disease) risk and transplant failure [58].

CysC has been associated with progression to end stage renal disease and mortality in patients with diabetes [59], acute kidney injury [60], CKD [61, 62], and end-stage CKD on dialysis [63]. CysC has been shown to portray an important role as a biomarker in CKD classification and overall risk and mortality, as shown by a meta-analysis, where a significant difference in GFR estimation using CysC compared with sCr was observed in pre-end-stage CKD [64]. This correlation between CysC and risk and mortality in CKD and end-stage CKD has been shown by many other studies, always compared with sCr [65]. CysC has been found to be more accurate than serum creatinine in many different patient populations [54]. It depicts earlier, more subtle changes in kidney function, while further research and development is needed to improve its cost-effectiveness [66]. This is its most significant limitation, as the cost of CysC, approximately 10-fold of sCr, is considered a significant prohibitive factor for routine use in clinical practice [65] while regarding other restrictions, it can be affected by thyroid disease, obesity, systemic inflammation and steroid use [67]. Lastly, while GFR estimation using CysC can still fall victim to its non-GFR determinants, such as thyroid function and steroid use, its independent association with CVD, end-stage CKD, and all-cause mortality warrants CysC the possibility of becoming a reliable biomarker for these clinical conditions [66].

 

Interleukin-18

Interleukin 18 (IL-18) is a cytokine promoting inflammation produced by a variety of cells including renal tubular cells [68, 69]. IL-18 has a possible role as a biomarker of AKI as inflammation resulting in parenchymal injury is heavily involved in the pathogenesis of AKI [70], whereas its release is also associated with pre-renal AKI causes such as ischemia, activated by the enzyme caspase-1 and released in urine [71]. IL-18 promotes inflammation and ultimately is a factor that can contribute towards renal fibrosis after AKI, as reported in a renal injury mouse model study in 2022, where possible deficiency of IL-18 in renal tubular cells in mice prevented alterations indicative of further progression of AKI into chronic kidney disease [71]. Also, this pro-inflammatory cytokine is associated with the development and progression of diabetic nephropathy through a wide range of mechanisms [72, 73].

IL-18 levels in urine rise after cardiovascular surgery [74–76] and in critically ill patients, such as septic patients, preceding the diagnosis of AKI [74, 75, 77, 78], while it is reported as both a reliable [69] and a poor [79] prognostic biomarker in these patients. Serum IL-18 levels in critically ill patients with AKI starting hemodialysis predicted the risk of death [80]. Promising results were also reported more in children and adolescents than adults with AKI in the above conditions (cardiovascular surgery, ICU patients), according to a meta-analysis [81]. Higher urinary IL-18 levels after heart surgery are associated with a longer duration of AKI [82], while serum IL-18 also increased within hours [83]. Urinary IL-18 levels were elevated earlier compared to serum creatinine in patients with AKI developing ARDS (acute respiratory distress syndrome) [74, 84, 85], as well as in patients receiving a kidney transplant, where high levels of urinary IL-18 were associated with delayed graft function [75, 84]. Urinary IL-18 in patients with cirrhosis could determine the cause of AKI, specifically for the diagnosis of acute tubular necrosis as well as predict mortality and progression of AKI [86]. The levels of urinary IL-18 were elevated within hours after liver transplantation combined with AKI as shown by a study [87], while another study showed that elevated plasma IL-18 levels post transplantation could also predict AKI [88].

Urinary IL-18 levels were elevated due to AKI in specific situations, such as cardiac catheterization [89], burn injuries [90] and urological interventions.

Serum IL-18 levels are higher in patients under hemodialysis compared to patients with AKI, while its levels rise with age [70]. Urinary IL-18 can also be elevated in autoimmune and inflammatory diseases [68, 84, 91], in various diseases of the urinary system and in diseases of the heart or the lungs [69].

Urinary IL-18 could not only detect AKI earlier compared to elevated serum creatinine levels, with better results in children than adults [68, 69], but also serve as a prognostic marker [92].

 

Kidney Injury Molecule-1 (KIM-1)

KIM-1 (Kidney Injury Molecule-1) or TIM-1 (T-cell immunoglobulin mucin receptor-1) or HAVCR 1 (Hepatitis A Virus Cellular Receptor 1) is a cellular membrane protein expressed in renal proximal tubular epithelial cells which under normal conditions is found at low levels in urine [93, 94]. Higher levels of this molecule are found after kidney injury as its extracellular portion is released into the urine [93, 94], with the contribution of MAPK (mitogen activated protein kinase) pathways [95]. KIM-1 function is associated with phagocytosis, tissue repair, fibrosis and inflammation, whereas increased levels of this biomarker are detected in the urine in a variety of renal diseases such as acute kidney injury, renal disease due to diabetes, chronic kidney disease, IgA nephropathy, lupus nephritis, polycystic renal disease, renal cell carcinoma as well as in patients with a transplanted kidney suffering from graft loss [93–97]. KIM-1 appears to promote repair of the kidney tubular epithelial cells through the ERK/MAPK signaling pathway [98].

KIM-1 is an FDA approved biomarker of drug induced renal injury, demonstrating encouraging outcomes regarding its use in incidents of cisplatin-induced acute kidney injury [94], as high levels of KIM-1 can be detected prior to creatinine increase [99].

In a meta-analysis by Shao et al in 2014, urinary KIM-1 had a sensitivity of 74% and specificity of 86% for the diagnosis of AKI, demonstrating better results in patients undergoing heart surgery, particularly when urine levels of KIM-1 were measured 2-12 hours post-operatively [100]. Additionally, promising results have been reported in infants and children in the same study compared to adults, while comorbidities and various technical issues regarding the detection methodology could alter the urinary KIM-1 levels [100]. Urinary KIM-1 levels also increased in cases of AKI post heart valve replacement surgery [101]. Furthermore, KIM-1 has been reported to be a promising biomarker of kidney injury associated with chronic heart failure or myocardial infarction [102].

Urinary KIM-1 can predict acute kidney injury 12 hours after coronary angiography, albeit with a lower specificity and sensitivity than NGAL [103].

In renal biopsies, KIM-1 staining was proved to be a valuable marker of acute tubular injury while the KIM-1/serum creatinine ratio appears to be a valuable marker of renal function recovery post injury, respectively [104].

Urinary KIM-1 is a potential early biomarker in instances of acute kidney injury diagnosis due to sepsis, while persistent high levels of this marker could be indicative of a poor prognosis [105].

Significantly increased levels of urinary KIM-1 in type 2 diabetic patients with diabetic nephropathy were associated with a poor prognosis regarding the progression of the renal disease [106]. Also, in patients with type 1 diabetes, increased levels of urinary KIM-1 can precede albuminuria [94]. In renal biopsy specimens of patients with diabetic nephropathy, KIM-1 expression in the renal tubules was found to correlate positively with the associated GFR decline, a correlation that was dependent on the urinary protein-to-creatinine ratio [107].

Urine levels of KIM-1 24 hours post transplantation were reported to be predictive of the recipients’ renal graft function [108], while an association between perfusate levels of this biomarker and delayed graft function, as well as an impaired eGFR three years after the transplantation, were also found [109]. KIM-1 staining in specimens received from transplanted kidneys was reported to be a specific and sensitive marker of proximal tubular injury that is negatively associated with the presence of functional epithelial cells of the proximal tubule and eGFR [110, 111] and positively correlated with the serum creatinine and blood urea nitrogen levels [112].

Serum KIM-1 levels correlated positively with the severity of histological features (acute tubular necrosis, interstitial fibrosis-tubular atrophy) and negatively with eGFR in patients suffering from ANCA-associated (antineutrophil cytoplasmic antibodies-associated) vasculitis with glomerulonephritis [113].

KIM-1 is a promising biomarker because it is normally detected in low levels in urine, but after kidney injury, its levels rise rapidly and have been associated with the degree of the injury. Furthermore, the extracellular domain (ectodomain) of KIM-1 that is released into the urine, is stable at room temperature [97]. On the other hand, there are limited data from clinical studies, KIM-1 is frequently measured in combination with other biomarkers to improve its diagnostic utility, its levels in urine may increase hours after the injury, the detection process of this biomarker is expensive, thus rendering it difficult to access, while comorbidities and technical issues regarding the detection methodology could also affect the urinary KIM-1 levels [100, 101, 114].

 

Future perspectives

Acute kidney injury affects 30-50% of critically ill patients and is associated with increased mortality, longer ICU stay and risk of progression to chronic kidney disease, mainly due to surgical procedures, nephrotoxic drugs, electrolyte imbalances or sepsis [115]. In those patients, a prospective biomarker must possess the ability to detect early and accurately the tubular injury before the decline in renal function becomes clinically apparent, to offer specificity and sensitivity to the various causes of AKI (prerenal, renal, postrenal), to stratify high-risk patients, and to assist in the identification of patients with possible progression to CKD and RRT. Among the biomarkers presented in this review, the most prevalent biomarker performing consistently in the ICU setting, either in sepsis-related [116], trauma-related [48] or post cardiac surgery AKI [117], is the Neutrophil Gelatinase-Associated Lipocalin or NGAL, as mentioned extensively in the corresponding section. Additionally, as already mentioned, sNGAL’s threshold values are reported to be in the range of 120-200 ng/ml, as reported by another study [118]. As for uNGAL, cut-off values are not sufficiently defined, however a recent 2025 study by Strander et al. in postoperative patients in the ICU after cardiac surgery reported the threshold value of uNGAL at 150 ng/mL, with satisfactory predictive performance [117].

It is necessary to emphasize again the usefulness of NGAL in predicting the progression of AKI to CKD with the need for RRT [50]. NGAL was found to detect patients with progressively deteriorating AKI, as observed in the ELAIN randomized clinical trial in 2016 [119], while in another study, the STARRT-AKI in 2022, sNGAL ≥ 400 ng/mL along with a two-fold increase in serum creatinine and oliguria was used as guiding criterion predicting the early start of RRT [120]. As already mentioned, NGAL can be affected by various factors, such as systemic or urinary tract inflammation, pre-existing kidney diseases, timing of sampling, and fluid imbalances.

Therefore, considering the multiple applications of NGAL in patients with mild disease, in the ICU, but also in predicting a possible need for RRT, we suggest NGAL as the most mature and clinically applicable biomarker for utilization in critical care of those presented in this study.

 

Conclusions

Acute kidney injury (AKI) is a common clinical syndrome, primarily diagnosed based on serum creatinine levels and urine output, markers that are affected by various factors such as diet, age, sex, medication and body muscle volume. Current evidence suggests that various novel biomarkers may provide a better alternative, allowing for an earlier and more precise detection of AKI. The most prevalent and clinically applicable biomarker, Neutrophil Gelatinase-Associated Lipocalin or NGAL, has been shown by a large number of studies to be a strong predictor of AKI, mainly in intensive care, showing efficacy in diagnosing AKI of various causes and in predicting the need for RRT. Kidney Injury Molecule-1 appears as a sensitive marker of proximal tubular injury, with significant shifts in concentration occurring hours to days prior to serum creatinine elevation. Cystatin C appears to be a precise marker of deteriorating renal function (eGFR), is produced and filtered at a constant rate, but its high cost prevents it from being utilized frequently in the clinical setting. Lastly, Interleukin-18, a cytokine promoting inflammation, is associated with pre-renal and intra-renal causes of AKI and has demonstrated better results in children rather than adults.

Incorporating these molecules into clinical practice, especially NGAL, offers the clinicians early detection tools, aiding in AKI diagnosis and management. To fully explore their potential in improving clinical results and possibly preventing the progression to chronic kidney disease, future research must focus most importantly on evaluating the accuracy and function of these biomarkers in AKI patients with various existing comorbidities, as well as establishing lab-standardized threshold values.

 

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Bidirectional Interaction Between the Gastrointestinal System and the Kidney: Pathophysiological and Clinical Perspective

Pubblicato il Scarica PDF

DOI: 10.69097/43-01-2026-09

Emre Leventoğlu1, Derya Cevizli1, Yavuz Emre Parlar2

1 Konya City Hospital, Department of Pediatric Nephrology, Konya, Turkey
2 Sincan Training and Research Hospital, Department of Gastroenterology, Ankara, Turkey

Corrispondenza a:
Emre Leventoğlu, MD
Address: Konya City Hospital, Department of Pediatric Nephrology, Konya, Turkey
Phone: +90 332 310 50 00, +90 506 608 66 86
E-mail: dremrelevent@gmail.com

 

Abstract

The gastrointestinal (GI) system and the kidneys, though anatomically separate, are functionally interconnected through shared responsibilities in maintaining fluid-electrolyte balance, acid-base homeostasis, immune regulation, and hormonal signaling. Disruptions in one system often lead to secondary complications in the other, highlighting the need for a comprehensive understanding of their bidirectional interactions. Kidney involvement in GI diseases commonly results from mechanisms such as fluid loss, malabsorption, systemic inflammation, and exposure to toxins, as seen in conditions like inflammatory bowel disease (IBD), celiac disease, liver failure, and enteric infections. Conversely, GI complications frequently arise in the context of chronic kidney disease (CKD), dialysis, and immunosuppressive therapies post-transplantation, manifesting as symptoms including uremic gastropathy, anorexia, and enteropathy. This review explores these interactions under two main categories: renal complications of GI diseases and GI manifestations of kidney disorders. It also discusses the underlying pathophysiological mechanisms and clinical implications, emphasizing the importance of an integrated, multidisciplinary approach. By highlighting current knowledge gaps, the review aims to foster future research in this complex and clinically significant area. Understanding these bidirectional interactions can inform individualized patient care and improve outcomes in both GI and renal disease contexts.

Keywords: Gastrointestinal system, Kidney diseases, Gut-kidney axis

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Overview of Gastrointestinal System and Kidney Interactions

The gastrointestinal (GI) system and kidneys are two distinct systems that play critical roles in maintaining intracorporeal homeostasis. Although there is no direct anatomical connection between these systems, there is a close cooperation through many physiological processes such as fluid-electrolyte balance, acid-base regulation, immune responses and hormonal signaling. Therefore, pathological conditions affecting one system can also influence the other [1]. This interaction is seen clinically in the form of kidney dysfunction that develops during GI diseases and GI complications that occur in kidney diseases [2].

Kidney involvement in GI diseases is often mediated by fluid and electrolyte loss, malabsorption, toxin exposure, or systemic inflammation. In particular, kidney function may be directly or indirectly affected in inflammatory bowel diseases (IBD), celiac disease, liver failure and enteric infections [3–6]. Similarly, the GI system can be significantly affected by kidney diseases. Complications such as uremic gastropathy, enteropathy and anorexia are common in patients with chronic kidney disease (CKD), and treatments such as hemodialysis and peritoneal dialysis may further exacerbate GI symptoms [7, 8]. In addition, post-transplant infections due to immunosuppression and drug side effects may also lead to GI complications [9, 10]. The main interactions between the GI system and the kidneys are shown in Figure 1.

In this review, kidney involvement in GI system diseases and GI complications arising in kidney diseases will be examined under two separate headings; the pathophysiological basis and clinical reflections of this interrelationship will be discussed (Table 1). The aim is to better understand these complex interactions in pediatric and adult patients and to draw attention to the importance of a multidisciplinary approach. It is also aimed to lay the groundwork for future research by revealing the knowledge gaps in these areas.

Bidirectional interactions between gastrointestinal system and the kidney.
Figure 1. Bidirectional interactions between gastrointestinal system and the kidney.
  Mechanisms of Kidney Involvement in GI Diseases
Upper GI System Disorders
GERD Use of PPI and associated ATIN
  Use of PPI and PPI-related nephropathy
H. pylori Infection Systemic inflammation induced by persistent infection
Immune complex-mediated kidney injury due to mucosal IgA secretion
  Metabolic disturbances such as insulin resistance and dyslipidemia due to H. pylori
Malabsorption Syndromes
Inflammatory Bowel Diseases Nephrolithiasis and nephrocalcinosis due to enteric hyperoxaluria
Glomerulonephritis due to antigen-specific immune responses
AKI and CKD due to systemic inflammation, medication toxicity, and malnutrition
Celiac Disease IgAN due to galactose-deficient IgA1
CKD due to increased intestinal permeability and immune activation
Diabetic nephropathy due to high prevalence of T1DM
Nephrolithiasis due to intestinal malabsorption or altered renal handling
UTI due to impaired urinary tract motility, dysfunction of the bladder, changes in gut microbiota
Liver Diseases
Primary Hyperoxaluria Nephrolithiasis/nephrocalcinosis and associated CKD due to hepatic enzyme deficiencies in glyoxylate metabolism
Wilson’s Disease Tubular dysfunctions due to copper deposition
Glomerular involvement due to immune complex-mediated mechanisms
Drug-induced nephrotoxicity caused by chelation therapy
Chronic Liver Disease Decreased kidney perfusion and reduced GFR due to splanchnic vasodilation, activation of RAAS system and sympathetic nervous system
Systemic inflammation due to impaired hepatic detoxification
Hepatorenal syndrome due to advanced liver disease
Enteric Infections
STEC-HUS Endothelial damage and subsequent thrombotic microangiopathy due to systemic dissemination of Shiga toxins
GI System Involvement in Kidney Diseases
Idiopathic Nephrotic Syndrome Edema of the bowel wall due to hypoalbuminemia
Mesenteric arterial thrombosis due to hypercoagulable state
Spontaneous bacterial peritonitis due to immunosuppression
Peptic ulcer disease and drug-related mucosal injury due to steroid therapy
Polycystic Kidney Disease Polycystic liver disease due to ADPKD
Congenital hepatic fibrosis due to ARPKD
Chronic Kidney Disease Uremic gastropathy or delayed gastric emptying due to uremia
GI bleeding due to mucosal fragility and platelet dysfunction
Abdominal discomfort or paralytic ileus due to bowel wall edema
Systemic inflammation due to translocation of endotoxins
Alterations in the gut microbiome (dysbiosis) due to uremia
Constipation due to restricted fluid intake, dietary limitations, and phosphate binders
Protein-energy wasting and deficiencies in essential nutrients due to decreased appetite
Kidney Replacement Therapies Hypotension-related gut hypoperfusion, mesenteric ischemia and colonic angiodysplasia-related bleeding due to hemodialysis
Increased intra-abdominal pressure, leading to early satiety, gastroesophageal reflux, abdominal fullness, or hernias due to peritoneal dialysis
Bacterial or sclerosing encapsulating peritonitis
Nausea, diarrhea, oral ulcers, and anorexia due to immunosuppressive therapy
Opportunistic infections due to immunosuppressive therapy
Table 1. Mechanisms of kidney involvement in GI system diseases and GI involvement arising in kidney diseases. GI: Gastrointestinal, GERD: Gastroesophageal reflux disease, PPI: Proton-pump inhibitor, ATIN: Acute tubulointerstitial nephritis, IgA: Immunoglobulin A, AKI: Acute kidney injury, CKD: Chronic kidney disease, IgAN: Immunoglobulin A nephropathy, T1DM: Type 1 diabetes mellitus, UTI: Urinary tract infection, GFR: Glomerular filtration rate, RAAS: Renin-angiotensin-aldosterone system, STEC-HUS: Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome, ADPKD: Autosomal dominant polycystic kidney disease, ARPKD: Autosomal recessive polycystic kidney disease.

 

Material and Methods

This article is a narrative review that examines the bidirectional interactions between the GI system and the kidneys, focusing on the underlying pathophysiological mechanisms and associated clinical outcomes, comprehensively reviewing of the current literature. Methodological rigor and principles of reproducibility were applied during both the literature selection and manuscript preparation processes. The literature search was conducted using the PubMed, Scopus, and Web of Science databases, covering publications from January 2000 to December 2024. Results were limited to studies published in English. The keywords and their combinations used were: “gastrointestinal system”, “kidney diseases”, “gut-kidney axis”, “renal replacement therapies”, and “microbiota”. The study included case reports and original research examining GI system findings or mechanisms in different stages of kidney disease, as well as review articles directly related to the topic. Publications and abstracts with limited relevance to the topic or that did not directly examine the kidney-GI relationship were excluded from the study.

In this narrative review, experimental studies such as animal models were used to understand potential biological pathways. While observational studies were evaluated to determine the relationships between the GI system and the kidneys in human populations, interventional studies provided the strongest evidence for potential effects. Unless supported by evidence from multiple study types, definitive causal statements were avoided, and neutral terms such as associated or linked were used.

 

Kidney Involvement in Gastrointestinal Diseases

Upper Gastrointestinal System Disorders

Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is a common chronic condition characterized by the retrograde flow of gastric contents into the esophagus, resulting in symptoms such as heartburn, regurgitation, and, in some cases, esophagitis. The pathophysiology of GERD involves a combination of factors including lower esophageal sphincter dysfunction, impaired gastric emptying, and increased intra-abdominal pressure. GERD affects a significant proportion of the global population and often requires long-term pharmacological management, particularly with proton pump inhibitors (PPIs), which are the mainstay of treatment. Although PPIs are effective in controlling acid-related symptoms and healing mucosal damage, their long-term use has raised concerns regarding potential adverse effects, including those on kidney functions [11].

One of the most recognized renal complications associated with PPIs is acute tubulointerstitial nephritis (ATIN). In a pediatric study, 11.1% of patients with ATIN had a history of PPI use [12]. This is an immune-mediated hypersensitivity reaction characterized by interstitial inflammation and tubular injury. Clinically, PPI-induced ATIN may present with non-specific symptoms such as fatigue, nausea, or subtle kidney dysfunction, often leading to underdiagnosis. Histological confirmation through kidney biopsy typically reveals interstitial edema, lymphocytic infiltration, and eosinophils [12].

Recent studies have identified an association between chronic PPI use and an increased risk of CKD and kidney failure in adults. Although a direct causal relationship is still under investigation, repeated or subclinical episodes of ATIN, as well as PPI-induced alterations in magnesium homeostasis and gut microbiota, have been proposed as contributing mechanisms [13]. The risk of PPI-related nephropathy appears to be more pronounced in elderly patients, individuals with pre-existing kidney impairment, and those using PPIs for prolonged periods without appropriate clinical indication. Importantly, PPI-related kidney injury may be partially reversible if recognized early and the offending agent is discontinued [14].

These findings underscore the need for cautious and evidence-based prescribing of PPIs, emphasizing regular reassessment of their indication and duration. In patients requiring long-term acid suppression, kidney function should be periodically monitored, and alternative therapies may be considered when appropriate.

Helicobacter pylori Infection

Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium that colonizes the gastric mucosa and is a well-established cause of chronic gastritis, peptic ulcer disease, and gastric malignancies. Beyond its GI manifestations, H. pylori infection has been increasingly studied for its potential systemic effects, including those on kidney function [15].

Several epidemiological and experimental studies have suggested a link between chronic H. pylori infection and kidney impairment, although the exact mechanisms remain incompletely understood, and pediatric data are limited. One proposed pathway involves systemic inflammation induced by persistent infection. H. pylori stimulates the release of pro-inflammatory cytokines such as interleukin-6, tumor necrosis factor-alpha, and C-reactive protein, which may contribute to endothelial dysfunction and glomerular injury, particularly in individuals with pre-existing susceptibility [16]. A second pathway is the activation of the immune complex-mediated mechanism due to mucosal immunoglobulin A (IgA) secreted against H. pylori. Chronic H. pylori infection has been associated with the development of immune-mediated renal diseases, including IgA nephropathy (IgAN). Molecular mimicry and immune cross-reactivity between bacterial antigens and kidney tissues may play a role in this association [17]. In addition, H. pylori may contribute to metabolic disturbances such as insulin resistance and dyslipidemia, which are recognized risk factors for CKD [18]. Although a direct causal relationship has not been definitively established, the cumulative evidence indicates that chronic infection could act as a modifiable risk factor in the progression of kidney dysfunction [18]. Moreover, in kidney transplant recipients, H. pylori infection is of particular clinical relevance due to the immunosuppressed state, which may alter the typical presentation and increase the risk of GI complications such as peptic ulcer disease and bleeding. Additionally, chronic H. pylori infection may contribute to systemic inflammation, potentially affecting graft function and long-term outcomes. Some studies in adults have suggested that pre-transplant screening and eradication of H. pylori may reduce the incidence of post-transplant GI morbidity and support better kidney graft survival [19]. In a study evaluating adult patients with membranous nephropathy and H. pylori infection, the mean proteinuria value before eradication therapy was 2.42 ± 3.24 g/day, while three months after eradication therapy, the proteinuria level decreased to 1.26 ± 1.73 g/day (p = 0.031) [20]. In another study, a high urine albumin-to-creatinine ratio was detected in adult patients with H. pylori-positive peptic ulcers, and a significant 51.5% decrease in the albumin-to-creatinine ratio was observed in these patients after eradication therapy [21]. These results suggest that eradication therapy is beneficial in alleviating kidney damage and reducing the risk of CKD.

Overall, while further research is needed to clarify the causal pathways, current data highlight a possible connection between H. pylori infection and renal involvement through systemic inflammation, immune dysregulation, and metabolic derangement. These findings raise important considerations regarding the evaluation and management of H. pylori in patients with or at risk of kidney disease.

Malabsorption Syndromes

Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBD), which include Crohn’s disease and ulcerative colitis, are chronic immune-mediated conditions of the GI tract. While ulcerative colitis is typically limited to the colon with continuous mucosal inflammation, Crohn’s disease may affect any segment of the GI tract and is characterized by transmural, patchy inflammation. IBD frequently begins in adolescence or early adulthood and follows a relapsing-remitting clinical course. Although primarily affecting the GI system, IBD is associated with numerous extraintestinal manifestations involving the skin, joints, eyes, liver, and kidneys. Several mechanisms contribute to kidney involvement in IBD, including metabolic disturbances related to malabsorption, drug-induced nephrotoxicity, immune-mediated glomerular disease, and structural complications such as nephrolithiasis and nephrocalcinosis [22].

Kidney involvement is increasingly recognized in children with IBD, yet remains underdiagnosed. One of the most clinically significant kidney complications is enteric hyperoxaluria, particularly in patients with Crohn’s disease involving the terminal ileum or those who have undergone ileal resection. Under normal physiological conditions, dietary calcium binds to oxalate in the intestinal lumen, forming insoluble complexes that are excreted in the feces. However, in IBD with fat malabsorption, unabsorbed fatty acids bind calcium, leaving oxalate unbound and more readily absorbed in the colon. This process is exacerbated by increased intestinal permeability and alterations in gut microbiota, particularly the depletion of Oxalobacter formigenes, a commensal bacterium that degrades oxalate. The result is enteric hyperoxaluria, which increases the risk of calcium oxalate nephrolithiasis and nephrocalcinosis. In chronic cases, nephrocalcinosis can lead to tubulointerstitial nephritis, interstitial fibrosis, and eventually CKD. Therefore, regular monitoring of kidney functions and urinary parameters is essential, especially in patients with extensive small bowel disease or surgical resections [23].

Emerging evidence suggests that glomerulonephritis (GN) in IBD may result either from antigen-specific immune responses originating in the inflamed gut or from shared genetic and environmental risk factors. GN appears both as an extraintestinal manifestation and as a potentially unrelated co-existing condition, with IgAN being the most frequently reported subtype. Although pediatric data are limited, the observed reduction in proteinuria with enteric budesonide therapy in adult patients with IgAN supports a pathogenic link between intestinal and kidney inflammation [24]. A study utilized bioinformatic and machine learning approaches to identify shared immune-infiltrating features, cross-talk genes, and pathways between IgAN and IBD using datasets from the Gene Expression Omnibus. Immune infiltration analyses revealed no major differences in immune cell profiles between the two diseases. Ten diagnostic cross-talk genes were identified, among which FDX1 and NFKB1 were notably elevated in the kidneys of IBD mouse models. Pathway analysis revealed 15 shared signaling pathways, highlighting lipid metabolism as a key contributor. These findings shed light on common immune mechanisms underlying IBD and IgAN, offering potential targets for further research [25].

The risk of acute kidney injury (AKI) and CKD is increased in IBD. The mechanisms underlying this association are not fully understood, but factors such as systemic inflammation, medication toxicity, and malnutrition may contribute. In an adult study assessing the prevalence of AKI and CKD in IBD, the results showed that individuals with IBD had a higher risk for both AKI (HR = 1.96) and CKD (HR = 1.57) compared to those without IBD, even after adjusting for demographic, lifestyle and health factors. Similar risks were found for Crohn’s disease and ulcerative colitis. Younger participants had stronger associations between IBD and kidney outcomes [26]. However, in another study, analyses based on genome-wide association data from individuals of European descent revealed that genetic predisposition to Crohn’s disease was significantly associated with an increased risk of CKD, while no such causal association was observed for ulcerative colitis. Furthermore, inverse Mendelian randomization analysis showed that genetic predisposition to CKD did not increase the risk of developing IBD, Crohn’s disease or ulcerative colitis. These findings suggest that Crohn’s disease has a unidirectional causal effect on CKD and underscore the need for routine renal function monitoring in patients with Crohn’s disease [27]. In a cross-sectional study of pediatric patients, one-quarter of 56 IBD patients had evidence of kidney disease, either previously diagnosed or detected by ultrasonography. Kidney length was significantly reduced compared to healthy peers. Use of infliximab was associated with smaller kidneys, while enteral nutrition correlated with preserved kidney size. These findings suggest that children with IBD are at risk for CKD, especially in severe cases, highlighting the need for early renal monitoring in this population [28].

Celiac Disease

Celiac disease is a chronic, immune-mediated enteropathy triggered by the ingestion of gluten – a protein found in wheat, barley, and rye – in genetically susceptible individuals. The pathophysiology involves an inappropriate immune response primarily in individuals carrying HLA-DQ2 or HLA-DQ8 alleles. Upon gluten exposure, tissue transglutaminase (tTG) modifies gluten peptides, increasing their affinity for HLA-DQ2/DQ8 molecules on antigen-presenting cells. This leads to the activation of gluten-specific CD4+ T cells in the lamina propria, resulting in the production of pro-inflammatory cytokines and tissue-damaging immune responses. Concurrently, anti-tTG autoantibodies are produced, which serve as both diagnostic markers and contributors to mucosal injury. The intestinal mucosa displays characteristic histological changes, including villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes, ultimately leading to malabsorption [29]. Celiac disease can present with both GI symptoms and a wide range of extraintestinal manifestations, including anemia, growth failure, osteoporosis, and even neurologic or renal involvement.

To investigate the association between celiac disease and kidney disease, genome-wide association from non-overlapping European cohorts was used and a Mendelian randomization study examining ten kidney traits was conducted. The analysis showed that genetic liability to celiac disease was causally associated with an increased risk of IgAN, chronic GN and a modest decrease in estimated glomerular filtration rate [30]. Although pediatric data are limited, findings from a meta-analysis have also shown that adult population with celiac disease have a significantly increased risk of developing kidney diseases, including IgAN and CKD. These findings highlight the need for greater clinical awareness and routine renal monitoring in patients with celiac disease to support early detection and prevention of kidney-related complications [4].

The IgAN is the most common primary GN worldwide, characterized by the deposition of IgA – particularly galactose-deficient IgA1 (Gd-IgA1) – in the glomerular mesangium. This triggers mesangial proliferation, inflammation, and eventually leads to varying degrees of proteinuria, hematuria, and progressive kidney dysfunction. Although the precise pathogenesis remains incompletely understood, IgAN is believed to result from a multi-hit process involving abnormal IgA1 glycosylation, the formation of autoantibodies against Gd-IgA1, and immune complex deposition in the kidney [31]. A potential link between IgAN and celiac disease has been increasingly recognized, given their shared immunological features and genetic predispositions – particularly involving HLA-DQ2/DQ8 alleles. In celiac disease, chronic mucosal inflammation and increased intestinal permeability may facilitate enhanced systemic exposure to dietary antigens and microbial components, leading to overproduction of aberrantly glycosylated IgA1. Moreover, mucosal immune activation in the gut-associated lymphoid tissue may promote the generation of nephritogenic IgA immune complexes that subsequently deposit in the glomeruli. Some studies have also suggested that a gluten-free diet may reduce proteinuria in patients with both IgAN and celiac disease, supporting the idea of gut-kidney axis involvement [4]. In a case series, kidney biopsies from nine IgAN patients, four of whom had celiac disease, were analyzed for the presence of IgA-tTG co-deposits. Circulating tTG antibodies were measured and frozen tissue sections were examined for colocalization of IgA and tTG. Among the celiac patients, three showed IgA-tTG deposits in the kidney, including two people who had not yet been diagnosed with celiac disease at the time of biopsy. Interestingly, no such deposits were observed in the patient on a gluten-free diet with known celiac disease [32].

In celiac disease, CKD may not only arise as a consequence of IgAN, but also through gut-kidney axis dysregulation, where increased intestinal permeability and immune activation contribute to systemic inflammation and kidney injury. Compromise of the intestinal barrier integrity may allow bacterial lipopolysaccharides to translocate into the systemic circulation. This translocation promotes systemic inflammation and uremic toxicity, both of which are recognized drivers in the onset and progression of CKD [7].

Diabetic kidney disease is increasingly observed in children as the prevalence of type 1 diabetes mellitus (T1DM) rises. Celiac disease, which shares genetic susceptibility with T1DM – especially via HLA-DR3-DQ2 and DR4-DQ8 – coexists in 3-12% of pediatric cases [7]. Celiac disease may also be an independent risk factor for both microvascular and macrovascular complications, potentially through mechanisms like intestinal malabsorption, micronutrient deficiencies such as folate, B vitamins, and hyperhomocysteinemia [33]. These findings support routine screening for celiac disease in T1DM patients and highlight the need for further research into the gut-kidney and gut-vascular axes in this context.

The association between celiac disease and urolithiasis was first reported in the 1970s, with studies identifying hyperoxaluria in over half of affected children [34]. More recent data confirm an elevated risk of recurrent kidney stones – particularly oxalate stones – in individuals with celiac disease. Stone formation requires urinary supersaturation with certain solutes, but in celiac disease, this may be exacerbated by intestinal malabsorption or altered renal handling of compounds like oxalate, calcium, and citrate. These imbalances promote crystallization and stone development [35]. Additionally, gut microbiota dysbiosis plays a role; reduced levels of butyrate-producing bacteria like Roseburia lead to increased intestinal oxalate absorption and inflammation, further promoting lithogenesis [36]. This complex interplay between gut permeability, immune activity, and microbial metabolism may explain the higher prevalence of kidney stones in celiac disease.

Individuals with celiac disease have a higher frequency of urinary tract infections (UTIs). This is due to a variety of factors, including impaired urinary tract motility, dysfunction of the bladder, changes in gut microbiota that can promote urinary contamination, reduced immune defense mechanisms, and dysregulated immune responses. In a study evaluating the association between celiac disease and UTIs in the absence of anatomical abnormalities, 22.7% of 97 patients with celiac disease reported at least one episode of UTI, with a female predominance. In the majority of cases, the UTI occurred before the diagnosis of celiac disease. Notably, the cumulative probability of being UTI-free by the age of 18 years was significantly lower in women with celiac disease compared to the general population [37]. These findings point to a possible increased risk of UTIs in female celiac disease patients and potentially warrant closer clinical attention.

Liver Diseases

Primary Hyperoxaluria

Primary hyperoxaluria (PH) is a group of rare, autosomal recessive metabolic disorders characterized by hepatic enzyme deficiencies involved in glyoxylate metabolism. These defects lead to the overproduction of oxalate in the liver, which subsequently binds with calcium to form calcium oxalate crystals. While oxalate is normally a minor end-product excreted by the kidneys, in PH, its excessive hepatic production surpasses kidney excretion capacity, resulting in crystal deposition in any organ. PH is classified into three types based on the specific hepatic enzyme affected. PH type 1 (PH1), the most severe and common form, results from mutations in the AGXT gene encoding the liver-specific enzyme alanine: glyoxylate aminotransferase. PH type 2 (PH2) is due to defects in GRHPR, and PH type 3 (PH3) involves mutations in HOGA1; both are also expressed in the liver but tend to present with milder clinical manifestations [38].

In PH, calcium oxalate crystals deposit primarily in the kidney tubules and interstitium, resulting in nephrocalcinosis and nephrolithiasis. The mechanical damage caused by the crystals, combined with inflammation and fibrosis, contributes to the development of tubulointerstitial nephritis. Progressive accumulation and stone formation ultimately lead to a decline in glomerular filtration rate and CKD. In many patients with PH1, this progression leads to kidney failure at an early age [38]. To date, distinct clinical forms of PH1 have been identified. Infantile oxalosis typically manifests within the first six months of life, presenting with nephrocalcinosis and early-onset kidney failure. In contrast, childhood-onset cases more commonly begin with symptoms related to kidney stone formation, such as renal colic, hematuria, or urinary tract infections. Additional presentations include disease recurrence following kidney transplantation and, in rare instances, recurrent kidney stones appearing later in adulthood [39]. A nationwide study evaluating the overall clinical characteristics of patients with PH1 found that 92.4% of patients had nephrolithiasis/nephrocalcinosis even at the time of diagnosis. Although individuals with infantile oxalosis were diagnosed at a younger age compared to individuals with childhood-onset PH1, they exhibited more advanced CKD or kidney failure requiring dialysis at the time of diagnosis [40]. Therefore, given the risk of early and progressive kidney involvement in PH, even in asymptomatic stages, timely evaluation of kidney function is essential; close collaboration between nephrology and gastroenterology is crucial to ensure comprehensive and coordinated patient care.

Wilson’s Disease

Wilson’s disease is a rare autosomal recessive disorder caused by mutations in the ATP7B gene, which encodes a copper-transporting ATPase responsible for incorporating copper into ceruloplasmin and excreting excess copper into the bile. Defective ATP7B leads to the accumulation of free copper in various tissues, most notably the liver, central nervous system, and cornea. Clinical manifestations are highly variable and age-dependent, ranging from hepatic dysfunction in children and adolescents to neurological and psychiatric symptoms in older individuals [41].

Although kidney involvement is less commonly recognized, it is a relevant extrahepatic manifestation of Wilson’s disease, particularly in untreated or advanced cases. Copper deposition in the kidneys may lead to tubular dysfunction, which can be present as aminoaciduria, low-molecular-weight proteinuria, hypercalciuria, or renal tubular acidosis, particularly the distal type. In some patients, nephrolithiasis and hypophosphatemia have also been reported [42]. Moreover, glomerular involvement, although rare, may manifest as proteinuria or even nephrotic syndrome, and IgAN potentially due to immune complex-mediated mechanisms [43]. Chelation therapy with agents such as D-penicillamine may also influence kidney function, either by improving copper overload or, conversely, causing drug-induced nephrotoxicity in some cases [44]. Thus, regular monitoring of kidney parameters should be performed in the management of Wilson’s disease, especially in patients receiving long-term chelation therapy.

Chronic Liver Diseases

Chronic liver disease encompasses a wide range of progressive liver disorders that lead to sustained liver inflammation, fibrosis, and ultimately cirrhosis. It can result from various etiologies including viral hepatitis (especially hepatitis B and C), autoimmune hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), metabolic and genetic disorders (such as Wilson’s disease or alpha-1 antitrypsin deficiency), and biliary tract diseases like primary sclerosing cholangitis. Over time, continuous liver damage impairs hepatic synthetic, metabolic, and detoxifying functions, potentially leading to complications such as portal hypertension, hepatic encephalopathy, ascites, coagulopathy, and increased susceptibility to infections [7].

Chronic liver disease and kidney involvement are closely interconnected through complex systemic and local mechanisms. As chronic liver disease progresses, portal hypertension develops, leading to splanchnic vasodilation. This vasodilation reduces the effective circulating blood volume, resulting in decreased kidney perfusion. In response, the body activates compensatory systems such as the renin-angiotensin-aldosterone system, the sympathetic nervous system, and antidiuretic hormone, which together cause renal vasoconstriction and subsequently a significant drop in glomerular filtration rate [5]. Furthermore, impaired hepatic detoxification allows bacterial endotoxins and inflammatory cytokines to enter the circulation, enhancing systemic inflammation and exacerbating kidney dysfunction. Additional contributing factors include acidosis, hyponatremia, hypoalbuminemia, and sepsis, all of which can further impair kidney function [45].

Hepatorenal syndrome (HRS) is a form of functional kidney failure that occurs in individuals with advanced liver disease, most commonly cirrhosis, in the absence of other identifiable structural kidney abnormalities. Based on the duration and progression of kidney dysfunction, HRS is currently classified into two main types: HRS-AKI and HRS-CKD [46].

HRS-AKI is characterized by:

  • A rapid decline in kidney function, typically identified by an acute rise in serum creatinine (≥0.3 mg/dL within 48 hours or ≥50% from baseline within seven days) in patients with cirrhosis and ascites.
  • It usually occurs following precipitating events such as infections, GI bleeding, or excessive diuretic use.

HRS-CKD refers to:

  • A gradual and sustained impairment in kidney function lasting three months or longer,
  • Long-standing portal hypertension and diuretic-resistant ascites.

Management of HRS includes prompt identification and treatment of precipitating factors such as infections, GI bleeding, or excessive diuretic use, administration of albumin together with vasoconstrictors such as terlipressin, and early evaluation for liver transplantation when indicated [46]. Given the intricate interplay between the liver and kidneys, early recognition and collaborative management of renal dysfunction in patients with chronic liver disease is essential to improve outcomes and guide appropriate therapeutic strategies.

Enteric Infections

Shiga toxin-producing Escherichia coli

Shiga toxin-producing Escherichia coli (STEC) infection is primarily a GI illness characterized by abdominal cramping, watery diarrhea that often progresses to bloody diarrhea (hemorrhagic colitis), and, in some cases, fever and vomiting. The GI manifestations are largely attributed to the direct mucosal damage caused by Shiga toxins, which are released by the bacteria in the colon. These toxins disrupt the intestinal epithelial barrier, leading to inflammation, epithelial cell apoptosis, and capillary hemorrhage. Colonoscopy or histological examination in severe cases may reveal mucosal edema, ulcerations, and hemorrhagic lesions predominantly in the distal colon. Importantly, while the GI symptoms are self-limiting in most patients, a subset – particularly young children and the elderly – are at risk for extraintestinal complications such as STEC-hemolytic uremic syndrome (HUS) (STEC-HUS) [47].

The pathogenic mechanism of kidney involvement in STEC-HUS is primarily driven by the systemic dissemination of Shiga toxins, particularly Stx2, following disruption of the intestinal epithelial barrier. Once in circulation, Shiga toxins exhibit high affinity for globotriaosylceramide (Gb3) receptors, which are abundantly expressed on endothelial cells within the kidney glomeruli. Upon binding to Gb3, the toxins are internalized and inhibit protein synthesis by inactivating the 60S ribosomal subunit, leading to endothelial cell apoptosis and dysfunction. This endothelial injury initiates a prothrombotic state characterized by platelet activation, increased release of von Willebrand factor, and reduced production of antithrombotic mediators such as prostacyclin and nitric oxide. The result is widespread microvascular thrombosis, particularly in glomerular capillaries, which manifests clinically as thrombotic microangiopathy. The ensuing microthrombi cause mechanical damage to erythrocytes, leading to microangiopathic hemolytic anemia, while the consumption of platelets contributes to thrombocytopenia. Concurrently, the glomerular filtration barrier becomes compromised, resulting in AKI, typically presenting with oliguria or anuria, elevated serum creatinine, and signs of fluid and electrolyte imbalance. Proteinuria and hematuria are frequently observed in urinalysis [47]. There is no specific therapy for STEC-HUS, and treatment is primarily supportive, focusing on fluid and electrolyte management, blood pressure control, and, in severe cases, renal replacement therapy. While most pediatric patients recover fully with appropriate supportive care, a subset may develop long-term complications such as CKD, hypertension, or proteinuria [48].

As can be seen, the kidney pathology in STEC-HUS illustrates the critical role of the gut-kidney axis, wherein enteric infections can precipitate severe extraintestinal consequences. STEC-HUS remains one of the leading causes of AKI in children and poses significant clinical challenges due to its rapid onset and potential for long-term renal sequelae.

 

Gastrointestinal System Involvement in Kidney Diseases

Idiopathic Nephrotic Syndrome

Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children and also affects adults, though with differing histopathological profiles. It is defined by the classic triad of massive proteinuria (>3.5 g/day), hypoalbuminemia, and generalized edema. In pediatric populations, minimal change disease is the most frequent histological subtype, while in adults, focal segmental glomerulosclerosis and membranous nephropathy are more common. Although the precise pathogenesis of INS remains incompletely understood, immune dysregulation – particularly involving T and B-cell dysfunction and circulating permeability factors – has been implicated in podocyte injury and proteinuria [49]. While the kidney manifestations are central to the diagnosis, INS is increasingly recognized as a multisystem disorder, including those affecting the GI system. GI involvement is often secondary to the systemic consequences of hypoalbuminemia, edema, thrombotic tendency, and immunosuppressive therapy [50].

One of the most common GI manifestations in INS is edema of the bowel wall, which may lead to abdominal discomfort, nausea, vomiting, and even paralytic ileus. In severe cases, bowel wall thickening can mimic conditions such as IBD or ischemia on imaging studies [51]. Additionally, the hypercoagulable state associated with INS increases the risk of mesenteric arterial thrombosis, a rare but life-threatening complication that can present with acute abdominal pain [52]. Moreover, patients with INS are at increased risk for infections, including spontaneous bacterial peritonitis, especially in those with ascites. The use of corticosteroids and other immunosuppressants further compromises GI immunity and mucosal defense, predisposing to opportunistic infections, peptic ulcer disease, and drug-related mucosal injury [53]. Malabsorption of fat-soluble vitamins (particularly vitamin D) may also occur due to protein loss and intestinal edema, contributing to metabolic bone disease in the long term [54]. Therefore, GI assessment and monitoring are essential components of comprehensive care in patients with INS, particularly in those with persistent hypoalbuminemia or GI symptoms.

Polycystic Kidney Diseases

Polycystic kidney disease (PKD) comprises a group of inherited disorders characterized by the progressive development of fluid-filled cysts in the kidneys, ultimately leading to kidney failure. The two main genetic forms are autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD), each with distinct clinical and genetic profiles. ADPKD is the most common hereditary kidney disorder, typically caused by mutations in the PKD1 or PKD2 genes. It usually manifests in adulthood with bilateral kidney enlargement, hypertension, and gradual loss of kidney function. ARPKD, in contrast, is a rarer and more severe form, caused by mutations in the PKHD1 gene and often present in infancy or early childhood with enlarged echogenic kidneys. While kidney manifestations are the hallmark of both forms, GI involvement is an important aspect of the disease, particularly in relation to hepatic and biliary complications [55].

In ADPKD, one of the most frequent extrarenal manifestations is polycystic liver disease (PLD), which occurs in up to 80% of patients over the age of 30 [56]. Although often asymptomatic, extensive liver cysts may cause abdominal distension, early satiety, gastroesophageal reflux, and even mechanical bowel compression. Cyst infection or hemorrhage can also cause acute abdominal pain and mimic intra-abdominal sepsis [57]. In ARPKD, the most prominent GI-related manifestation is due to congenital hepatic fibrosis, which can lead to portal hypertension. This may result in splenomegaly, esophageal varices, hematemesis, and ascites, posing serious risks, especially in pediatric patients. The combination of hepatobiliary and kidney dysfunction in ARPKD is sometimes referred to as a hepatorenal fibrocystic disease [58]. In both forms of PKD, GI symptoms may also arise from complications of CKD, such as uremic gastropathy, anorexia, and nausea, or from treatment-related factors, including immunosuppressive therapy following transplantation [57]. Thus, careful GI assessment is essential in the multidisciplinary management of PKD patients, particularly those with advanced disease or hepatic involvement.

Chronic Kidney Diseases

Chronic kidney disease is a progressive condition characterized by a sustained reduction in glomerular filtration rate and the accumulation of uremic toxins. While the kidney and cardiovascular consequences of CKD are well known, GI involvement is also frequent and significantly affects morbidity, nutritional status, and quality of life. Many of the GI manifestations in CKD stem from uremia-related metabolic disturbances, chronic inflammation, altered intestinal permeability, and the effects of therapeutic interventions [59].

Common uremic symptoms such as anorexia, nausea, vomiting, metallic taste, and weight loss are frequently reported and may reflect uremic gastropathy or delayed gastric emptying. In advanced stages, mucosal fragility and platelet dysfunction can predispose patients to GI bleeding, while bowel wall edema may cause abdominal discomfort or paralytic ileus [2]. Uremia also contributes to impaired gut barrier function, leading to increased intestinal permeability – often referred to as “leaky gut” – which facilitates the translocation of endotoxins and contributes to systemic inflammation through the gut-kidney axis [7].

Oral and esophageal manifestations, including dry mouth, oral ulcers, gingivitis, and uremic fetor, are commonly observed [60]. In parallel, CKD is associated with significant alterations in the gut microbiome (dysbiosis), including the proliferation of urease-producing and proteolytic bacteria. This dysbiosis increases the generation of gut-derived uremic toxins such as indoxyl sulfate and p-cresyl sulfate, which have been implicated in endothelial dysfunction, cardiovascular disease, and further progression of kidney injury [61].

Gastrointestinal motility disturbances are also common; constipation often results from fluid restriction, a low-fiber diet, oral iron supplementation, or use of phosphate binders. Conversely, diarrhea may occur due to certain medications such as magnesium-based antacids, antibiotics or infectious etiologies, especially in immunosuppressed patients [62]. Nutritional impairment is another major consequence of GI involvement in CKD. Reduced oral intake due to GI symptoms, combined with malabsorption and inflammation, can lead to protein-energy wasting and deficiencies in essential nutrients, including fat-soluble vitamins, vitamin B12, and folate. This contributes to muscle wasting, frailty, and increased vulnerability in elderly CKD patients [63].

In summary, the GI system plays a central and multifaceted role in the clinical course of CKD. A comprehensive understanding and management of GI involvement is essential to improve outcomes, reduce complications, and enhance the overall well-being of CKD patients.

Kidney Replacement Therapies

Kidney replacement therapies (KRT), including hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation, are life-sustaining treatments for patients with kidney failure. Each modality has distinct physiological impacts and potential GI complications, which should be considered in patient management and nutritional planning. GI symptoms may arise due to the dialysis process itself, associated fluid shifts, metabolic changes, or immunosuppressive therapy [8].

Hemodialysis is the most commonly used modality for KRT. GI complications during or after dialysis sessions are frequent and may include nausea, vomiting, abdominal cramps, and hypotension-related gut hypoperfusion. HD is also associated with increased gut permeability, which can facilitate endotoxemia and systemic inflammation [64]. Constipation is common due to restricted fluid intake, dietary limitations, and phosphate binders [65]. Rare but serious GI complications include mesenteric ischemia and colonic angiodysplasia-related bleeding, particularly in long-term HD patients [66].

Peritoneal dialysis involves the instillation of dialysate into the peritoneal cavity, and its GI manifestations are often related to increased intra-abdominal pressure, leading to early satiety, gastroesophageal reflux, abdominal fullness, or hernias [67]. Peritonitis is a significant complication and may present with abdominal pain, fever, and diarrhea or paralytic ileus [68]. Chronic exposure of the peritoneum to dialysate can lead to sclerosing encapsulating peritonitis, a rare but severe condition causing intestinal obstruction [69]. Additionally, glucose absorption from dialysate may exacerbate dyslipidemia, insulin resistance, and obesity, contributing indirectly to metabolic complications that affect gut function [70].

While kidney transplantation restores kidney function and offers superior quality of life, it introduces unique GI risks, primarily due to immunosuppressive therapy. Common GI side effects of calcineurin inhibitors and mTOR inhibitors include nausea, diarrhea, oral ulcers, and anorexia [71]. Mycophenolate mofetil is particularly associated with diarrhea, colitis, and GI bleeding, sometimes mimicking IBD [72]. Strategies to mitigate drug-related GI adverse effects include dose splitting, using enteric-coated formulations, or switching to an alternative immunosuppressive class when feasible [72–74]. Opportunistic infections, such as cytomegalovirus colitis or Clostridioides difficile infections, are more frequent in the post-transplant setting. They should be considered in patients with new or worsening GI symptoms; cytomegalovirus infection can be initially screened with polymerase chain reaction (PCR) or antigen testing, while Clostridioides difficile should be evaluated with stool toxin assays or PCR [75, 76]. Moreover, long-term immunosuppression also increases the risk of GI malignancies, including colorectal and gastric cancers [77].

 

Conclusion

The complex and dynamic interplay between the GI system and the kidneys reflects a bidirectional relationship in which dysfunction in one organ system can significantly impact the other. GI symptoms are common across all stages of kidney disease and may arise from uremia, dialysis modalities, immunosuppressive therapies, or alterations in gut microbiota. Conversely, GI disorders such as infections, inflammatory conditions, and medication-induced mucosal injury can contribute to kidney injury through immune activation, systemic inflammation, or volume and electrolyte disturbances. Recognizing these interactions is crucial for early diagnosis, targeted management, and prevention of complications. A multidisciplinary approach that incorporates nephrologic and gastroenterologic expertise will be essential to optimize outcomes in patients affected by these intertwined organ systems.

 

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Il ruolo del Tocilizumab nel trapianto renale: revisione narrativa sulla desensibilizzazione e sul trattamento del rigetto anticorpo-mediato

Pubblicato il Scarica PDF

Sonila Mocka

DOI: 10.69097/43-01-2026-08

Sonila Mocka1,2, Stefano Ferraro2, Michele Marchini1, Michela Ardini1, Matteo Trezzi1, Lucio Manenti1

1 U.O.C. Nefrologia e Dialisi, Ospedale Sant’Andrea Via Vittorio Veneto 197, 19121, La Spezia, Italy
2 U.O.C. Nefrologia e Dialisi, Ospedale San Paolo Via Genova 30, 17100, Savona, Italy

Corrispondenza a:
Sonila Mocka
U.O.C. Nefrologia e Dialisi, Ospedale San Paolo
Via Genova 30, 17100, Savona, Italy
Tel. 019 840 4241
E-mail: s.mocka@asl2.liguria.it

 

Abstract

Il trapianto di rene è ampiamente considerata l’opzione terapeutica ottimale per i pazienti con malattia renale allo stadio terminale. Tuttavia, una quota rilevante di candidati in lista d’attesa per il trapianto – pari a quasi un terzo – presenta anticorpi anti–antigene leucocitario umano donatore-specifici, una condizione che riduce significativamente l’accesso al trapianto e aumenta il rischio di complicanze immunologiche nel periodo post-trapianto. Tra i fattori che influenzano la sopravvivenza del graft, la risposta immunitaria riveste un ruolo centrale nel determinare gli esiti a lungo termine. In questo contesto, il rigetto anticorpo-mediato rappresenta ancora una sfida clinica rilevante, contribuendo sia al danno acuto del trapianto sia a una progressiva compromissione cronica del graft, fino a comprometterne la sopravvivenza.

L’interleuchina-6 è coinvolta in numerosi pathway infiammatori e di regolazione immunitaria ed è implicata nella patogenesi delle risposte alloimmuni nel trapianto renale. In particolare, si ritiene che l’Interleuchina-6 favorisca la persistenza delle plasmacellule e faciliti le interazioni tra linfociti T e B, sostenendo così la produzione anticorpale. Il blocco del segnale dell’Interleuchina-6 potrebbe pertanto rappresentare una strategia per interferire con questi meccanismi e limitare l’entità del danno immune-mediato. Tocilizumab, un anticorpo monoclonale diretto contro il recettore dell’Interleuchina-6, originariamente sviluppato per il trattamento di patologie autoimmuni, ha recentemente suscitato interesse nel campo del trapianto renale. Le evidenze emergenti suggeriscono un potenziale ruolo del Tocilizumab sia nei protocolli di desensibilizzazione dei pazienti iperimmuni sia nel trattamento del rigetto anticorpo-mediato, supportandone l’impiego come opzione terapeutica aggiuntiva nel trapianto di rene.

Parole chiave: interleuchina-6, desensibilizzazione, rigetto anticorpo-mediato cronico, trapianto di rene, tocilizumab

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

Kidney transplantation (KT) remains the gold standard treatment for end-stage kidney disease (ESKD), providing superior survival, quality of life, and cost-effectiveness compared to dialysis [1, 2]. Approximately 30% of patients on the kidney transplant waiting list are sensitized, as indicated by panel reactive antibody (PRA) levels greater than 0%, and nearly 15% are classified as highly sensitized (HS), with PRA levels exceeding 80%. Pre-formed anti-donor specific antibodies (DSAs) constitute a major immunological barrier, often preventing transplantation and prolonging dialysis dependence in HS patients [3, 4]. The presence of DSAs cannot only limit access to KT but also increase the risk of antibody-mediated rejection (AMR) after transplantation, adversely affecting both short- and long-term graft survival rates [3, 5]. Morever, post-transplant development of de novo DSAs can occur, exerting a detrimental effect on graft survival comparable to that of preformed DSAs [6]. These antibodies can lead to AMR, a significant complication that occurs in approximately 1-10% of kidney transplant recipients overall and in nearly 30% of KT recipients with pre-formed DSAs desensitized before transplantation. AMR represents a major cause of progressive and irreversible graft dysfunction, and it poses a significant therapeutic challenge [7].

Attempts to inhibit the DSA production, to remove or reduce the serum levels, to decrease their strength, or, at last, to modify their activity are therefore important. New desensitization (DES) protocols have been developed in the latest years, usually applied before KT (or rarely in the early post-transplant period) in HS patients, intending to make possible the access to transplantation [8–11], and different scheme therapies have been used to treat AMR episodes in the post-transplant period [12–15].

The most common strategies of desensitization and AMR treatment protocols include the use of low or high doses of intravenous Immunoglobulins (IVIg), and anti-CD20 monoclonal antibody- Rituximab (RTX) alone or combined with plasmapheresis (PLEX), which are considered the current standard of care (SC) [16, 17]. These approaches aim to down-regulate B cell activity, reduce antibody production, and promote antibody removal with the aim of facilitating transplantation in HS patients and managing AMR in post-transplant period. However, despite their widespread use, these strategies remain largely empirical and not supported by standardized protocols or high-level evidence. In approximately 25-30% of patients, the antibody cannot be effectively eliminated prior to KT [18, 19], and clinical outcomes following AMR treatment remain suboptimal.

Recent studies have failed to demonstrate a clear beneficial effect of SC in AMR management [20–22], and a multicenter randomized trial comparing PLEX/IVIg with or without RTX showed no significant improvement in chronic AMR outcomes [23]. Similarly, other therapy options, such as Bortezomib or Eculizumab, did not achieve nephroprotective endpoint in KT [24, 25]. These limitations highlight a major unmet need for more effective and targeted therapies to improve graft outcomes in this high-risk population.

Alternative therapies targeting cytokine immune pathways have gained attention in KT treatment protocols. Of relevant interest was Interlukin 6 (IL-6), which is known to have a deleterious impact on inflammatory and immune response [26]. In KT, IL-6 can promote antibody production, acute and/or chronic rejection in solid organ transplantation [27]. Recently, IL-6 has become a therapeutic target in KT.

Tocilizumab (TCZ), the first-in-class humanized monoclonal antibody targeting the IL-6 receptor, can bind to both soluble and membrane-bound forms of the IL-6 receptor, thereby blocking IL-6 activity [28]. The efficacy of TCZ was confirmed in a clinical trial involving patients with Castelman disease; it is now approved for the treatment of several autoimmune-mediated diseases [29]. Starting from these data, many authors have analyzed the role, the impact, and the space that TCZ can have in KT. Another IL-6 targeting agent has also been evaluated in small clinical studies, Clazakizumab – a monoclonal antibody that directly binds IL-6 rather than the IL-6 receptor – has shown encouraging preliminary results in desensitization and AMR treatment in HS patients [30–32].

This narrative review article gives an overview of the molecular mechanisms of IL-6 blockade that provide the rationale for the use of TCZ in KT. In addition, we aimed to summarize the limited clinical evidence on this topic, particularly regarding the use of TCZ for desensitization of anti-HLA-immunized kidney transplant candidates on the WL, and for patients who have developed AMR after transplantation. These emerging therapies further support the pivotal role of IL-6 signaling in modulating alloimmune responses and provide a broader therapeutic context in which TCZ should be considered.

Methodology

For this narrative review, a literature search was performed using PubMed, Web of Science, and the Cochrane Library. The search employed the keywords: “kidney transplantation”, “interleukin-6”, “desensitization”, “antibody-mediated rejection”, “chronic active antibody-mediated rejection”, and “tocilizumab”, and covered the period between January 2015 and January 2024. We considered all relevant articles published in English up to the time of writing, focusing on the clinical use, recent advances, and safety profile of TCZ in desensitization DES protocols and treatment of antibody-mediated rejection in KT. The population studied consisted of HS patients on the transplant waiting list and KT patients who manifest biopsy-proven AMR.

In all the studies the intervention involved the use of TCZ at a dosage of 8 mg/kg, up to a maximum of 800 mg monthly in monotherapy or combined with standard of care (SC) therapy for at least 6 months of treatment.  The expected outcomes for studies where TCZ was used in DES protocol were made by reduction rate of DSAs serum levels, the degree of B and T cells maturation, and access to transplantation after 6 months of treatment. Whereas the expected outcomes for studies where TCZ was used to treat AMR were to be compared to baseline data, with outcomes assessed by comparing the initial and final kidney graft function (eGFR and proteinuria), DSAs levels expressed as mean fluorescence intensity (MFI) and histological changes. Assessment of patient and graft survival rates was included in the outcomes of AMR treatment studies.

Exclusion criteria comprised follow-up periods of less than six months, studies that included pediatric patients and animals, single case reports, SC different from RTX + PLEX + IVIg, TCZ used in KT with graft dysfunction with other indication rather than AMR, and research published in languages other than English.

We identified 22 studies where TCZ was used in the setting of KT.  We excluded studies that did not meet our inclusion criteria, as shown in the flow Diagram 1.

We would like to point out that this study did not adhere to PRISMA guidelines and was not registered in PROSPERO, as a full systematic review was beyond the scope and objectives of the article.

Diagram 1. Flow diagram of study selection.
Diagram 1. Flow diagram of study selection.

Donor-specific antibody

Sensitization is defined by the presence of anti-Human Leukocyte Antigen (HLA) antibodies and is quantified using panel reactive antibody (PRA), a measure that reflects the risk of a positive crossmatch [33]. Preformed DSAs arise from prior exposure to HLA antigens via transplantation, pregnancy, or transfusion, and can impact transplant eligibility [34]. De novo DSAs develop in 13-30% of previously non-sensitized recipients, typically within the first year. Risk factors include high HLA mismatches (especially DQ), insufficient immunosuppression, nonadherence, and graft inflammation due to infection, ischemia, and rejection [35, 36]. Detection relies on Luminex single antigen bead assays. Clinically significant DSAs are usually defined by mean fluorescence intensity (MFI) thresholds of ≥3000 for class I and ≥5000 for class II of HLA [3, 37].

Antibody-mediated rejection

AMR results from antibody-driven injury to the microvascular endothelium, primarily driven by DSAs. The diagnosis of AMR in KT relies on a multimodal approach that integrates clinical, serological, and histopathological data, as well as molecular data when available. Clinically, AMR typically presents with graft dysfunction, such as rising serum creatinine, new-onset or worsening proteinuria, or hypertension. These signs are nonspecific and may overlap with other causes of allograft injury, including T cell-mediated rejection, calcineurin inhibitor nephrotoxicity, or recurrent primary disease. Therefore, kidney allograft biopsy remains the gold standard for the definitive diagnosis of AMR.

Histopathological assessment is guided by the Banff 2022 [38] classification, which provides standardized criteria for the diagnosis and reporting of AMR.

Diagnosis is based on the integration of three main categories of evidence:

  • Histologic evidence of acute or chronic tissue injury: Microvascular inflammation (MVI), with glomerulitis (g > 0) and/or peritubular capillaritis (ptc > 0), in the absence of recurrent or de novo glomerulonephritis.
    Intimal or transmural arteritis (v > 0). Thrombotic microangiopathy (TMA) not attributable to other causes and/or acute tubular injury without alternative explanation.
  • Evidence of antibody–endothelial interaction, demonstrated by at least one of the following: linear C4d deposition in peritubular capillaries, detected by immunohistochemistry or immunofluorescence; moderate or severe microvascular inflammation, defined as a combined score of glomerulitis and peritubular capillaritis (MVI = g + ptc) ≥ 2; increased expression of validated gene transcripts in the biopsy, strongly associated with AMR, as assessed by molecular diagnostics.
  • Serologic evidence of circulating DSAs: detection of circulating DSA remains a central criterion. In the absence of detectable DSA, positive C4d staining in peritubular capillaries and/or detection of validated gene expression consistent with antibody-mediated injury may provide supportive evidence.

The Banff 2022 introduced two additional diagnostic categories to better capture the spectrum of antibody-mediated injury:

Probable AMR:

Defined as cases with incomplete fulfillment of classic AMR criteria – typically positive DSA with sub-threshold histologic findings, or ambiguous molecular signals – where antibody-mediated injury is suspected but not fully confirmed.

MVI, DSA-negative and C4d-negative:

Refers to cases with significant MVI in the absence of DSA or C4d. These are not classified as classical AMR but are recognized as clinically relevant and require careful clinicopathologic correlation.

Furthermore, acute tubular injury is no longer considered sufficient for AMR diagnosis in isolation. Likewise, arterial intimal fibrosis is no longer accepted as evidence of active antibody-mediated injury without additional supportive findings.

Chronic active AMR is characterized by persistent or recurrent microvascular injury, most notably glomerulitis (g) and peritubular capillaritis (ptc), reflecting inflammation of glomerular and peritubular capillary compartments. These lesions are semiquantitatively scored, and a combined MVI score (g + ptc) ≥ 2 strengthens the suspicion for AMR.

Additional histological features may include intimal or transmural arteritis, TMA, or acute tubular injury, not attributable to other causes. Chronic injury markers – such as transplant glomerulopathy and interstitial fibrosis/tubular atrophy – often coexist and influence prognosis [39].

 

Role of IL-6 in Kidney Transplantation  

In 1986, Kishimoto et al. identified IL-6 as B-cell stimulating factor 2 (BSF-2) and its role in the promotion of immunoglobulin synthesis by activated B cells [40]. Aberrant IL-6 production and signaling contribute to chronic immune, cardiovascular, neuroendocrine, and metabolic disorders, as well as tumorigenesis [41]. It is a pleiotropic cytokine and is implicated in innate and adaptive immunity response, cellular and humoral response, determining itself the main factor of graft damage in KT [27] (Figure 1).

An increase of IL-6 in serum, urine, and biopsy tissue is observed during kidney allograft rejection, and levels correlate with the degree of inflammatory cell infiltration in human KT recipients [41]. Moreover, in the setting of a brain death donor, the pro-inflammatory process mediated by IL-6 starts before organ procurement [42]. Additionally, the kidney cold static preservation promotes the upregulation of intra-graft IL-6 production after the organ transplantation. This process promotes the pro-inflammatory cells’ recall, cytokine production, and up-regulation of adhesion molecules, which lead to graft damage/injury. IL-6 promotes the CD8+ T cell memory expansion and CD4+ T cell differentiation to Th17, which are implicated in acute and chronic graft rejection [43]. In a murine model of KT, following the graft rejection, intra-graft expression of IL-6 was upregulated and Foxp3+ Tregs were decreased [44]. Foxp3+ Tregs are critical for maintaining immune homeostasis and immune tolerance in transplantation [45]. IL-6 is a main growth factor involved in the differentiation of B cells to IgG-secreting plasmablasts and plasma cells, so the upregulation of antibody production in KT can lead to AMR [27, 46]. Morever, IL-6 is implicated in innate immunity by binding Natural Killer (NK) cells, subsequently, it induces cytotoxicity to endothelial cells and promotes collagen synthesis by fibroblast and endothelial cell activation, which results in chronic graft injury [27]. This theory was also confirmed in the experimental model of chronic allograft nephropathy, in which interstitial fibrosis/tubular atrophy (IFTA) was shown to be mediated by the presence of chemokines and cytokines, including IL-6 produced by B cells [47].

Due to its pleiotropic activity, IL-6 has become a therapeutic target; it was supposed that inhibiting IL-6 signaling effectively reduces B cell activation, plasmablast differentiation, and antibody production (both primary and recall). B-cell depletion resulted in decreased intra-graft B cells, chemokines, and IL-6 levels, limiting in this way the allograft interstitial fibrosis and tubular atrophy, leading to better tolerance and graft survival rates [48]. IL-6 inhibition can also promote regulatory T cells (T-reg) generation, which counterbalances the effects of alloreactive Th17 lymphocytes [49]. Indeed, Chandran et al. showed that KT recipients with biopsy-proven intra-graft inflammation treated with IL-6 inhibitor developed significantly higher proportions of Treg as well as substantially lower proportions of T effector cells as compared to control patients, indicating that IL-6 inhibition shifts T cell maturation towards Tregs in the absence of IL-6 signaling [50].

Role of IL-6 in immunity.
Figure 1. Role of IL-6 in immunity. IL-6 involvement in humoral, cellular and innate immune responses. IL-6 production by APCs is an important stimulus for IL-21 production by naive T cells which mature toward the Tfh phenotype expressing CXCR5 and IL-21.  Naive B cells migrate to the germinal centers in response to CXCR5+ Th cells. This activates B cell maturation to memory B cells and IL-6 producing plasmablasts that further promote germinal center formation and progression to antibody-producing plasma cells driving pathogenic antibody production and tissue injury. Impact of anti–IL-6/IL-6R therapy on reducing Tfh activation and subsequent plasmablast and plasma cell development with reductions in pathogenic antibody production and tissue injury. IL-6 by binding NK cells can induce cytotoxicity toward endothelial cells and promotes collagen synthesis by fibroblast and endothelial cell activation, which results in chronic graft injury. AMR: antibody-mediated rejection; APC: antigen-presenting cell; DSA: donor-specific HLA antibody; IL: interleukin; Tfh: T-follicular helper cells; NK: natural killer.

 

Role of Tocilizumab in Kidney Transplantation

TCZ is a humanized monoclonal antibody (IgG1 subclass) that binds IL-6 Receptor (IL-6R). It has been approved for the treatment of moderate to severe rheumatoid arthritis and idiopathic juvenile arthritis [51]. Many studies have shown that using TCZ as an add-on therapy induced an intense relative reduction of DSAs in terms of MFI; although the reduction was not clinically significant, it was a tendency to induce lower post-transplantation antibody rebound [52]. Moreover, TCZ appears to be a safe and feasible strategy for managing AMR in sensitized kidney transplant recipients [53].

The mechanism of action of TCZ is illustrated in Figure 2.

IL-6 receptor targets of Tocilizumab in the development of AMR
Figure 2. IL-6 receptor targets of Tocilizumab in the development of AMR. Impact of Tocilizumab inhibiting IL-6 pathway can reduce Tfh activation and subsequent plasmablast and plasma cell development with reductions in pathogenic antibody production and tissue injury. In addition, anti–IL-6 therapy inhibits T effector cell function and enhances Treg cell/Breg cell differentiation which likely inhibits DSA formation and allograft injury. AMR: antibody-mediated rejection; IL-6: interleukin-6; IL-21: interleukin-21; Tfh: T-follicular helper cell.

Efficacy of Tocilizumab in Desensitization Protocols for Highly Sensitized Kidney Transplant Candidates

The use of TCZ in desensitization protocols for HS kidney transplant candidates remains an area of emerging investigation. Preclinical data derived from an HLA-incompatible skin graft mouse model suggest that TCZ not only reduces circulating anti-HLA antibody levels but also significantly decreases the frequency of antibody-secreting plasma cells in both the bone marrow and spleen, supporting its potential role in modulating humoral alloimmune responses [54].

In clinical settings, TCZ has been evaluated both as monotherapy and as part of combination regimens. The following is a synthesis of three principal studies investigating the efficacy of TCZ in HS patients, with specific focus on changes in DSA levels, lymphocyte subset dynamics, access to transplantation, and posttransplant outcomes.

A summary of the findings is presented in Table 1.

Vo et al. evaluated the efficacy of TCZ in a cohort of 10 HS kidney transplant candidates who had previously failed standard desensitization (SC) protocols involving IVIG and RTX. Patients received IVIG (2 g/kg on days 0 and 30) and TCZ (8 mg/kg on day 15), followed by monthly TCZ infusions for six months. TCZ enabled transplantation in 50% of participants. A statistically significant reduction in DSA MFI was observed (p = 0.03), and no episodes of AMR were detected in posttransplant surveillance biopsies. The treatment was well tolerated, suggesting that TCZ may represent a valuable adjunct in desensitization protocols for HS patients unresponsive to conventional therapy [55].

Daligault et al. investigated TCZ monotherapy in 14 HS patients on the transplant waitlist, all with anti-HLA DSAs exhibiting MFI ≥10,000. Patients received monthly TCZ infusions (8 mg/kg). The therapeutic goal was to reduce DSA MFI values below the 10,000 thresholds. While a modest reduction in both the number and intensity of DSAs was achieved, the response was insufficient to enable clinically meaningful desensitization. Only one patient proceeded to transplantation after TCZ monotherapy, whereas 11 required subsequent SC therapy, which allowed successful transplantation in eight cases. The authors concluded that TCZ monotherapy provides limited benefit in treatment-naïve HS patients, due to its modest and narrow impact on DSA reduction [56].

In a third prospective single-center study conducted by Jouve et al., TCZ monotherapy was assessed in 13 naïve HS patients with DSAs >10,000 MFI. Patients received 8 mg/kg every four weeks for six months. Immunologic endpoints included quantitative and qualitative changes in anti-HLA DSAs (MFI, panel reactive antibody [PRA] levels), as well as phenotyping of T and B cell subsets, including follicular helper T cells (Tfh), regulatory T cells (Tregs), and circulating cytokine/chemokine profiles (IL-6, IL-6R, IL-21, CXCL10, CXCL13). After six months, DSA MFI values showed only marginal changes without statistical significance, and no variation in PRA levels was detected. TCZ had negligible effects on CD3+ T cell and B cell compartments, except for a significant increase in naïve B cells (p = 0.020) and a decrease in post-germinal center B cells. No significant changes were observed in Th cells, Tregs, or circulating cytokine/chemokine levels. None of the patients achieved transplant eligibility following TCZ monotherapy. However, seven eventually underwent successful KT after receiving adjunctive SC therapy. The authors concluded that TCZ monotherapy had limited efficacy as a standalone desensitization strategy, though its effect on B-cell maturation may support its use in preventing post-transplant humoral rebound [57].

As summarized in Table 1, two of the three reviewed studies demonstrated that TCZ monotherapy exerts only modest effects on DSA reduction and access to transplantation in HS patients. In contrast, when combined with SC protocols, TCZ appears to enhance transplant eligibility and may contribute to reducing the risk of post-transplant AMR. These findings suggest that the primary role of TCZ may lie not in its desensitizing capacity per se, but rather in its ability to modulate long-term humoral alloimmune responses and prevent post-transplant DSA rebound, thereby potentially improving graft survival rates.

Encouraging and similar data have also been recorded in studies conducted in other types of solid organ transplantation. Sommer et al. examined the effect of TCZ in cardiac transplant patients who had pre-transplant pre-formed DSA and received TCZ in the context of desensitization protocols. Post-transplant rejection rates were significantly lower than those of controls, and no graft failures were reported. This suggests TCZ’s potential in reducing DSA rebound and preventing graft rejection, though the benefits likely stemmed from its use in a multi-drug combo therapy regimen [58].

Study Design / Setting Population Intervention Outcomes Main results
Outcomes on DSAs Transplantation Rate Immunological Findings Key Conclusions
Vo et al.
Transplantation 2015 [55]		 Phase I/II uncontrolled, single-center 10 HS patients refractory to IVIG + RTX +/- PLEX IVIG (2 g/kg on days 0 & 30) + TCZ (8 mg/kg on day 15) monthly × 6 months + IVIG at D0 and D30

Efficacy

– % of patients receiving Kidney transplant

– rejection at 6 months biopsy

– DSAs at 6 months

Significant DSA MFI reduction (p = 0.03)

No DSAs at M6

5/10 (50%) transplanted

No AMR in post-transplant biopsies M6

1 AMR at M12, no graft loss

TCZ effective as adjunct in SC-refractory patients
Daligault et al.
Transplantation Direct 2021 [56]		 Phase II uncontrolled, single center

14 naïve HS patients with DSA ≥10,000 MFI

First DES attempt

TCZ monotherapy (8 mg/kg every 4 weeks x 6 months)

No other prior or DES therapies

Efficacy

– MFI of anti-HLA immunodominant Ab

– Number of anti-HLA Ab with MFI>10000

– % of patients received transplant

 Modest DSA decline, insufficient for clinical DES 1/14 transplanted with TCZ; 8/11 transplanted after rescue SC No AMR data TCZ monotherapy has limited efficacy in naïve HS patients
Jouve et al.
AJT 2021 [57]		 Controlled non-randomized, single-center

13 naïve HS patients with DSA >10,000 MFI

Control group: HS patients remaining in dialysis without DES attempt; healthy subjects

TCZ monotherapy (8 mg/kg every 4 weeks × 6 months)

No other prior or DES therapies

Rates evolution of: Tfh 1, 2, and 17 Treg; plasmablasts, plasma-cells, B memory cells; evolution of anti HLA Ab MFI

Marginal MFI reduction; no significant PRA change

T population: no significant changes in Tfh 1, 2, 17 Treg

B population: blocking post germinal B cells, plasmablasts, plasma-cells

 0/13 transplanted with TCZ; 7 transplanted after SC No AMR data TCZ monotherapy has limited efficacy in naïve HS patients
Table 1. Tocilizumab for Desensitization in Highly Sensitized Kidney Transplant Candidates. Abbreviations: Ab, antibody; AMR, antibody-mediated rejection; DES, desensitization; IVIG, intravenous immunoglobulin; HS, highly sensitized; MFI, mean fluorescence intensity; SC, standard of care; DSA, donor-specific antibodies; KT, kidney transplant; TCZ, tocilizumab; RTX, rituximab; T fh, T follicular helper cells; T reg, T regulatory cells.

Efficacy of Tocilizumab in Antibody-Mediated Rejection in Kidney Transplant Patients

This section summarizes evidence from eight clinical studies assessing the efficacy of TCZ in the treatment of AMR with particular focus on its effects on renal allograft histopathology, graft function over time, DSA trends, graft and patient survival, and safety profile.

All key findings of those studies are presented in Table 2.

Study (Year) Design / Sample Type of AMR Baseline data TCZ Use Histological Outcomes Renal Function

(eGFR and/or proteinuria)

 DSA Response Key Notes
Choi et al. Am J

Transplant

2017 [60]

 Open-label case study, n=36 Chronic active Mean eGFR 48.4 ml/min/1.73m2

DSAs + 91,7%

Mean DSAs 1.91

 Rescue therapy 6–36 months

 

 ↓ g + ptc (p=0.0175), ↓ C4d (p=0.0318) Stable eGFR at 36 months

(38.8 ± 10.4 ml/min/1.73 m2 in adults) over 3.26 years

 ↓ DSA (p=0.043 at 24 months) First report; abrupt TCZ withdrawal led to graft loss
Lavacca et al. Clin

Transplant

2020 [62]

 

open-label case study

n=15

 Chronic active Mean eGFR 45.1 ml/min/1.73m2

Mean of

proteinuria 1.1 g/day

DSA + 100%

 First-line monotherapy ↓ g+ ptc at 6 months (p=0.014).  no changes in C4d deposition or chronic lesions (cg and IFTA)

(p= 0.206,

p= 0.180,

p= 0.608 respectively)

 Stable eGFR and proteinuria

eGFR decline 4.4 mL/ min/1.73 m2 after 12 months of treatment vs 10.5 ml/min/ min/1.73m2/year baseline

1.1 before treatment and 1 g/day after treatment

 ↓ DSA

22600, pre-TCZ and 18200 post-TCZ

 First-line TCZ effective in active inflammation
Potteboun et al. Transplant

Direct

2020 [59]

Retrospective,

single-center n=7

 Acute DSAs + 100%% Adjunct to SC Not reported Improved/stabilized in all patients ↓ DSA in 4/6 patients (reduction of 50%) Acute AMR setting; TCZ enhanced DSA reduction
Kummar et al. Kidney360

2020 [63]

 

 Observational single-center cohort study n=10 Chronic active DSA+ 80% Adjunct, to SC

Belatacept in 7 patients

 ↓ g+ptc  and C4d at 12 months

(4.8 ± 1.4 to 4.2 ± 2.0; p = 0.39)

 eGFR:

42 ± 18 to 37±24 ml/min/1.73 m2; P = .27), and the slope of eGFR decline remained unchanged (−0.14 ± 0.9 to −0.33 ± 1.1; p = 0.25).

 ↓ DSA (NS)

(p=0.629)

 Combined with Belatacept; 47.3% discontinued TCZ
Massat et.al. Am J

Transplant

2021 [64]

 

Retrospective,

single-center n=46

9/46

Control group 37/46

 Chronic active and mixed DSAs were present in 66,7% of patients

Mean eGFR 40ml/min/1.73m2

Mean g + ptc 3.0+/-0.82

 9/46 Rescue

12 months

 ↓ g + ptc

↓ t (0.07)

 No differences between groups

(↓ eGFR by – 4 ml/min/1.73m2/year)

 

 ↓ DSA

In MFI at 12 months (−48 ± 44%)

 TCZ rescue therapy provide significant DSAs reduction
Noble et al. Front Med

2021 [65]

Retrospective, single-center

n=40

 Chronic active Mean e-GFR 43 ±

17 ml/min/1.73m2

Mean proteinuria

1± 0.9 g/L

DSAs + 55%

 7/40 TCZ in monotherapy;

 

33 /40 TCZ + SC

 No change in g+ptc Stable (e-GFR p=0.12 and proteinuria p=0.95 at 6 month and p=0.28 at 12 months) Not assessed Baseline severity predicted graft loss
Khairallah et al. Clin

Transplant

2023 [66]

Retrospective,

single-center n=38

 Chronic active Mean e-GFR 41±17 ml/min/1.73m2, mean proteinuria 0.6 ± 0.5g

DSAs + 82%

 35/38 rescue

3/38 first line

 ↓ interstitial inflammation (p=0.03), no change in others ↓ slope of eGFR decline (p=0.002)

34 ± 15 ml/min/1.73 m2 at 3 months

36 ± 15 ml/min/1.73 m2 by 6 months

no significant change in terms of proteinuria (p=0.07

 No change

MFI of DSA Baseline 3450

At 6months

4000

 DSA unchanged despite functional stabilization
Boonpheng et al. Clin

Transplant

2023 [67]

Retrospective,

single-center n=11

 Chronic active 64% DD-Cf-DNA

mean proteinuria 1.19 g/g

 Mixed (6 rescue, 5 first-line) Limited data (2 biopsies)

↓ g+ptc

 

 Stable eGFR, ↓ proteinuria (NS, p=0.7)

eGFR of 57 ± 18 ml/min/1.73 m2 pretreatment eGFR of 56 ± 17 ml/min/1.73 m2 at 6 months

and 60 ± 24 ml/min/1.73 m2 at 12 months

proteinuria baseline 1.19g/g and 0.97g/g at 12 months

 ↓ dd-cfDNA (p=0.01 ant 6 moths),

↓ DSA (p=0.047 at 12 months)

 First to monitor dd-cfDNA; potential biomarker use
Table 2. Tocilizumab for the treatment of AMR in kidney transplantation. Abbreviations: NA, not assessed; SC, standard of care; TCZ, tocilizumab; e-GFR, estimated glomerular filtration rate; AMR, chronic antibody-mediated rejection; DSAs, donor-specific antibodies; ptc, peritubular capillaritis; g, glomerulitis; cg, chronic glomerulopathy; IFTA, interstitial fibrosis and tubular atrophy; DD-Cf-DNA, Donor Derived Cell free DNA; NS, not significant.

Efficacy of Tocilizumab in Acute Antibody-Mediated Rejection in Kidney Transplant Patients

In a single-center retrospective observational study, Potteboun et al. [59] studied the efficacy of TCZ as an adjunct to SC therapy in seven KT recipients with biopsy-proven acute antibody-mediated rejection (a-AMR). DSAs levels were measured at the time of diagnosis and monitored longitudinally over a 24-month follow-up period. This study provides novel insights into the therapeutic potential of IL-6 blockade in the setting of a-AMR, a condition associated with a high risk of progression to chronic AMR and subsequent graft dysfunction or loss. Given the central pathogenic role of DSAs in AMR, therapeutic strategies aimed at depleting circulating antibodies or suppressing their production are of critical importance. While SC therapy-PLEX, IVIg, and RTX-typically result in a modest reduction of DSA levels (approximately 15-35%, depending on the specificity of anti-HLA antibodies and the intensity of PLEX), the authors identified a 50% reduction in DSA MFI as a clinically relevant threshold, reflective of a meaningful immunologic response with potential impact on graft survival. In this case series, the addition of TCZ to SC therapy was associated with stabilization or improvement of renal function in all patients, along with a notable reduction in DSA levels in most cases. These findings suggest that TCZ may enhance the efficacy of conventional immunomodulatory strategies in patients with a-AMR and could play a role in delaying or preventing the progression of alloimmune-mediated graft injury. However, the limited sample size and retrospective design underscore the need for prospective controlled trials to validate these preliminary observations.

 

Efficacy of Tocilizumab in Chronic Active Antibody-Mediated Rejection in Kidney Transplant Patients

The first clinical investigation into the use of TCZ in chronic active AMR (ca-AMR) was conducted by Choi et al. [60], who evaluated 36 kidney transplant recipients with biopsy-proven, SC-resistant ca-AMR. Patients received monthly intravenous infusions of TCZ at 8 mg/kg (maximum dose: 800 mg) for a treatment duration ranging from 6 to 36 months. Baseline histological assessments revealed high Banff scores [61] for microvascular inflammation, including glomerulitis and peritubular capillaritis, along with C4d deposition hallmarks of active AMR. After 12 months of TCZ treatment, follow-up biopsies performed in nine patients demonstrated a significant reduction in glomerulitis (p = 0.0175), peritubular capillaritis, and C4d staining (p = 0.0318). These changes reflect an attenuation of the immunologic injury. Glomerulitis and peritubular capillaritis are typically associated with poor long-term graft prognosis. DSA levels were monitored quarterly, while renal function was assessed via estimated eGFR, and was evaluated monthly throughout the study period. A sustained decline in DSA levels was observed, particularly for immunodominant specificities, with a statistically significant reduction noted at 24 months of therapy (p = 0.043). At six years post-ca-AMR diagnosis, graft and patient survival rates were 80% and 91%, respectively. Treatment discontinuation in four patients due to financial constraints (n = 3) or clinical indications (n = 1) was associated with subsequent graft loss. The authors hypothesized that abrupt cessation of TCZ may have triggered an IL-6 rebound effect, exacerbated by IL-6 accumulation during prolonged receptor blockade. Notably, all four patients experiencing graft failure harbored class II DSAs (HLA-DQ or HLA-DR). Among patients who remained on therapy, renal function was stable, with no significant decline in eGFR at 36 months. Lavacca et al. evaluated the efficacy and safety of TCZ as a first-line therapeutic approach in KT recipients with biopsy-proven ca-AMR. In this open-label, prospective study conducted between 2016 and 2018, 15 patients meeting Banff criteria for ca-AMR [38, 61] were enrolled. None of the participants had received prior targeted anti-rejection therapy. TCZ was administered intravenously at a dose of 8 mg/kg (maximum 800 mg) every four weeks. One patient with advanced graft dysfunction was converted to Belatacept-based maintenance immunosuppression prior TCZ initiation. Patients were followed for a median duration of 20.7 months. Outcome measures included graft function (assessed by eGFR rate and proteinuria), patient survival, serum levels of DSAs and anti-angiotensin II type 1 receptor antibodies (AT1R-Abs), histopathological changes, and adverse events. Protocol biopsies were performed at 6 months post-treatment initiation to assess early histological response. TCZ treatment was associated with stabilization of eGFR and proteinuria, along with a significant reduction in circulating DSA levels (p = 0.002). Histological analysis demonstrated a reduction in microvascular inflammation, particularly in glomerulitis and peritubular capillaritis scores. However, no significant improvements were observed in chronic injury markers, including interstitial fibrosis/tubular atrophy and C4d deposition. These findings suggest that TCZ, when used as first-line therapy in ca-AMR, may contribute to the attenuation of active alloimmune injury and stabilization of graft function, although its impact on chronic injury progression remains limited. eGFR and 24-hour proteinuria showed stabilization at the 12-month follow-up. eGFR declined by 10.5 mL/min/1.73 m2 (median) in the 12 months before ca-AMR diagnosis compared with 4.4 mL/ min/1.73 m2 the first year after diagnosis. Median proteinuria at diagnosis and at the 12-month follow-up were 1.1 and 1 g/day, respectively. Mean MFI values significantly declined after TCZ treatment (22600 pre-TCZ and 18200 post-TCZ with complete negativization in one patient). This trend was also confirmed for AT1R-Ab [62].

A retrospective study conducted by Kumar et al. evaluated the efficacy of TCZ in 10 kidney transplant recipients with biopsy-proven ca-AMR refractory to SC therapy. Notably, seven of these patients were maintained on Belatacept-based immunosuppression. Serial graft biopsies were performed at baseline and one year following initiation of TCZ therapy. At 6 months post-treatment initiation, there was an improvement in the mean of eGFR, but not statistically significant, while proteinuria levels remained unchanged throughout follow-up. A reduction in DSA MFI was also observed at 6 months, although this did not reach statistical significance (p = 0.5). Histological analysis demonstrated a reduction in microvascular inflammation following 12 months of TCZ therapy, mirroring the findings reported by Choi et al. [60]. Specifically, reductions in glomerulitis, peritubular capillaritis, and C4d deposition were noted, as detailed in Table 2. TCZ was discontinued in 47.3% of patients (18/38 in the overall cohort), after a median treatment duration of 10.4 months. In three cases, the decision to withdraw TCZ was made upon stabilization of graft function, highlighting the ongoing uncertainty regarding optimal treatment duration. Discontinuation was also necessitated by the development of HPV-positive tonsillar carcinoma in one patient, and by infectious complications in four others. Collectively, the studies by Choi et al. and Kumar et al. demonstrate consistent histological improvements in patients with refractory ca-AMR treated with TCZ, particularly in the reduction of MVI (p = 0.0175) and C4d deposition (p = 0.0318), suggesting a potential disease-modifying role for IL-6 blockade in this setting [63].

A retrospective study investigated the efficacy of TCZ as adjunctive SC in nine kidney transplant recipients with biopsy-proven graft rejection. Of these, six patients were diagnosed with ca-AMR, while the remaining three exhibited mixed rejection characterized by features of both AMR and T cell-mediated rejection. All patients had detectable circulating DSAs at the time of diagnosis and had demonstrated resistance to prior SC therapies. TCZ was administered intravenously at a dose of 8 mg/kg (maximum 800 mg) monthly. Outcomes were compared to those of a control group comprising 37 patients with AMR who had received SC therapy alone. At 12-month follow-up, the TCZ-treated group exhibited a significant reduction in the MFI of DSAs across both HLA class I and class II antigens (p = 0.01). Despite this immunological response, there were no statistically significant differences between the TCZ and control groups in terms of graft survival or decline in renal function over the same period. Histopathological evaluation revealed a modest improvement in inflammatory indices, including a reduction in tubulitis scores, following TCZ treatment. However, the progression of AMR-related lesions and chronic glomerulopathy remained largely comparable between the two cohorts. The incidence of infections did not differ significantly between TCZ-treated patients and those receiving SC alone [64].

Noble et al. [65] recently published a single-center retrospective study evaluating the efficacy of TCZ in 40 KT recipients with biopsy-proven ca-AMR. TCZ was administered intravenously at a dose of 8 mg/kg (maximum 800 mg) every four weeks. Seven patients received TCZ as first-line monotherapy, whereas the remaining patients were treated with TCZ in combination with other immunosuppressive agents, including corticosteroids (52.5%), RTX (40%), PLEX (20%), and anti-thymocyte globulin (5%). One patient had received Belatacept prior TCZ initiation, and 18 additional patients were converted to Belatacept-based maintenance immunosuppression following the diagnosis of AMR and the initiation of TCZ. The primary endpoints were changes in graft function, assessed by eGFR rate and proteinuria, and histological progression at one year. Compared with baseline values, no statistically significant differences were observed in eGFR decline (p = 0.102) or proteinuria (p = 0.28) after 12 months of TCZ therapy. Likewise, histopathological assessment revealed no significant changes in Banff lesion scores after one year of treatment. During follow-up, six patients (15%) experienced graft loss. These patients had more severe baseline clinical and histological parameters compared with the rest of the cohort, including lower baseline eGFR (24.5 ± 16 mL/min/1.73 m²), higher levels of proteinuria (1.8 ± 1.0 g/L), and more advanced chronic injury on biopsy, with significantly higher scores of tubular atrophy (ct; p = 0.007), interstitial fibrosis (ci; p = 0.002), and intimal arteritis (v; p = 0.001). The study did not include longitudinal monitoring of donor-specific antibodies (DSAs) or systematically report adverse events related to TCZ, thus limiting the interpretation of immunological efficacy and safety outcomes.

Khairallah et al. [66] conducted a retrospective study to evaluate the impact of TCZ on allograft function and histopathological features in 38 kidney transplant recipients with biopsy-proven ca-AMR. Among the included patients, 35 had previously failed SC therapies, while TCZ was administered as first-line therapy in the remaining three. At the time of TCZ initiation, 15 patients had detectable DSAs. TCZ was administered intravenously at a dose of 8 mg/kg monthly. Follow-up biopsies were performed in approximately half of the cohort after a median of 5.1 months from treatment initiation. Histological analysis revealed a significant reduction in interstitial inflammation scores (p = 0.03), while other Banff parameters such as glomerulitis, tubulitis, peritubular capillaritis, arteritis, glomerulosclerosis, and C4d deposition-remained unchanged. No significant variation in DSA levels was observed following TCZ treatment (p = 0.5). Graft function remained stable during the six months following TCZ initiation. A significant deceleration in the rate of eGFR decline was observed, with a difference in slope of 2.6 mL/min/1.73 m² per month before and after treatment initiation (p = 0.002). Proteinuria did not change significantly over the observation period (p = 0.07).

Boonpheng et al. conducted a study involving 11 kidney transplant recipients with biopsy-proven ca-AMR treated with TCZ. DSAs and donor-derived cell-free DNA (dd-cfDNA) were serially monitored to assess immunologic activity and allograft injury during follow-up. In six patients, TCZ was initiated following failure of SC therapy, while in the remaining five patients was used as a first-line treatment. At six months, a significant reduction in dd-cfDNA levels was observed (p = 0.01), suggesting a potential attenuation of alloimmune-mediated graft injury. Among the six patients who completed 12 months of treatment, ddcfDNA levels remained significantly reduced compared to baseline at both six and twelve months (p = 0.05 and p = 0.04, respectively). The authors also reported a decline in the MFI of immunodominant DSAs over time. While the reduction did not reach statistical significance at six months (p = 0.13), it became significant at twelve months (p = 0.047), indicating a potential immunomodulatory effect of IL-6 inhibition on humoral alloimmunity. Graft function remained stable during TCZ treatment. The eGFR rate at six months did not differ significantly from baseline (p = 0.25), and in the subgroup of patients treated for at least 12 months, eGFR remained unchanged at six and twelve months (p = 0.29 and p = 0.48, respectively). Proteinuria showed a decreasing trend, but the differences were not statistically significant; mean proteinuria declined from 1.19 g/g at baseline to 0.97 g/g at twelve months (p = 0.70). Only two patients underwent follow-up biopsies after 16 months of treatment, which revealed modest improvements in microvascular inflammation [67].

Tocilizumab safety profile

Adverse events are summarized in Table 3. Across published studies, the safety profile of TCZ in KT recipients has been overall acceptable and comparable to that observed in other clinical settings. The most frequently reported adverse events were infectious complications, particularly bacterial and viral infections, consistent with the immunomodulatory effects of IL-6 blockade.

In the largest available series, Choi et al. [60] reported infectious events in approximately 25–30% of patients treated for ca-AMR, while Lavacca et al. [62] documented infections in one-third of their cohort, mainly urinary and respiratory tract infections and cytomegalovirus (CMV) viremia. Similarly, Kumar et al. [63] observed infections in 50% of patients, including opportunistic infections, and in several cases, this led to treatment discontinuation. In other retrospective cohorts [64–66], the incidence of infections ranged from 20% to 30%, without a statistically significant difference compared to SC therapy. Boonpheng et al. [67] reported three non-severe events (uncomplicated diverticulitis, localized herpes zoster, and mild COVID-19), and Potteboun et al. [59] observed no serious adverse events in acute AMR patients. In the desensitization setting, TCZ was very well tolerated across three studies [55–57], with no severe infections reported.

The most common infectious events included urinary tract infections, respiratory infections, CMV reactivation, herpes zoster, and, less frequently, gastrointestinal infections. No invasive fungal infections were documented.

Non-infectious adverse events were uncommon. One case of HPV-positive tonsillar carcinoma was reported during prolonged TCZ treatment; the event was not directly TCZ-related [63], and a single episode of diverticulitis [67]. Mild, transient laboratory abnormalities (e.g., elevated transaminases) were occasionally described but were not clinically significant. Only one study reported a cardiovascular event in two patients: non-ST-segment elevated myocardial infarctions and one stroke. However, the causal relationship with TCZ therapy is not clear. There were no reports of TCZ-related nephrotoxicity. Importantly, several studies reported no significant increase in infection rates compared with SC alone [64], suggesting that TCZ does not substantially increase the infectious burden when used in experienced transplant centers with appropriate prophylaxis and monitoring. TCZ infusion was overall well tolerated across the included studies.

Overall, TCZ demonstrates a favorable and manageable safety profile in kidney transplant recipients. Infectious events remain the main clinical concern but are generally controllable. The drug is well tolerated both as adjunctive therapy for AMR and as part of desensitization strategies, supporting its use in selected high-risk populations under close clinical surveillance.

Study Infection Others
Vo et al. Transplantation 2015 [55] 1 episode of colonic diverticulitis with perforation (possible correlation with TCZ)

Anemia and hypertension during time of treatment.

1 episode of acute pulmonary edema unrelated to TCZ and
Daligault et al. Transplantation

Direct 2021 [56]

 1 episode of Spondylodiscitis Hypogammaglobulinemia
Jouve et al. AJT  2021 [57] 1 episode of  spondilodiscitis hypogammaglobulinemia
Choi et al. Am J Transplant.  2017 [60]

13/36

5 CMV viremia

3 BKV viremia

7 bacterial infections

3/36

1 stroke

2 NSTEMI

1/36 transient visual disturbance

8/36 hypogammaglobulinemia
Lavacca et al. Clin Transplant. 2020 [62]

5/15 bacterial Infection

4/5 UTI

1/5 low respiratory tract infection

1/15 encephalitis of undefined origin

2/15 interstitial lung disease infection

4/15 hypogammaglobulinemia

3/15 asymptomatic mild alterations in liver enzymes
Pottebaum et al. Transplant Direct. 2020 [59] 1/7 CMV esophagitis 1 potential hypersensitivity reaction
Kummar et al. Kidney360. 2020 [63] 3/ 19 bacterial infections

1/10 viral with HSV

5/10  leukopenia

1/19 severe diarrhea
Massat et al Am J Transplant. 2021. [64]

 

6/9 (SC+TCZ) *

2 bacterial infections

2 viral infections

2 fungal infections

NA
Noble et al. Front Med. 2021 [65] NA NA
Khairallah et al. Clin Transplant. 2023 [66]

3/38 CMV viremia

3/3 BKV viremia

1/3 EBV viremia

1/38 pneumonia

1/38 cellulitis

3/38 pyelonephritis

15/3 leucopenia

16/38 thrombocytopenia

7/38 asymptomatic mild alterations in liver enzymes
Boonpheng at al. Clin Transplant. 2023 [67]

 

1/11 VZV

1/11 uncomplicated diverticulitis

1/11 mild covid 19 infection

1/11 clostridium difficile colitis

 NA
Table 3. Tocilizumab Adverse effects. NA, not assessed. CMV: cytomegalovirus; BKV: poliomavirus BK; EBV: Epstein-Barr virus; VZV: varicella zoster virus; HSV: herpes simplex virus; NSTEMI: non–ST-segment elevation myocardial infarction; UTI: urinary tract infection; TCZ: tocilizumab. *There were no significant differences between the SC group and the SC+TCZ group.

Critical Comparison and Limitations of Studies Evaluating Tocilizumab in AMR

Across the current body of literature, TCZ has emerged as a potentially effective therapeutic agent for the management of AMR, particularly in patients who are refractory to SC therapies. Although most available studies are single-center, retrospective, and non-randomized, with limited sample sizes (ranging from 7 to 40 patients per study) and often lacking adequately matched control groups, they consistently demonstrate a significant attenuation of microvascular inflammation, including reductions in glomerulitis and peritubular capillaritis scores, accompanied by stabilization of renal allograft function.

In the pivotal study by Choi et al. [60], TCZ administered as rescue therapy was associated histological improvements and sustained reductions in DSA levels over a long-term follow-up, supporting its disease-modifying potential in ca-AMR. Similarly, Kumar et al. [63] and Lavacca et al. [62] reported concordant findings, with significant reductions in microvascular inflammation and stabilization of e-GFR, although DSA declines were more variable and not consistently statistically significant across all patients.

By contrast, the study by Noble et al. [65], which included a larger and more heterogeneous cohort of patients treated with TCZ in combination with other immunomodulatory agents, did not show significant changes in either histological lesions or functional parameters after one year of therapy. This discrepancy may be attributable to more advanced chronic injury at baseline, differences in treatment timing and duration, and the absence of standardized immunological monitoring protocols. Importantly, heterogeneity in treatment duration – ranging from a few months to three years –, timing of TCZ administration (first-line vs rescue therapy), and baseline histopathological severity likely influenced clinical and immunological outcomes. Furthermore, the use of TCZ as monotherapy versus combination therapy represents an additional source of variability. While some studies suggested promising effects of TCZ monotherapy in mitigating microvascular inflammation, most cohorts received combination regimens, making it challenging to isolate the specific contribution of IL-6 blockade.

The timing of intervention and extent of baseline histological injury also appear to modulate therapeutic response. In acute AMR, early initiation of TCZ (Potteboun et al.) was associated with stabilization of graft function and significant reductions in DSA levels, suggesting a beneficial effect on ongoing alloimmune injury. In contrast, in ca-AMR, TCZ consistently reduced microvascular inflammation and C4d deposition but exhibited limited effects on chronic injury parameters such as IFTA, transplant glomerulopathy, and intimal arteritis, particularly in patients with advanced structural damage at baseline (e.g., Noble et al.). These findings support the hypothesis that IL-6 blockade may exert its maximal therapeutic effect when introduced in earlier phases of the disease, before the establishment of irreversible chronic allograft injury.

Additional mechanistic insights were provided by Khairallah et al. [66] and Boonpheng et al. [67], who explored eGFR slope dynamics and donor-derived cell-free DNA (dd-cfDNA), respectively, as surrogate markers of graft injury and immunological activity. Khairallah et al. observed a significant deceleration in the rate of eGFR decline following TCZ initiation, even in the absence of significant DSA changes, suggesting an anti-inflammatory effect independent of antibody clearance. Boonpheng et al. demonstrated both dd-cfDNA and DSA reductions over 12 months, indicating a dual anti-inflammatory and immunomodulatory mechanism of IL-6 blockade. Importantly, the therapeutic benefit of TCZ appeared more pronounced in early or moderate ca-AMR, whereas its impact in advanced stages with extensive fibrosis and glomerulopathy remained limited.

By targeting IL-6 signaling, TCZ can reduce DSA levels, suppress their production, and mitigate histological damage in both the short and long term.

Given the lack of standardized treatment algorithms for AMR, accumulating evidence supports a potential role for TCZ as an adjunctive therapy, particularly in patients with inadequate responses to SC. By targeting the IL-6 signaling pathway, TCZ has the capacity to modulate both humoral and inflammatory components of the alloimmune response, reduce DSA production, and attenuate histological injury in both the short and long term.

Within this therapeutic landscape, Belatacept, a fusion protein that selectively inhibits CD28-mediated T-cell co-stimulation, may represent a synergistic partner for TCZ. Its calcineurin inhibitor-sparing properties and capacity to suppress T-cell activation make it an attractive strategy for high-immunological-risk recipients. Data from randomized phase 3 trials (BENEFIT and BENEFIT-EXT) have shown reduced DSA production with Belatacept, supporting the rationale for dual targeting of both T- and B-cell compartments to achieve more effective immunological control, reduce microvascular inflammation, and prevent DSA rebound [68, 69]. Consequently, the combination of TCZ and Belatacept represents a promising and biologically rational therapeutic approach that warrants further evaluation in prospective clinical trials, particularly in patients with high immunological risk or resistance to conventional therapies.

Alternatives in IL-6 pathway inhibition – Clazakizumab

Clazakizumab is a humanized monoclonal IgG1 antibody that bind with high affinity and neutralizes human IL-6. In 2016 it was used to treat 10 patients with chronic AMR. Findings from this study demonstrating a stabilization of eGFR after initiation of clazakizumab therapy (eGFR −24 months [52], 0 month [38], +12 months [41], and +24 months [38]), reductions in DSA levels and Banff scores for C4d and g + ptc scores. The authors noted a trend to reductions in total IgG levels and an increase in Treg cells at 24 months post treatment [30].

In a randomized, double-blind, placebo-controlled, parallel-group phase II pilot trial conducted and published in 2021, that included 20 KT patients with DSA-positive AMR after a median of 10.6 years post-transplantation. KT patients were randomly assigned to receive Clazakizumab or a placebo to assess safety, tolerability, and efficacy of the molecule. Within 12 weeks of therapy DSA MFI decreased by 77%, without significant differences in AMR and T-cell–mediated rejection between the two groups. The key results of the secondary endpoint analysis were a slowed decline in eGFR and, after extended treatment, modulation of rejection-associated gene expression patterns, reduction of C4d scores, and, in some patients, resolution of AMR activity. These results were promising [31].

In addition to TCZ, Clazakizumab has been investigated in early-phase studies involving 20 HS kidney transplant candidates.  Clazakizumab desensitization protocols, after PLEX + IVIg, appear safe with significant reductions in HLA class I and II antibodies. The treatment allowed 18 of 20 patients to receive transplantation with no de novo DSA generation [32].

The data suggest that Clazakizumab can reduce circulating DSA levels and modulate humoral alloimmune responses, potentially facilitating access to transplantation in difficult-to-match patients. Compared with TCZ, Clazakizumab may provide a more complete and sustained blockade of IL-6 signaling, although evidence remains limited and mostly derived from small, non-randomized cohorts. Ongoing randomized trials, including the IMAGINE trial (NCT03744910), will be crucial to clarify the role of IL-6 inhibition in kidney transplantation.

 

Comparative Therapeutic Landscape of AMR: IL-6 Blockade, CD38 Targeting, and Complement Inhibition

Over the past decade, increasing understanding of the complex immunopathology of antibody- AMR has prompted the development of several novel therapeutic strategies beyond conventional ones. So, IL-6 blockade with tocilizumab and Clazakizumab, CD38-targeting monoclonal antibodies, proteasome inhibition, and complement inhibition represent the most promising emerging approaches. Each of these strategies acts on distinct – but potentially complementary – pathogenic pathways of AMR, and their comparison provides important insights into future treatment algorithms.

CD38-targeting monoclonal antibodies, including Daratumumab and Felzartamab, have recently emerged as a promising class of agents with a distinct and potentially more rapid mechanism of action. CD38 is highly expressed on plasma cells and NK cells, two key effector populations in AMR pathogenesis. By targeting CD38, these agents deplete both DSA-producing plasma cells and Fc receptor–expressing NK cells, thus intervening at multiple levels of the alloimmune cascade. Felzartamab, evaluated in a randomized, placebo-controlled phase 2 trial in late AMR, demonstrated histologic resolution of AMR activity in over 80% of patients after six months of therapy, with a marked reduction in MVI scores and AMR transcriptomic activity, along with significant depletion of circulating NK cells. These effects occurred despite minimal changes in immunodominant DSA levels, supporting the hypothesis that targeting effector mechanisms downstream of DSA may be sufficient to attenuate graft injury. Importantly, dd-cfDNA levels – a biomarker of active allograft injury – declined rapidly during treatment, although recurrence of molecular and histologic activity was observed after therapy cessation, indicating that prolonged or combination regimens may be required [70].

Daratumumab, an anti-CD38 antibody with a well-established safety profile in hematology, has been used off-label in several case reports and small series involving both early and late AMR. These studies consistently showed reduction in DSA mean fluorescence intensity, NK cell depletion, attenuation of MVI, and stabilization or improvement of graft function. In some cases, significant dd-cfDNA reduction paralleled these effects, further supporting its immunomodulatory potential [71–74].

Notably, sequential or combination strategies, such as Daratumumab followed by TCZ, have been associated with enhanced and more sustained immunologic responses, suggesting a synergistic effect between plasma cell depletion and IL-6 blockade [75].

Similarly, complement inhibition, particularly with anti-C5 (eculizumab), has shown promise in acute AMR by attenuating complement-mediated endothelial injury and reducing C4d deposition, but its effect on long-term graft survival remains uncertain, and its use is currently limited to selected high-risk cases or rescue therapy [25].

Taken together, these findings underscore the heterogeneity and complementarity of available immunomodulatory strategies. While IL-6 blockade primarily targets upstream inflammatory and B cell–mediated pathways, CD38-targeting antibodies intervene at both the level of antibody production and effector mechanisms, resulting in rapid attenuation of rejection activity even in late stages. Proteasome and complement inhibition offer additional therapeutic angles, targeting upstream plasma cell survival and downstream complement-mediated injury, respectively. In this context, rational combinatorial or sequential approaches may offer the most effective strategy for patients with refractory or advanced AMR. Ongoing phase 3 trials with Felzartamab (TRANSCEND) and Daratumumab (DARTABMR)-based regimens are expected to define their position in the therapeutic armamentarium, and their potential integration with IL-6 blockade or other targeted therapies may further improve allograft outcomes in high immunological risk populations.

 

Conclusions

The current evidence on the use of TCZ for the treatment of AMR and for desensitization in HS kidney transplant candidates is promising but remains limited. Most available studies are retrospective, include small patient cohorts, and lack randomized controlled trials (RCTs), which hinders the ability to draw definitive conclusions regarding the efficacy of TCZ either as monotherapy or in combination with standard therapies. Larger, prospective, randomized studies are needed to better define the role of TCZ in these contexts and to optimize treatment protocols. TCZ has shown encouraging results in attenuating microvascular inflammation, stabilizing graft function, and reducing DSA levels, particularly when used as rescue therapy in patients with AMR refractory to SC. Its continuation after transplantation in patients undergoing desensitization may be justified, as it could help prevent DSA rebound and reduce the risk of post-transplant humoral rejection, especially in highly sensitized recipients. These findings suggest that TCZ could be strategically positioned as both an adjunctive therapy and a maintenance option in selected high-risk patients.

In summary, IL-6 pathway inhibition represents a promising and biologically targeted strategy in the management of AMR and desensitization in kidney transplantation. However, further high-quality studies are required to determine the optimal timing, duration, and combination strategies for IL-6 blockade.

 

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Dalla congestione alla protezione cardiorenale: il nuovo equilibrio terapeutico tra SGLT2-inibitori e diuretici dell’ansa nello scompenso cardiaco

Pubblicato il Scarica PDF

Massimino Senatore

DOI: 10.69097/42-06-2025-09

Massimino Senatore1, Maria Chiara Biancu1, Emanuela D’Anello2, Giovanna Pisanu1, Sandro Grussu1, Donatella Finetti1, Michele Provenzano3

Sono stati utilizzati strumenti di intelligenza artificiale a supporto della revisione linguistica e della traduzione, ma i contenuti sono originali e interamente elaborati dagli autori. Nessun apporto dell’IA è stato introdotto senza supervisione umana.

1 S.C. Nefrologia e Dialisi, ASL n.1 Sassari, Italia
2 Emodialisi Amantea, ASP Cosenza, Italia
3 UOC Nefrologia, Dialisi e Trapianto, Università della Calabria, Ospedale “S. Annunziata”, Cosenza, Italia

Corrispondenza a:
Dr. Massimino Senatore
S.C. Nefrologia e Dialisi – ASL n.1 Sassari
Ospedale Civile di Alghero
Via Don Minzoni snc
07041 Alghero (SS)
E-mail: massimino.senatore@aslsassari.it
Tel. 334.3085358

 

Abstract

Gli inibitori del cotrasportatore sodio-glucosio di tipo 2 (SGLT2i) hanno introdotto un nuovo paradigma nella gestione dello scompenso cardiaco (HF), sia con frazione di eiezione ridotta (HFrEF) che preservata (HFpEF). Tradizionalmente, il trattamento si è basato sull’uso di diuretici per il controllo della congestione, con limitato impatto prognostico e rischio di effetti collaterali dose-dipendenti. Gli SGLT2i, inizialmente sviluppati per il diabete mellito tipo 2, hanno dimostrato in trial randomizzati di ridurre ospedalizzazioni e mortalità cardiovascolare, con benefici estesi anche ai pazienti non diabetici.
Il loro meccanismo d’azione combina natriuresi osmotica moderata, riduzione selettiva del volume extracellulare, protezione renale e modulazione neuro-ormonale minima. Rispetto ai diuretici dell’ansa, che inducono un rapido calo volemico e attivazione del RAAS, gli SGLT2i stabilizzano il bilancio idrosalino senza compromissione emodinamica significativa. Nella pratica clinica, la combinazione con diuretici richiede attenta titolazione per prevenire ipovolemia, ipotensione e disfunzione renale, soprattutto negli anziani fragili.
Le evidenze suggeriscono che gli SGLT2i possano ridurre il fabbisogno diuretico cronico, migliorare la funzione renale e offrire protezione cardiovascolare aggiuntiva. Questi dati supportano il loro impiego precoce e integrato, posizionandoli come pilastro nella strategia terapeutica dello scompenso cardiaco contemporaneo.

Parole chiave: SGLT2-inibitori, diuretici, scompenso cardiaco, protezione cardiorenale, natriuresi osmotica, terapia combinata

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

For many years, the management of patients with heart failure with preserved ejection fraction (HFpEF) was based on symptomatic approaches, primarily focused on reducing congestion and controlling comorbidities, in the absence of pharmacological options able to significantly modify prognosis. Guidelines recommended empirical treatments (diuretics, beta-blockers, RAAS antagonists), but with limited or inconclusive evidence in patients with HFpEF or mildly reduced ejection fraction (HFmrEF) [1].

The paradigm shifted with the introduction of sodium-glucose cotransporter-2 inhibitors (SGLT2i), particularly dapagliflozin and empagliflozin, which have demonstrated significant benefits in this population, regardless of diabetes status (Table 1). Randomized controlled trials such as EMPEROR-Preserved and DELIVER documented a reduction in the composite risk of heart failure hospitalizations and cardiovascular mortality, in addition to improvements in quality of life, functional status (assessed by KCCQ), and slowing of renal function decline [2].

In the DAPA-HF trial (n = 4744), dapagliflozin significantly reduced the risk of the composite endpoint of cardiovascular death or worsening HF compared with placebo (HR 0.74; 95% CI 0.65–0.85), with benefits consistent in patients with and without type 2 diabetes [3, 4]. Similarly, the EMPEROR-Reduced trial (n = 3730) demonstrated that empagliflozin reduced the primary composite outcome of CV death or HF hospitalization (HR 0.75; 95% CI 0.65–0.86), with additional slowing of the decline in renal function [5].

Beyond chronic HFrEF, evidence also extends to patients with recent acute decompensation. The SOLOIST-WHF trial (n = 1222) evaluated sotagliflozin, a dual SGLT1/2 inhibitor, in patients with type 2 diabetes and recent worsening HF requiring hospitalization or intravenous therapy. Sotagliflozin significantly reduced the risk of the composite of total CV deaths, hospitalizations, and urgent visits for HF (HR 0.67; 95% CI 0.52–0.85), with consistent benefits across EF categories [6].

Despite these favorable clinical results, the pathophysiological mechanisms through which SGLT2i exert their effects remain under investigation. Leading hypotheses include:
• moderate and selective reduction of intravascular volume via osmotic natriuresis without significant neurohormonal activation;
• improvement in ventricular filling pressures and reduction of pulmonary congestion;
• attenuation of glomerular hyperfiltration, resulting in renal protection;
• stimulation of erythropoiesis mediated by increased erythropoietin and improved tissue oxygenation;
• activation of metabolic pathways mimicking a state of energy restriction, with increased ketone body production and improved mitochondrial efficiency [2, 7].

A surrogate marker frequently observed in clinical trials is the increase in hematocrit and hemoglobin concentration, reflecting both selective diuretic effect (with hemoconcentration) and stimulation of renal erythropoiesis. Post hoc analyses from the EMPA-REG OUTCOME trial suggested that the increase in hematocrit may represent one of the main mediators of empagliflozin’s effect on reducing cardiovascular risk [8, 9].

The combination of SGLT2i with conventional diuretics (e.g., furosemide) is common in clinical practice, particularly in patients with more congestive phenotypes. However, such an association requires careful volume status assessment, as natriuretic effects may be additive, increasing the risk of dehydration, hypotension, and renal function deterioration, especially in elderly and frail patients. In such cases, a re-evaluation of diuretic dosing may be necessary when initiating SGLT2i therapy.

Overall, SGLT2i are redefining the role of diuretics in heart failure, shifting the therapeutic target from mere fluid removal to optimization of hemodynamic, metabolic, and renal balance. Their early and systematic use, even in patients without hyperglycemia, is now a cornerstone strategy for the integrated management of chronic heart failure across the entire spectrum of ejection fraction.

Trial N. of patients Population Mean eGFR (ml/min/1.73m²) % with eGFR >60 Main Outcome
DAPA-HF (2019) 4744 HFrEF (LVEF ≤40%), con/senza T2D ~66 ~70% ↓ CV death/HHF
EMPEROR-Reduced (2020) 3730 HFrEF (LVEF ≤40%), con/senza T2D ~62 ~63% ↓ CV death/HHF; ↓ eGFR decline
EMPEROR-Preserved (2021) 5988 HFpEF/HFmrEF (LVEF >40%) ~61 ~60% ↓ HHF; benefit independent of diabetes
DELIVER (2022) 6263 HFpEF/HFmrEF (LVEF >40%) ~61 ~65% ↓ HHF/CV death
SOLOIST-WHF (2021) 1222 Recent WHF hospitalization, T2D only ~58 ~55% ↓ CV death/HHF/urgent visits
Table 1. Key randomized trials of SGLT2 inhibitors in heart failure.

 

Loop diuretics: essential drugs but with a clinical cost

Loop diuretics, such as furosemide, torasemide, and bumetanide, remain an irreplaceable cornerstone in the treatment of heart failure with signs of volume overload. They act by blocking the sodium-potassium-chloride cotransporter (NKCC2) in the thick ascending limb of the loop of Henle, inducing powerful natriuresis and consequently reducing ventricular filling pressures and both systemic and pulmonary congestion [10].

However, chronic use is associated with several clinical drawbacks. Massive inhibition of sodium reabsorption stimulates marked neurohormonal activation, increasing renin, angiotensin II, aldosterone, norepinephrine, and vasopressin levels. Over time, this can offset the therapeutic effect, leading to diuretic resistance and worsening clinical outcomes [11, 12] (Table 2). In addition, loop diuretics can cause hypovolemia, hypotension, acute kidney injury, and electrolyte disturbances (hypokalemia, hypomagnesemia, hyponatremia), thereby increasing the risk of arrhythmias and mortality [13].

For these reasons, international guidelines recommend using the lowest effective dose to achieve symptomatic control of congestion, avoiding chronic and unnecessary escalation [1]. The clinical goal is not complete elimination of edema, but achieving a functional and tolerable balance for the patient.

In this context, SGLT2i are emerging as physiological modulators of sodium-water balance. Unlike loop diuretics, they act upstream in the proximal tubule, promoting a milder and more sustained osmotic natriuresis without significant neurohormonal activation [2]. This “gentler” but continuous mechanism enables therapeutic synergy with loop diuretics and, in some cases, allows for a reduction in loop diuretic dose.

In the DAPA-HF and EMPEROR-Preserved trials, the addition of SGLT2i avoided the need for diuretic dose escalation in clinically stable patients and, in selected subgroups, even allowed for a dose reduction over time [2, 6]. Furthermore, despite additive natriuretic effects, the incidence of adverse events related to volume depletion, such as symptomatic hypotension, renal dysfunction, and dehydration, was lower in SGLT2i-treated groups than in placebo [14].

This “diuretic-sparing effect,” combined with greater hemodynamic stability, gives SGLT2i a unique therapeutic profile, justifying their early and integrated use in heart failure management, particularly in patients at risk of iatrogenic complications from conventional diuretics.

Class Main Site of Action RAAS/Sympathetic Activation Typical Side Effects Clinical Notes
Loop Diuretics
(furosemide, torasemide, bumetanide)		 NKCC2 in the thick ascending limb of the loop of Henle Marked neurohormonal activation (↑ RAAS, ↑ SNS) Hypovolemia, hypotension, AKI, hypokalemia, hypomagnesemia, hyponatremia, arrhythmias Powerful; essential in acute congestion. Chronic high-dose use may lead to resistance
Thiazides
(hydrochlorothiazide, metolazone, chlorthalidone)		 NCC in the distal convoluted tubule Moderate RAAS activation Hyponatremia, hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia Effective for hypertension; less potent in severe congestion; often used in combination therapy
Mineralocorticoid Receptor Antagonists (MRAs)
(spironolattone, eplerenone)		 Mineralocorticoid receptor in the collecting duct Inhibit aldosterone-mediated activation Hyperkalemia, gynecomastia (spironolactone) Prognostic benefit in HFrEF; use with caution in CKD
SGLT2i
(dapagliflozin, empagliflozin, ecc.)		 SGLT2 (+NHE3) in the proximal tubule Minimal or no neurohormonal activation Genital mycotic infections, rare euglycemic ketoacidosis, mild initial “dip” in eGFR Moderate, gentle, and self-limiting osmotic natriuresis; reduce HHF and CKD progression even in non-diabetics
Table 2. Comparative table: site of action, neurohormonal activation and adverse effects of diuretics vs SGLT2i.

 

Pharmacological differences: diuretics vs SGLT2i

Diuretics are a heterogeneous class of drugs with marked differences in pharmacodynamic and pharmacokinetic profiles. Loop diuretics, such as furosemide, torasemide, and bumetanide, act on the sodium-potassium-chloride cotransporter (NKCC2) in the thick ascending limb of the loop of Henle, inducing potent natriuresis. They display a steep dose-response curve with a well-defined ceiling effect: beyond a certain threshold, further dose increases do not enhance efficacy but only increase toxicity [15].

Thiazide diuretics, which act on the sodium-chloride cotransporter (NCC) in the distal convoluted tubule, have a flatter dose-response curve, implying a smaller gap between the minimum effective dose and the maximum dose [16]. This makes them potentially more predictable in blood pressure management, but less effective in treating severe congestion.

An additional critical aspect of loop diuretics is the variability in oral bioavailability. Furosemide, in particular, exhibits highly variable bioavailability (10–100%) due to differences in intestinal absorption, food interactions, and saturation of active tubular transport [17]. Conversely, torasemide and bumetanide have higher and more consistent bioavailability (>80%), making them preferable in certain clinical settings, especially in patients with impaired gastrointestinal absorption.

Individual response to diuretics is further influenced by genetic and biological factors. Polymorphisms in genes encoding tubular transporters, hepatic metabolism, and active renal transport can significantly affect efficacy and tolerance. Biological sex has also been associated with pharmacokinetic differences, likely due to hormonal influences, lean body mass, and hepatic and renal function [18 –20].

In contrast, SGLT2i display more stable and predictable pharmacokinetic profiles (Table 3). Drugs such as dapagliflozin, empagliflozin, and ertugliflozin have high oral bioavailability (78–90%), long half-lives (10–13 hours), hepatic metabolism (via UGT1A9 or CYP3A4, depending on the compound), and minimal urinary excretion of the active drug, with low risk of accumulation or direct renal toxicity [21]. These features allow fixed once-daily dosing, regardless of meals, with minimal interindividual variation and low potential for drug-drug interactions.

Beyond the initial natriuretic effect, SGLT2i induce a sustained reduction in body weight over time, initially due to extracellular fluid loss and subsequently attributable to selective reduction in visceral fat mass. This is mediated by metabolic changes such as increased lipolysis, ketogenesis, and improved insulin sensitivity [7, 22].

These differences make SGLT2i particularly suited for long-term management of patients with heart failure or type 2 diabetes, with fewer pharmacokinetic fluctuations, lower risk of electrolyte disturbances, and greater hemodynamic stability compared to conventional diuretics.

Molecole (Italy) Dose in major CV/renal trials SGLT2:SGLT1 selectivity (≈) Outcome evidence (summary) Dosing by eGFR and minimum threshold (EU SmPC) Indications
Dapagliflozin 10 mg qd (DAPA-HF, DELIVER, DAPA-CKD) ≈1200:1 ↓ CV death/HF hospitalization in HFrEF/HFpEF; ↓ CKD progression and all-cause mortality, with or without diabetes Single 10 mg dose; do not initiate if eGFR <25 mL/min; reduced hypoglycemic effect <45 Also for non-diabetic patients (HF, CKD, T2D)
Empagliflozin 10 mg qd (EMPEROR-Reduced/Preserved, EMPA-KIDNEY) ≈2700:1 ↓ HF hospitalization and CV mortality in HF; ↓ CKD progression 10 mg qd; initiation not recommended if eGFR <20 mL/min; reduced hypoglycemic effect <45 Also for non-diabetic patients (HF, CKD, T2D)
Canagliflozin 100 mg qd (CREDENCE); 100–300 mg qd (CANVAS) ≈160–200:1 ↓ composite renal and CV events in DKD (T2D); ↓ MACE (CANVAS) 100 mg qd; initiation not recommended if eGFR <30 mL/min; indicated only for DKD with T2D Diabetic patients only (T2D ± DKD)
Ertugliflozin 5–15 mg qd (VERTIS-CV) ≈2000:1 Non-inferior for MACE in T2D; signal for ↓ HF hospitalization (post hoc); no HF/CKD indication Initiation not recommended if eGFR <60; discontinue if <45; contraindicated <30 Diabetic patients only (T2D)
Table 3. Pharmacological differences: SGLT2 inhibitors available in Italy.

 

Renal adaptations to SGLT2i and clinical significance: modulation of sodium balance and hemodynamic impact

The human kidney filters the entire plasma volume approximately 30–40 times daily, producing over 170 liters of ultrafiltrate per day. About 99% of this is reabsorbed along the nephron. The proximal tubule, responsible for reabsorbing 60–70% of filtered water and sodium, represents a key physiological hub for fluid-electrolyte balance and is the primary site of SGLT2i action [23, 24].

Initially developed for type 2 diabetes mellitus, SGLT2i exert their natriuretic effects through dual inhibition of the sodium-glucose cotransporter SGLT2 and the sodium-hydrogen exchanger NHE3, both located in the S1-S2 segment of the proximal tubule [23, 25]. This dual mechanism reduces reabsorption of sodium, glucose, and water, producing an osmotic effect that increases diuresis and natriuresis, leading to modest reductions in plasma volume and blood pressure [26].

However, despite blocking up to 20-25% of proximal sodium reabsorption, the clinical impact on volume status is modest and self-limiting. This is attributable to the distal nephron’s substantial capacity – particularly the thick ascending limb of the loop of Henle, distal tubule, and collecting duct – to activate compensatory sodium and water reabsorption mechanisms [27]. These adaptations occur rapidly, effectively preventing marked hypovolemia or dehydration while preserving renal perfusion.

From a hemodynamic perspective, SGLT2i reduce intraglomerular pressure through restoration of tubuloglomerular feedback: increased sodium delivery to the macula densa triggers afferent arteriolar vasoconstriction, thereby reducing glomerular hyperfiltration – a key pathogenic mechanism in diabetic and non-diabetic nephropathies [28, 29]. This effect is entirely distinct from conventional diuretics, such as thiazides or loop diuretics, which produce more marked plasma volume reductions, often associated with symptomatic hypotension, acute kidney injury, RAAS activation, and electrolyte disturbances (hypokalemia, hyponatremia) [10].

Moreover, unlike traditional diuretics, the natriuretic effect of SGLT2i diminishes over time, stabilizing at a new physiological set point without chronic sodium or volume loss. This “plateau” aligns with their safety profile, even in elderly or frail patients, and contributes to their excellent tolerability [30].

Overall, SGLT2i provide a modulated and self-regulating diuretic and natriuretic action compatible with renal and systemic hemodynamic protection. This unique pharmacodynamic profile supports their use not only in diabetic patients but also in those with heart failure or chronic kidney disease, regardless of glycemic status, as confirmed by recent clinical trials (EMPA-REG OUTCOME, DAPA-HF, EMPEROR-Reduced, CREDENCE, DAPA-CKD) [26–30].

 

Renal function and therapeutic use

Renal function deterioration is one of the main negative prognostic factors in patients with heart failure and is associated with increased risk of mortality, hospitalizations, and functional decline [35]. This condition, known as cardiorenal syndrome, is often exacerbated by chronic, high-dose use of loop diuretics which – although essential for congestion control – can induce renal hypoperfusion, neurohormonal activation, and electrolyte imbalances, further compromising glomerular function [35, 37].

Numerous observational studies and clinical trials have shown a direct correlation between the intensity of diuretic therapy and adverse outcomes, suggesting that diuretics are more a marker of disease severity than a causal determinant, but nonetheless emphasizing the importance of titrating to the lowest effective dose. ESC and ACC/AHA/HFSA guidelines recommend periodic reassessment of diuretic therapy and progressive dose reduction in the setting of clinical stabilization and absence of residual congestion [1, 39].

Unlike conventional diuretics, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown a favorable impact on the course of kidney disease and hemodynamic stability, even in patients with advanced renal impairment. Although their action occurs in the proximal tubule, the mechanism is not strictly dependent on glomerular filtration rate (GFR), and clinical efficacy is preserved even at reduced eGFR levels, although the glucose-lowering effect progressively diminishes [41].

Multiple clinical trials (CREDENCE, DAPA-CKD, EMPA-KIDNEY) have demonstrated that SGLT2i significantly slow the progression of chronic kidney disease, reduce the need for dialysis, and lower hospitalization and mortality from cardiovascular and renal causes, with benefits evident even at eGFR values below 30 mL/min/1.73m² [48]. Recent evidence, including the EMPA-KIDNEY trial, supports safe use of SGLT2i down to an eGFR of 20 mL/min/1.73 m², extending therapeutic indications to patients in the pre-dialysis stage [33, 34].

Furthermore, the initial decline in eGFR observed after SGLT2i initiation represents a predictable hemodynamic response, attributable to the reduction in intraglomerular pressure and restoration of tubuloglomerular feedback. This phenomenon, known as the “transient dip,” stabilizes within weeks and does not predict progressive kidney injury; in fact, it is associated with a slower decline in renal function over the long term [34].

Beyond the expected and generally benign “transient dip,” dedicated analyses suggest that an initial eGFR decline >30% may be associated with worsening renal function in vulnerable subgroups. In the supplementary analyses of EMPEROR-Reduced, a >30% dipping was correlated with adverse renal outcomes, highlighting the importance of identifying and monitoring at-risk patients [51]. In EMPA-REG OUTCOME, baseline diuretic use and higher KDIGO risk were predictive of eGFR dip after SGLT2i initiation, although without attenuating the cardio-renal benefits of treatment [52]. In real-world cohorts, loop diuretics were associated with both a more pronounced dipping and worse composite renal outcomes during SGLT2i therapy, whereas RAAS inhibitors retained a favorable association with long-term outcomes [53]. A large-scale analysis further showed that the presence of dipping does not negate the clinical benefits of SGLT2i, but underscores the need to contextualize this phenomenon within the overall frailty profile of each patient [54].
In clinical practice, particularly in frail elderly patients receiving polypharmacy (especially those on loop diuretics), it is prudent to: (i) re-evaluate the overall loop diuretic dose at SGLT2i initiation; (ii) optimize hydration and reassess potentially nephrotoxic or volume-depleting medications; (iii) recheck serum creatinine/eGFR approximately 30 days after initiation (or earlier in the presence of symptoms or hypotension) and subsequently as clinically indicated; (iv) consider loop diuretic down-titration if signs of volume depletion or significant dipping occur. This approach helps balance, in the context of cardiorenal syndrome, the cardiac and renal prognostic axes, prioritizing the net clinical benefit of treatment rather than optimization of a single domain.

Taken together, these findings position SGLT2i as first-line cardiorenal protective agents in the integrated management of heart failure and chronic kidney disease, including patients with reduced renal function, in whom traditional diuretics may be more unstable and potentially iatrogenic.

 

Therapeutic implications in the elderly and in clinical practice

In clinical practice, managing diuretic therapy in frail elderly patients or those with multimorbidity requires particular caution. Chronic, non-individualized use of diuretics is frequently associated with adverse events such as fatigue, reduced exercise tolerance, orthostatic hypotension, and acute kidney injury, especially in individuals with impaired physiological reserve and altered extracellular volume homeostasis [36, 50].

These effects are worsened by common prescribing errors, such as the use of diuretics for peripheral edema secondary to calcium channel blocker therapy (e.g., amlodipine), or for fluid retention induced by neuroactive drugs such as gabapentinoids or antipsychotics. When such interventions are not based on an adequate etiopathogenetic evaluation, they constitute typical examples of a prescribing cascade, i.e., a drug prescribed to treat the adverse effects of another medication without addressing the underlying cause [36, 37]. These situations not only expose patients to further side effects but also compromise quality of life and functional independence.

The introduction of SGLT2i into the treatment of heart failure and chronic kidney disease has significantly modified the therapeutic approach in elderly patients. While they exert a mild but physiological natriuretic and diuretic effect, SGLT2i can interact additively with conventional diuretics, increasing the risk of dehydration, hypotension, electrolyte imbalance, and renal function deterioration, particularly in frail and hypovolemic individuals [2, 34].

For this reason, combined use of SGLT2i and diuretics requires careful clinical and laboratory monitoring, with possible diuretic dose reduction when starting SGLT2i, especially in the presence of concomitant hypotension or renal function decline.

Despite their generally favorable safety profile, SGLT2i are not without risks. Known adverse effects include an increased risk of genital and urinary tract infections, mainly mycotic, particularly in women, and rare cases of euglycemic ketoacidosis, often associated with metabolic stress (e.g., prolonged fasting, infections, surgery) [36, 37]. Some observational studies and meta-analyses have also suggested a possible increased risk of digital amputations (particularly with canagliflozin) [55] and bone fractures, although these data remain debated and not uniformly confirmed [56].

An additional contribution comes from the EMPA-ELDERLY trial [57], a randomized, double-blind, placebo-controlled study conducted in Japan in patients aged ≥ 65 years with type 2 diabetes, with a follow-up of 52 weeks, designed to assess the efficacy and safety of empagliflozin 10 mg in an elderly population. The trial showed that empagliflozin, compared with placebo, reduced HbA₁c (–0.57%, 95% CI –0.78; –0.36) and body weight (–2.37 kg, 95% CI –3.07; –1.68) without significant loss of muscle mass or handgrip strength. No ketoacidosis or severe volume-depletion events occurred, even in participants ≥ 75 years. Although UTIs were not reported as a leading adverse event, “drug-related adverse events” were more frequent with empagliflozin (24.6% vs 9.4%), underscoring the need for careful monitoring of frail older patients, particularly those predisposed to UTIs.

Therefore, the use of SGLT2i in the geriatric population should be considered within a personalized approach, integrated into a deprescribing model and periodic medication review, aimed at reducing inappropriate polypharmacy and optimizing the risk-benefit profile.

 

Heart failure and innovative drugs with diuretic effect

A further consideration concerns the role of angiotensin receptor-neprilysin inhibitors (ARNI), particularly sacubitril/valsartan, in the management of heart failure. Beyond their established prognostic benefits, ARNI exert indirect diuretic and natriuretic effects through augmentation of endogenous natriuretic peptides, which promote vasodilation, natriuresis, and inhibition of maladaptive neurohormonal activation [58, 59]. In clinical practice, these effects can contribute to a reduction in loop diuretic requirements, potentially mitigating diuretic-related adverse events in frail or multimorbid patients [60]. Nevertheless, careful monitoring remains essential, as the concomitant use of ARNI and conventional diuretics may still predispose to hypotension, electrolyte disturbances, and renal dysfunction, especially in the elderly population.

 

Conclusions

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) represent a major breakthrough in the management of heart failure, both with reduced (HFrEF) and preserved (HFpEF) ejection fraction, due to their multifactorial and integrated mechanism of action. In addition to improving clinical symptoms, these agents are associated with significant reductions in cardiovascular mortality, heart failure hospitalizations, and progression of kidney disease, with benefits extending to non-diabetic patients [2].

Unlike conventional diuretics, which act rapidly but forcefully on sodium-water balance, SGLT2i provide a modulated, physiological diuretic action mediated by osmotic natriuresis in the proximal tubule. This mechanism allows selective reduction of extracellular volume while preserving intravascular volume and maintaining renal perfusion, without activating the renin-angiotensin-aldosterone system (RAAS) or the sympathetic nervous system [2, 39, 61].

This approach translates into superior hemodynamic and renal protection, with lower incidence of adverse events such as dehydration, orthostatic hypotension, and renal function deterioration compared to loop diuretics, particularly in elderly and frail patients [17, 62]. In addition, favorable effects on hematocrit and endothelial function suggest potential benefits on microcirculation and tissue oxygenation [5].

SGLT2i should therefore not be regarded as mere “add-on diuretics” but rather as modulators of volume set-point and cardiovascular homeostasis, capable of targeting deep pathophysiological mechanisms such as glomerular hyperfiltration, low-grade chronic inflammation, mitochondrial dysfunction, and insulin resistance [7–63].

Given the accumulated evidence, early placement of SGLT2i in the integrated therapeutic strategy for heart failure is now recommended by international guidelines, regardless of ejection fraction or diabetes status, making them one of the most revolutionary drug classes in contemporary cardiology and nephrology [1].

 

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  44. Heerspink HJL, Cherney DZI, et al. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation, 2016 Sep 6;34(10):752-772. https://doi.org/10.1161/CIRCULATIONAHA.116.021887.
  45. Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892–1903. https://doi.org/10.1056/NEJMoa1303154.
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La dialisi a bassa temperatura: esiste ancora un razionale? Sintesi delle evidenze dell’ultimo decennio

Pubblicato il Scarica PDF

Lorenzo D'Elia

DOI: 10.69097/42-06-2025-08

Lorenzo D’Elia1, Deborah Di Vico1, Isabella Marucci1, Giovanni Otranto1, Paola Peverini2, Flavia Sessa1, Annalisa Villani1, Vincenzo Barbera1

1. UOC Nefrologia e Dialisi Ospedale “Leopoldo Parodi Delfino” Asl Roma 5 Colleferro (RM)
2. UOCA Nefrologia e Dialisi, Nuovo Ospedale dei Castelli Asl Roma 6 Ariccia (RM)

Corrispondenza a:
Lorenzo D’Elia
UOC Nefrologia e Dialisi Ospedale “Leopoldo Parodi Delfino”
Piazza Aldo Moro 1 00034 Colleferro (RM)
Tel.: 06.97223225
E-mail: lorenzo.delia@aslroma5.it

 

Abstract

Il trattamento emodialitico con dialisato a basse temperature (< 36 °C) rappresenta una strategia efficace nella prevenzione dell’ipotensione intradialitica e, più in generale, nel miglioramento della stabilità emodinamica del paziente. Ulteriori benefici di questo approccio possono interessare anche altri sistemi, tra cui quello cardiovascolare e il sistema nervoso centrale. Accanto a tali effetti favorevoli, sono stati tuttavia riportati alcuni svantaggi, come l’accentuato discomfort percepito dal paziente, mentre i dati riguardanti l’efficienza depurativa appaiono ancora contrastanti. Alla luce di queste considerazioni, e attraverso l’analisi dei principali studi pubblicati su PubMed® nell’ultimo decennio, proponiamo una valutazione complessiva ed esaustiva della cosiddetta “cool dialysis”.

Parole chiave: dialisi a bassa temperatura, dialisato raffreddato, stabilità emodinamica

Introduzione

L’emodialisi rappresenta un trattamento salvavita per i pazienti affetti da End-stage Renal Disease (ESRD). Tuttavia, una percentuale variabile tra il 20% e il 40% di tali pazienti muore entro un anno dall’inizio della terapia sostituiva, prevalentemente per cause cardiovascolari [1–3]. Evidenze ottenute mediante tecniche di imaging hanno mostrato come l’emodialisi possa favorire l’insorgenza di danni subclinici a livello cardiaco, cerebrale e di numerosi altri organi vitali principalmente attraverso ripetuti episodi di ipotensione intradialitica seguiti da ischemia distrettuale ricorrente [4, 5].

 

Effetti clinici del trattamento emodialitico

Danno miocardico e myocardial stunning

Oltre all’ipotensione, un ruolo cruciale nelle alterazioni cardiovascolari è svolto dalle risposte adattative che ne conseguono. È stato dimostrato che, durante una seduta standard di emodialisi, la pressione arteriosa può ridursi fino a 20 mmHg, determinando ipoperfusione tissutale – in particolare a livello coronarico – con rilevanti ripercussioni sulla contrattilità miocardica. Questo fenomeno, noto come “myocardial stunning”, è principalmente attribuibile a una riduzione transitoria e significativa del flusso ematico locale, che può raggiungere valori fino al 30% [6, 7]. Il myocardial stunning (o stordimento miocardico) può essere definito come il ritardato recupero della funzione contrattile miocardica dopo un episodio di ischemia-riperfusione, anche in assenza di danni irreversibili a seguito del ripristino del flusso ematico distrettuale [8]. Le cause eziopatogenetiche di questa condizione sono molteplici; tra le più rilevanti si annoverano la deplezione di fosfati ad alta energia, la compromissione microvascolare, le alterazioni delle risposte neurosensoriali, l’aumentata produzione di specie reattive dell’ossigeno (ROS) e le disfunzioni nell’omeostasi del calcio; le alterazioni del magnesio, pur evidenziate, non sembrano correlarsi con questo fenomeno e non si osservano miglioramenti dopo la sua correzione [9, 10]. Lo stordimento miocardico indotto dalla dialisi risulta particolarmente importante essendo associato a un maggior tasso di aritmie ventricolari intra- e postdialitiche con conseguente incremento della mortalità per cause cardiovascolari (morte cardiaca improvvisa e scompenso cardiaco) [11].

Emodialisi e ipoperfusione tissutale

L’ipoperfusione è essenzialmente il risultato di una serie di eventi direttamente associati alla circolazione extracorporea (CEC) e delle risposte adattative messe in atto dall’organismo. Come illustrato nella Figura 1, la riduzione del volume ematico circolante determina, inizialmente, una vasocostrizione periferica, finalizzata a preservare la pressione arteriosa e a mantenere un’adeguata perfusione tissutale. Successivamente si instaura vasodilatazione sistemica, meccanismo di compenso volto a dissipare il calore accumulato durante la procedura. In questo contesto, la modulazione termica della dialisi – la cosiddetta cool dialysis – si propone come strategia in grado di attenuare la risposta vasodilatatoria migliorando la stabilità emodinamica e riducendo il rischio di ipoperfusione tissutale con conseguenti danni d’organo.

Fattori eziopatogenetici dell’ipotensione intradialitica.
Figura 1. Fattori eziopatogenetici dell’ipotensione intradialitica.

L’emodialisi determina importanti cambiamenti emodinamici, il cui effetto più significativo è rappresentato dall’ipotensione intradialitica. Quest’ultima, soprattutto nei pazienti con aumentato rischio di malattia coronarica, costituisce un fattore precipitante lo sviluppo di ischemia miocardica [12]. Tuttavia, lo stunning miocardico può manifestarsi anche in assenza di pregressa coronaropatia, spesso attraverso una genesi multifattoriale complessa.
Diversi studi hanno individuato nell’incremento delle ROS e nell’aumento stato infiammatorio, i principali «trigger» di tali eventi, soprattutto nei pazienti emodializzati, mentre il coinvolgimento risulta meno marcato nei pazienti in trattamento dialitico peritoneale [13].

Cause e meccanismi fisiopatologici di danno miocardico nei pazienti in emodialisi
Figura 2. Cause e meccanismi fisiopatologici di danno miocardico nei pazienti in emodialisi (modificato da [9]).
Effetti sul sistema nervoso centrale

Oltre al coinvolgimento miocardico, il sistema nervoso centrale può risultare interessato, in particolare la corteccia cerebrale [14]. Uno studio condotto da Yu H et al. [15] ha evidenziato come i pazienti con ESRD in trattamento dialitico sottoposti a risonanza magnetica cerebrale presentino una diffusa riduzione dello spessore e del volume corticale rispetto ai controlli, soprattutto in alcune aree cerebrali quali: il giro paracentrale, il giro temporale trasverso e la corteccia occipitale. Inoltre, attraverso il neuroimaging è stato evidenziato l’interessamento di strutture cerebrali profonde come la radiazione talamica anteriore, il fascicolo longitudinale superiore, il tratto spinale corticale, il fascicolo uncinato e il nucleus accumbens soprattutto nei pazienti in trattamento dialitico da lungo tempo. Le alterazioni in queste sedi risultano correlate a deficit cognitivi, valutabili mediante scale specifiche come la Wechsler (Adult) Intelligence Scale (WISC/WAIS) e la Montreal Cognitive Assessment (MoCA) [16, 17]. Anche nel danno cerebrale, l’origine appare multifattoriale, riconducibile all’ipoperfusione d’organo, all’aumento dello stato infiammatorio e alla presenza di endotossine sieriche. In condizioni fisiologiche, il cervello riceve circa il 15-20% della gittata cardiaca e il flusso ematico rimane costante, anche in presenza di notevoli variazioni pressorie, in virtù dei molteplici meccanismi autoregolatori locali. Tali meccanismi sono mediati dall’«unità neurovascolare», espressione dell’interazione tra cellule gliali e vasi sanguigni.

Figura 3. Interazioni presenti nell’unità neurovascolare (modificato da [18]).
Figura 3. Interazioni presenti nell’unità neurovascolare (modificato da [18]).
Tuttavia, nei pazienti sottoposti a trattamento emodialitico, la capacità di regolazione del tono vascolare e, di conseguenza, l’adattamento del flusso ematico cerebrale, risultano compromessi, come evidenziato dallo studio Rotterdam, Sedaghat e coll. [19]. L’utilizzo del dialisato freddo sembrerebbe mitigare il danno ultrastrutturale a livello della corteccia bianca cerebrale. Come riportato da Eldehni [4], la riduzione delle oscillazioni pressorie, conseguente a una maggiore stabilità emodinamica, risulta evidente ed è stata ulteriormente confermata da studi di imaging cerebrale, che hanno documentato un minor grado di danno microvascolare. In tali studi, la valutazione del microcircolo cerebrale è stata condotta impiegando una forma di risonanza magnetica chiamata a tensore di diffusione (RMN-DTI) che ne consente una valutazione più dettagliata [20].

Altri effetti clinici e finalità dello studio

Tra le conseguenze dirette dell’emodialisi si annovera la stanchezza intraprocedurale (fatigue), che si verifica in circa il 70% dei pazienti e che può persistere anche nel periodo post dialitico [21]. Altri effetti rilevanti sono in gran parte correlati allo stato infiammatorio tipico di questa popolazione. Scopo del presente lavoro è quello di analizzare gli studi clinici condotti nel decennio 2015-2025, relativi agli effetti del trattamento emodialitico a bassa temperatura sui principali outcome clinici, quali la stabilità pressoria intradialitica, la disfunzione miocardica e gli effetti sul sistema nervoso centrale (SNC) e proporre uno schema di lavoro finalizzato a stimolare il dibattito sull’adozione personalizzata di questa procedura.

 

Fisiologia della termoregolazione e patogenesi dell’ipertermia dialisi-indotta

Prima di analizzare gli effetti dell’emodialisi a basse temperature, è opportuno richiamare alcune nozioni fondamentali di fisiologia, necessarie alla comprensione dei meccanismi determinanti l’incremento della temperatura corporea interna osservabile durante il trattamento emodialitico.

In condizioni fisiologiche, la temperatura corporea (Tb) è regolata dal SNC entro un intervallo ristretto di circa 3-4 °C rispetto a un valore medio a riposo di circa 36,8 °C [22]. Per tali ragioni, la temperatura corporea interna si mantiene generalmente nel range compreso tra 37 ± 0,5 °C (98,6 ± 0,9 °F), intervallo considerato ottimale per il corretto funzionamento dei processi metabolici e delle funzioni enzimatiche [23]. Il mantenimento di tale omotermia è garantito da complessi meccanismi di regolazione centrali, localizzati prevalentemente a livello ipotalamico, che integrano gli input provenienti dai termocettori periferici e centrali e modulano le risposte efferenti, volti a bilanciare la produzione e la dispersione di calore. Deviazioni anomale della temperatura corporea, anche di soli 2 gradi, possono compromettere i meccanismi termoregolatori, poiché oscillazioni di temperatura al di fuori dell’intervallo fisiologico di omotermia possono risultare potenzialmente fatali. Ad esempio, valori superiori a 42 °C determinano fenomeni di citotossicità e denaturazione proteica, con compromissione della sintesi del DNA, mentre temperature corporee inferiori a 27 °C risultano incompatibili con la vita [24].

Come anticipato, nell’uomo i meccanismi di termoregolazione si realizzano attraverso l’interazione tra specifiche aree cerebrali, recettori di temperatura centrali e periferici e sistemi effettori. Alcune aree ipotalamiche, in particolare, come il nucleo sovraottico, rivestono un ruolo cruciale. Quest’ultimo mediante la via spinotalamica laterale riceve input termici provenienti dai recettori periferici (neuroni termosensoriali). I neuroni termosensoriali sono principalmente nocicettori polimodali, in grado di rilevare stimoli chimici e meccanici, mentre esiste anche una popolazione distinta di neuroni termocettivi specifici, che rispondono esclusivamente alle variazioni di temperatura. Questi trasmettono gli impulsi attraverso fibre mieliniche di grosso calibro di tipo Aδ e sottili fibre amieliniche C, i cui corpi cellulari sono localizzati nel ganglio della radice dorsale. I termocettori sono principalmente distribuiti a livello cutaneo e mucosale, ma sono presenti anche nelle pareti viscerali, nel tessuto muscolare, nelle vie aeree, nei vasi sanguigni e nel midollo spinale [25]. Sulla base delle informazioni termiche ricevute, vengono attivati meccanismi effettori distinti, differenziati in risposta a stimoli di temperatura elevata o, viceversa, bassa.

Schema riassuntivo dei meccanismi di termoregolazione nell’uomo.
Figura 4. Schema riassuntivo dei meccanismi di termoregolazione nell’uomo.

Le risposte descritte, illustrate nella Figura 5, sono regolate da molteplici sistemi neurologici che integrano il sistema nervoso centrale con gli effettori periferici.

Figura 5. Rappresentazione schematica dell’integrazione tra vie afferenti ed efferenti nel controllo della termoregolazione corporea.
Figura 5. Rappresentazione schematica dell’integrazione tra vie afferenti ed efferenti nel controllo della termoregolazione corporea.

Dagli studi condotti dal fisiologo austriaco Schnedititz [26] e successivamente ripresi da Pizzarelli [27] per comprendere i meccanismi responsabili dell’incremento della temperatura corporea durante la seduta emodialitica è necessario analizzare separatamente le componenti termiche presenti nei vari distretti del CEC e nell’organismo, distinguendo quest’ultimo in circolazione superficiale e profonda.

Il trasferimento di calore che si realizza in corso di emodialisi può essere descritto dall’equazione:

E = c × ρ × (Tven − Tart) × Qb

dove:

E: rappresenta l’energia termica trasferita;

c: costante calorica specifica del sangue, indica la quantità di calore necessaria per aumentare di 1 grado Celsius la temperatura di 1 grammo di sangue;

ρ (rho): rappresenta la densità ematica della massa di sangue per unità di volume;

Tven: temperatura del sangue lungo la linea ematica inflow (venosa);

Tart: temperatura del sangue lungo la linea ematica outflow (arteriosa);

Qb: velocità della pompa sangue.

Questa formulazione consente di quantificare il calore scambiato tra sangue e dialisato, sottolineando come il trasferimento termico dipenda dalla differenza di temperatura (ΔT) tra sangue venoso e arterioso, dalla portata ematica e dalle proprietà termofisiche del sangue. La comprensione di questi meccanismi costituisce il razionale fisiopatologico alla base delle strategie di cool dialysis.

La temperatura venosa (Tven) e quella arteriosa (Tart) durante la dialisi sono modulate da diversi fattori, tra cui lunghezza e conduttività termica delle linee del circuito extracorporeo, temperatura ambientale e ricircolo della fistola arterovenosa (FAV). L’uso di un dialisato a 37 °C, comunemente giustificato dalla vicinanza di tale valore alla temperatura corporea, risulta tuttavia un approccio riduttivo e non riflette pienamente le complesse dinamiche termiche del paziente durante la procedura. La temperatura corporea varia in funzione del distretto di misurazione: risulta superiore a 37 °C nei vasi e negli organi splancnici, mentre è inferiore nei distretti periferici. Tale differenza è particolarmente evidente nelle FAV distali, dove tra l’arteria radiale e le principali vene del gomito si osserva frequentemente uno scarto di circa 2 °C [28]. Un ulteriore elemento da considerare è la relazione tra questo parametro, la temperatura del dialisato, la velocità della pompa peristaltica e il flusso della soluzione dialisante. Ad esempio, un paziente con valore basale di 36°C sottoposto a trattamento con dialisato a 37 °C, Qb di 200 ml/min e con una velocità del flusso di dialisato (Qd) di 450 ml/min mostrerà una tendenza progressiva all’aumento della temperatura nel corso della seduta.

 

Concetto di “Cool Dialysis” – dialisi a temperatura ridotta

Come riportato da Jeffries et al. [29] nel 2011 e successivamente da Eldehni et al. [4] nel 2015, il concetto di cool dialysis indica una strategia emodialitica che prevede l’impostazione della temperatura del dialisato ad almeno 1 °C al di sotto rispetto al set-point standard dei sistemi per emodialisi, solitamente pari a 37 °C. Questo approccio prevede l’utilizzo di un dialisato a temperatura generalmente compresa tra 35 °C e 36 °C, con l’obiettivo di modulare la risposta emodinamica e ridurre l’incidenza degli episodi di ipotensione intradialitica. Una strategia alternativa, più graduale, proposta da Pizzarelli [30], consiste nella personalizzazione della temperatura del dialisato in base alle caratteristiche individuali del paziente. Tale modalità si basa sull’impostazione della temperatura del dialisato circa 0,5 °C al di sotto della temperatura corporea interna a riposo, determinata mediante misurazioni specifiche: ciò al fine di ottimizzare la tolleranza emodinamica durante la dialisi. Il razionale di questa strategia deriva dall’osservazione che la dialisi a “temperatura standard” non garantisce il mantenimento dell’isotermia per l’intera seduta; durante il trattamento si registra infatti un incremento termico medio di 0,5-0,7 °C, che può favorire l’insorgenza di episodi ipotensivi ricorrenti e determinare effetti sistemici sfavorevoli nel lungo periodo.

 

Analisi della letteratura clinica (periodo 2015-2025)

Gli studi clinici inclusi nell’analisi sono stati identificati tramite la piattaforma PubMed®, utilizzando come parole chiave i seguenti termini: «cooler dialysis», «cooler dialysate» e «cooler dialysate and haemodinamic stability». La ricerca è stata condotta considerando il periodo compreso tra il 1° gennaio 2015 e il 31 luglio 2025. Sono stati identificati quattordici studi, cinque dei quali esclusi perché non rilevanti all’argomento trattato, in quanto riportavano esiti clinici non coerenti con quelli oggetto della presente overview. L’analisi ha quindi incluso nove studi clinici.

Autore / anno Disegno dello studio Partecipanti Temperatura del dialisato Outcome principali Messaggi chiave
Veerappan et al., 2015 Prospective crossover 60 Personalizzata vs standard Ipotensione intradialitca (IDH), Variabilità PA ↓ IDH, Aumento della stabilità emodinamica
MyTEMP Trial (2017–2021) Pragmatic, cluster multicententrico > 15.000 Personalizzata vs standard Mortalità CV, IMA, stroke, Ospedalizzazione per cause cardiovascolari

Riduzione della mortalità per cause CV non significativa; Incremento della stabilità pressoria;

↑ discomfort termico
Ouyang et al., 2022 (Bayesian reanalysis of MyTEMP) Post-hoc analisi statistica Bayesiana > 15.500 Simile al  MyTEMP Endpoint CV compositi elevati benefici clinici
Odudu et al., 2020 Trial randomizzato 73 Personalizzata vs standard Disfunzione sistolica Ventricolo sn, IDH

↓ IDH,

Effetti protettivi sul Ventricolo sn
Dasgupta et al., 2023 Studio pilota randomizzato 100 Personalizzata vs standard Differenze nelle performance cognitive Assenza di differenze nelle performance cognitive
Eldehni et al., 2015 Studio attraverso analisi Imaging 70 Personalizzata vs standard

Microcircolo cerebrale

(DTI-MRI)

 Minori danni vascolari a livello della corteccia bianca
Yu et al., 2019 Cross-sectional neuroimaging 120 Personalizzata vs standard Cortical thickness/volume (MRI) Possibile effetto protettivo sulla corticale cerebrale
Sedaghat et al., 2016 (Rotterdam Study) Coorte suddivisa in sottogruppi > 500 Non standardizzata Autoregolazione del flusso ematico cerebrale La dialisi fredda mitiga il danno a livello del flusso ematico cerebrale
FHN Trial, 2012 (exploratory link) RCT, not designed for temp but relevant 245  

Standard vs. dialisi intensiva

 Massa Ventricolare sn, outcome cardiaci Evidenzia ruolo della dialisi fredda come cardioprotezione
Tabella 1. Studi clinici utilizzati.

 

Discussione

Il primo studio analizzato, condotto da Veerappan e coll. [31], ha valutato gli effetti del trattamento emodialitico a bassa temperatura. La temperatura media del dialisato nel gruppo di intervento era di 36,5 ± 0,2 °C, con un ΔT compreso tra 35,7 e 37,5 C. Lo studio, di tipo prospettico crossover, randomizzato, ha arruolato 60 pazienti suddivisi in due gruppi: uno sottoposto a dialisi a bassa temperatura e un gruppo di controllo. La durata complessiva delle sedute era di 240 minuti e la durata media del follow-up è stata di 12 mesi. I risultati hanno evidenziato che l’utilizzo del dialisato più freddo, personalizzato in base alle caratteristiche del paziente, determinava una minore incidenza di ipotensione intradialitica (IDH) e di concomitanti episodi ipotensivi. Inoltre, le oscillazioni pressorie nel corso delle sedute apparivano meno marcate nel gruppo trattato con dialisi a freddo, suggerendo un miglioramento della stabilità emodinamica.

Il trial Major Outcomes with Personalized Dialysate Temperature (MyTEMP) rappresenta a tutt’oggi lo studio più ampio in termini di numerosità campionaria tra quelli che hanno valutato gli effetti del dialisato a bassa temperatura. A differenza di studi precedenti, i cui risultati suggerivano un evidente beneficio della dialisi a freddo sia sulla stabilità emodinamica che nel ridurre gli episodi ipotensivi, MyTEMP ha riportato risultati parzialmente divergenti, evidenziando come l’impatto clinico della personalizzazione della temperatura del dialisato possa essere meno marcato su alcuni outcome cardiovascolari primari. Lo studio ha arruolato oltre 15.000 pazienti randomizzati in due gruppi, con un follow-up medio di 4 anni; gli endpoint valutati sono stati: mortalità cardiovascolare, ospedalizzazioni per eventi cardiaci e ipotensione intradialitica. Ciononostante, alcuni benefici secondari, quali una più lieve instabilità pressoria e un minor discomfort durante la seduta, sono stati comunque osservati nei pazienti trattati con dialisato personalizzato a temperatura più bassa. Più in dettaglio, lo studio MyTEMP è un ampio trial pragmatico cluster-randomizzato condotto in Ontario, Canada, volto a valutare l’impatto della dialisi con dialisato a temperatura personalizzata rispetto alla dialisi a temperatura standard (36,5 °C) su outcome cardiovascolari maggiori in pazienti sottoposti ad emodialisi [32]. Il trial ha incluso oltre 15.000 pazienti distribuiti in 84 centri, con più di 4,3 milioni di sedute dialitiche registrate tra il 2017 e il 2021.

Nel gruppo sperimentale, la temperatura del dialisato era impostata tra 0,5 e 0,9 °C inferiore alla temperatura corporea pre-dialisi del paziente, con un minimo di 35,5 °C, mentre nel gruppo di controllo la temperatura standard, era pari a 36,5 °C. L’outcome primario era composito di morte cardiovascolare o ospedalizzazione per infarto del miocardio, ictus ischemico o insufficienza cardiaca congestizia.

I risultati hanno evidenziato che non vi erano differenze significative tra i due gruppi in termini di eventi cardiovascolari maggiori (Hazard Ratio aggiustato 1,00; IC 95%: 0,89-1,11; p = 0,93). Le oscillazioni pressorie durante le sedute dialitiche risultavano simili, con una differenza media di 0,5 mmHg (p = 0,14). Tuttavia, i pazienti sottoposti a dialisi a temperatura personalizzata hanno riportato un maggiore disagio termico, suggerendo che l’adozione di questa strategia potrebbe non conferire benefici a livello di popolazione generale. Gli autori hanno concluso che la dialisi a temperatura personalizzata non riduce significativamente il rischio di eventi cardiovascolari maggiori, e che futuri studi dovrebbero focalizzarsi su sottogruppi di pazienti potenzialmente più sensibili a questa strategia.

Un approfondimento recente sul trial MyTEMP è stato condotto da Ouyang Y et al. [33], che hanno applicato un’analisi bayesiana ai dati del trial cluster-randomizzato. L’analisi bayesana, detta anche inferenza bayesana, è un approccio statistico in cui le probabilità non sono interpretate come frequenze, proporzioni o concetti analoghi, ma come livelli di fiducia nel verificarsi di un dato evento. L’impiego di questa metodica statistica appare utile poiché consente l’inclusione di studi precedenti allanalisi statistica in corso. Per tali motivi, a differenza dei metodi frequentisti (tradizionali), che esaminano solo i dati raccolti durante lo studio, i metodi bayesani consentono ai ricercatori di partire da una aspettativa iniziale (ipotesi) sull’efficacia di un dato trattamento ed integrarvi le prove ottenute in studi successivi e dallo stesso studio in corso [34]. In tal modo è possibile interpretare i dati con maggiore flessibilità rispetto alle analisi frequentiste tradizionali. L’applicazione di quest’analisi sembra suggerire che la dialisi a temperatura personalizzata possa conferire vantaggi significativi, sebbene il trial MyTEMP originale non avesse riportato una differenza statisticamente significativa per quanto riguardava endpoint principali.

Per contro, uno studio clinico di dimensioni ridotte (73 pazienti) condotto tra settembre 2009 e gennaio 2013, da Odudu A. et al. [35], supporta l’utilizzo della dialisi a temperatura personalizzata avendo messo in evidenza una riduzione nella progressione della cardiomiopatia associata all’emodialisi. Il trial ha confrontato due gruppi di pazienti: uno trattato con dialisato a temperatura standard e l’altro con dialisato raffreddato in maniera individualizzata, calcolata sulla base della temperatura corporea basale di ciascun soggetto. Gli endpoint principali erano la variazione della funzione sistolica segmentaria del ventricolo sinistro e la frequenza di episodi di ipotensione intradialitica. I risultati hanno mostrato che l’utilizzo di dialisato personalizzato a bassa temperatura è associato ad una significativa riduzione degli episodi di IDH e a una minore riduzione transitoria della funzione contrattile miocardica, confermando l’effetto protettivo su quest’ultima osservato in studi precedenti. Questo trial, insieme alle evidenze derivanti dagli studi di Veerappane dallo studio MyTEMP, rafforza l’ipotesi che la modulazione termica del dialisato possa rappresentare una strategia efficace per migliorare la stabilità emodinamica e ridurre il rischio di danno cardiaco nei pazienti emodializzati, pur sottolineando la necessità di studi futuri su campioni più ampi e con follow-up prolungati. L’indagine presenta tuttavia delle limitazioni, tra cui la ridotta numerosità del campione e la mancata valutazione di esiti clinici complessi, quali il tasso di ospedalizzazione e la mortalità (tali endpoint non rientravano negli obiettivi principali dello studio). Tuttavia, i risultati dello studio di Odudu risultano coerenti con quelli riportati dal Frequent Hemodialysis Network del 2012 [36], in cui gli autori ipotizzano che la maggiore stabilità emodinamica indotta dall’uso di dialisato a temperatura ridotta possa contribuire agli effetti cardioprotettivi osservati (riduzione della Massa ventricolare sinistra e del volume telesistolico del ventricolo sinistro in assenza di variazioni della frazione di eiezione a 12 mesi).

In merito alle influenze del dialisato refrigerato sulle funzioni cognitive dei pazienti sottoposti a emodialisi, un recente studio pilota condotto da Dasgupta e coll. [37] ha valutato, attraverso un trial randomizzato controllato, un gruppo trattato con dialisato a temperatura ridotta (cool dialysis) con un controllo a temperatura standard. Dopo 12 mesi di follow-up, non sono emerse differenze significative nei punteggi dei test cognitivi tra i due gruppi, sebbene l’intervento sia risultato ben tollerato e senza eventi avversi gravi, suggerendo la necessità di studi più ampi per confermare eventuali effetti benefici.

 

Conclusioni

Come evidenziato dagli studi analizzati, l’utilizzo del dialisato raffreddato presenta numerosi benefici in termini di stabilità emodinamica e prevenzione dell’ipotensione intradialitica. Studi su piccola scala, tra cui quello di Veerappan et al. e Odudu et al., hanno documentato una significativa riduzione degli episodi di ipotensione e un effetto protettivo sulla contrattilità ventricolare, suggerendo un beneficio diretto sulla funzione cardiaca. Anche trial di maggiori dimensioni, come il MyTEMP e l’analisi bayesiana ad esso correlata di Ouyang et al., confermano tale tendenza, pur evidenziando effetti più modesti sul lungo termine. Gli effetti long-term sulla microcircolazione cardiaca e cerebrale non risultano ancora chiaramente definiti, così come non sono stati dimostrati benefici consistenti in termini di riduzione del deterioramento cognitivo, come suggerito da Dasgupta et al. Il limite principale degli studi condotti nell’ultima decade risiede soprattutto nella scarsa numerosità campionaria e nella ridotta partecipazione multicentrica, fattori che determinano limitazioni importanti in termini di generalizzabilità dei risultati.

La recente analisi dello studio MyTEMP suggerisce che, sebbene l’applicazione sistematica della metodica non appaia giustificata, il dialisato raffreddato potrebbe comunque essere impiegato in pazienti «responder» per controllare eventuali episodi ipotensivi, senza ulteriori benefici clinici finora dimostrati. In conclusione, le evidenze descritte sembrano supportare l’ipotesi che l’emodialisi a temperatura personalizzata possa rappresentare una strategia efficace per migliorare la stabilità emodinamica e proteggere la funzione cardiaca in tali pazienti, pur sottolineando la necessità di ulteriori studi multicentrici randomizzati, con campioni più ampi e follow-up prolungati, per chiarire l’impatto su eventi cardiovascolari maggiori, ospedalizzazioni e mortalità.

 

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Trattamenti non biologici di supporto epatico extracorporeo: esperienze e prospettive nella gestione dell’insufficienza epatica acuta

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Fabrizio Cristiano

DOI: 10.69097/42-06-2025-07

Fabrizio Cristiano1,2, Julian Camilo Ramirez-Acosta3, Nigel Osvaldo Fernandez-Claros3, Fernando Lombi4, Guillermo Rosa-Diez3

1 Department of Neuroscience, Imaging and Clinical Science, Gabriele d’Annunzio University of Chieti and Pescara, Chieti, Italy
2 Nephrology and Dialysis Unit, Ortona Hospital, ASL 2 Lanciano Vasto Chieti, Italy
3 Servicio de Nefrologia – Hospital Italiano Buenos Aires, Argentina
4 Servicio de Nefrología, Hospital Británico de Buenos Aires, Buenos Aires, Argentina

Corrispondenza a:
Fabrizio Cristiano
Nephrology and Dialysis Unit, Ortona Hospital, ASL 2 Lanciano Vasto Chieti, Italy
Department of Neuroscience, Imaging and Clinical Science, University “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy;
E-mail: fabrizio.cristiano@asl2abruzzo.it

 

Abstract

L’insufficienza epatica acuta (ALF) e l’insufficienza epatica acuta su cronica (ACLF) rappresentano condizioni cliniche gravemente compromesse, caratterizzate da elevata mortalità e spesso candidabili a trapianto epatico. Negli ultimi anni, i trattamenti extracorporei non biologici (ECLSD) hanno acquisito un ruolo crescente come supporto temporaneo, attraverso la rimozione di tossine idrosolubili e legate all’albumina. Il presente lavoro offre una panoramica dei principali dispositivi disponibili, tra cui SPAD (single pass Albumin Dialysis), MARS (Molecular Adsorbent Recirculation System), Prometheus (Fractionated Plasma Separation and Adsorption), Cytosorb, CPFA (Coupled Plasma Filtration Adsorption) e DPMAS (Dual Plasma Molecular Adsorption System), illustrandone caratteristiche tecniche, efficacia e limiti. Particolare attenzione è rivolta all’esperienza del nostro centro con le tecniche RAED (Recirculated Albumin Extended Dialysis) e RHENOB (Reemplazo Hepático No Biológico), basate su circuiti di albumina ricircolata, con o senza rigenerazione mediante DPMAS. In una serie di sette pazienti con ALF o ACLF trattati con RHENOB, è stata osservata una riduzione significativa della bilirubina (25-50%) già dopo poche sedute, senza eventi avversi emodinamici. Un paziente ha successivamente ricevuto con successo un trapianto epatico, completando il percorso di stabilizzazione biochimica. Le tecniche RAED e RHENOB si configurano come approcci innovativi, efficaci, economicamente sostenibili e applicabili anche in centri privi di tecnologia avanzata. Sono tuttavia necessari studi prospettici controllati per consolidarne l’utilizzo nella pratica clinica.

Parole chiave: insufficienza renale acuta, supporto epatico extracorporeo, MARS, Cytosorb, RHENOB, RAED, DPMAS

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

Chronic liver disease affects 10% of the world’s population, and acute liver failure compromises approximately 5 million patients per year in Western countries [1]. Liver failure prevents the liver from performing normal functions, such as detoxification, biotransformation, excretion and synthesis, with accumulation of toxins and lethal complications [2]. Its causes include undetermined aetiology, secondary to drugs, viral infection, exotoxic from alcohol abuse and autoimmune diseases [2]. Acute liver failure (ALF) describes a dysfunction with encephalopathy, impaired liver synthesis, and metabolic function. Acute-on-chronic liver failure (ACLF) describes an exacerbation of underlying chronic disease such as alcohol-based exotoxic hepatopathy, HBV and HCV viral infections [2]. ACLF has a high mortality rate of between 50% and 90% with development of jaundice, systemic port encephalopathy and multiple organ failure [3]. Endogenous toxins found in patients with acute liver failure include bilirubin, ammonium, glutamine, lactate, aromatic amino acids, free fatty acids, phenol, mercaptans, and pro-inflammatory cytokines. The loss of hepatocytes promotes a progressive increase in apoptosis and hepatic necrosis. The liver has a great capacity to regenerate itself after partial hepatectomy or iatrogenic intoxication such as paracetamol, maintaining sufficient liver function for adequate homeostasis [4].  Hepatic toxins are hydrophobic with a molecular weight < 1000 Da (Bilirubin = 406 Da, cholic acid = 283 Da, chenodeoxycholic acid = 272 Da) and have a protein bond that prevents free diffusion of bilirubin and bile acids resulting in toxicity in human tissue. These characteristics explain why classical renal dialysis techniques based on convection and diffusion are not effective in removing these toxins [5]. Orthotopic liver transplantation has been the treatment of choice, but there are no available organs. High mortality rate needs new treatment as a “bridge” to liver transplantation or as a replacement treatment until spontaneous recovery of liver function [6]. Extracorporeal liver support devices (ECLSDs) serve as a bridge until a donor liver becomes available or hepatic recovery occurs. There are two main types of ECLSDs: artificial and bioartificial [7]. Biological methods are difficult to implement and very expensive; non-biological ECLSDs are the most commonly used. The main indications for the use of ECLSDs are: ALF from paracetamol intoxication, ALF from hepatitis A and B, ACLF from chronic hepatopathy, type 1 or 2 hepatorenal syndrome, severe acute cholestatic hepatitis, pruritus unresponsive to medical therapy, systemic port encephalopathy and hyperbilirubinemia while waiting for a liver transplant, primary or secondary dysfunction of a liver transplant [6]. Understanding how ECLSDs operate requires acknowledging that liver failure primarily compromises the liver’s detoxification capacity. Therefore, water-soluble (or non-albumin-bound, such as ammonium) and hydrophobic (or albumin-bound, non-removable with dialysis, such as bilirubin and bile acids) substances accumulate in the plasma. ECLSDs aim to remove liver toxins and were developed from the experience and technology of renal function replacement treatments with haemodialysis. Some toxins such as small water-soluble toxins like ammonium can be removed easily with haemodialysis techniques of haemodiafiltration; for larger, protein-bound molecules, other methods combining diffusion, convection techniques together with filtration and adsorption are required [8]. Principles for the extraction of hydrophobic (lipid-soluble) and albumin-bound toxins are: pheresis, direct removal of plasma or albumin from the patient, taking the albumin-bound toxins with it; adsorption, direct extraction of the toxins present in the albumin, through the use of sorbents; facilitated diffusion: indirect method using a dialysate with albumin.  Thus, the albumin circuit enables the facilitated diffusion of albumin-bound toxins, driven by oncotic pressure gradients. The solutes in question are separated from the patient’s albumin and subsequently bind to the albumin in the dialysate to be removed through the passage of a dialysis membrane.

ECLSDs improve symptoms (systemic port encephalopathy, pruritus) and survival by reducing ammonium, bilirubin, and transaminase levels. Bilirubin is used as a biochemical marker of treatment efficacy due to the toxins’ characteristics, high affinity for proteins, and ease of measurement in any laboratory. The binding between bilirubin and albumin is extremely effective (9.5 × 10⁷ M⁻¹) and just one ninety-fifth millionth of a mole of bilirubin is able to saturate 50% of the albumin bonds. The direct adsorption technique is the best option for removing albumin-bound toxins. ECLSDs techniques with filtration and adsorption show better removal of protein-bound toxins and water-soluble toxins [9].

Taking into account the physical principles mentioned, ECLSD techniques are based on diffusion, convection, adsorption and pheresis mechanisms, applied singly or in combination. The common goal of these methods is the removal of liver toxins that accumulate in patients with acute or acute-on-chronic liver failure through elimination of both water-soluble toxins (ammonium), hydrophobic toxins bound to albumin (bilirubin and bile acids), an elimination that cannot be achieved with conventional dialysis alone. The various technologies differ in terms of technical configuration, materials used (presence or absence of albumin, need for adsorbent cartridges), blood flows, costs, and system complexity. In the following sections, the main solutions available today will be described in detail, with a focus on the advantages and limitations of each system.

Plasmapheresis SPAD (Single Pass Albumin Dialysis) MARS (Molecular Adsorbent Recirculation System) PROMETHEUS (Fractionated Plasma Separation and Adsorption) CPFA (Coupled Plasma Filtration Adsorption) DPMAS (Dual Plasma Molecular Adsorption System) Cytosorb
Albumin or plasma yes yes yes no no no no
Collaboration with TRRC no yes yes no yes yes yes
plasmapheresis yes no no yes albuminopheresis yes yes no
adsorption cartridge no no yes (two) yes (two) yes yes (two) yes
special device no no yes yes yes no no
blood flow (ml/min) 100-150 100-250 100-150 200-350 100-200 100-200 100-350
Table 1. Summary table of different non-organic extracorporeal liver support devices (ECLSDs).

 

Plasmapheresis

Plasmapheresis and haemoperfusion were the first techniques used as ECLSDs. The former involves the direct extraction of plasma (apheresis), while the latter consists of the direct adsorption of fat-soluble solutes from the blood through an activated charcoal cartridge. Both techniques have demonstrated limited efficacy and are not without complications (infection, thrombocytopenia, hypoglycemia), so they are not currently used as liver support therapies [10].

MARS (Molecular Adsorbent Recirculation System)

The MARS is an extracorporeal detoxification technique that combines conventional haemodialysis with albumin dialysis. It utilizes a standard haemodialysis or haemofiltration device integrated with a specific module that circulates human albumin (10-20%) as a dialysate [11]. The patient’s blood passes through a filter where albumin-bound and water-soluble toxins diffuse across a semipermeable membrane (cutoff ~50 kDa), binding to the exogenous albumin. The albumin-containing dialysate, enriched with toxins, then flows through a conventional dialysis filter (removing hydrophilic solutes) and two adsorber cartridges (resin and activated charcoal), which eliminate albumin-bound substances. The purified albumin is recirculated, allowing continuous detoxification. A typical session lasts 6-8 hours and is usually performed daily [12]. This system removes both water-soluble and albumin-bound toxins, improves liver function parameters and stabilizes patients as a bridge to recovery or transplantation, and improves renal function in hepatorenal syndrome [13]. There are limitations like specialized equipment and trained staff; adverse events include transient haemodynamic instability and thrombocytopenia [15]. Cost and session duration (6-8 hours) may limit widespread applications. Most clinical studies on MARS have been performed in patients with acute liver failure (ALF) or acute-on-chronic liver failure (ACLF). Only three randomized trials have assessed its effect on survival. In a prospective randomized controlled trial, Mitzner et al. (2000) demonstrated improved renal and liver function and increased survival in patients with hepatorenal syndrome treated with MARS compared to standard medical therapy [13]. A subsequent randomized study in ACLF patients confirmed similar results [14]. Moreover, one economic analysis suggested that MARS may be cost-effective compared to conventional therapy [15].

 

SPAD – Single Pass Albumin Dialysis

SPAD is based on conventional dialysis equipment and does not require special modules. It relies on the principle of diffusion using an albumin-enriched dialysate bath. Unlike MARS, the albumin dialysate is single-pass and discarded, without the need for an interposed circuit with adsorbent cartridges. SPAD can be performed with any standard haemodialysis or haemofiltration device. A variant, Single-Pass Albumin Extended Dialysis (SPAED), includes an additional high-flow haemodialysis filter to enhance toxin removal. Advantages are simplicity of use with conventional haemodialysis equipment, does not require additional cartridges or modules, lower cost of disposable material compared to MARS and other non-biological liver support systems [16]. The limitations are large amounts of albumin, which increases overall cost, limited efficiency in a single-pass configuration, since the dialysate is discarded after one use. Clinical experience remains limited, mostly to case reports [18]. Two in-vitro studies compared SPAD with MARS, showing that SPAD may be more effective in removing bilirubin and bile acids, though findings on cost-effectiveness were controversial [17]. A retrospective clinical study in patients with acute liver failure reported comparable efficacy between SPAD and MARS. To overcome the limitation of single-pass use, a modified approach – Multiple Pass Albumin Extended Dialysis (MAED or RAED) – was tested in a small patient cohort. This method, based on recirculation of albumin without regeneration and combined with prolonged haemodialysis, showed a significant reduction in bilirubin levels [18]. However, published clinical evidence on SPAD, SPAED, and MAED is still confined to case reports.

 

PROMETHEUS (Fractionated Plasma Separation and Adsorption)

Prometheus is an extracorporeal liver support technique based on fractionated plasma separation and adsorption (FPSA). The system consists of two circuits in series. In the first circuit, the patient’s albumin is selectively fractionated through the Albuflow filter. The separated albumin is then directly purified by adsorption using two specific resin cartridges (Prometh 01 with neutral resin and Prometh 02 with anion-exchange resin). The detoxified albumin is subsequently reinfused into the bloodstream, closing the first circuit. In the second circuit, the patient’s blood passes through a high-flux dialyser (FX dialyser), which allows conventional haemodialysis and the removal of water-soluble substances. It does not require an exogenous albumin circuit, unlike MARS and SPAD/MAED; it has lower consumption of replacement albumin, since patient’s endogenous albumin is purified and recirculated. It provides combined clearance of both albumin-bound and hydrophilic toxins but requires specialized filters and cartridges [19].  A limitation is a slight reduction in plasma albumin concentration, that may occur at the end of treatment. Clinical efficacy on overall survival remains controversial. The HELIOS (Prometheus European Liver Disease Outcome) study evaluated the impact of Prometheus on survival in patients with cirrhosis and liver failure. This prospective, randomized, international multicentre trial included 145 patients with chronic liver failure (bilirubin > 5 mg/dL; Child-Pugh ≥ 10). Patients were randomized to conventional medical therapy (n = 68) or conventional therapy plus Prometheus (n = 77) for 21 days, with 90-day follow-up. Results showed a trend toward improved overall survival in the Prometheus group, with significantly longer survival observed in the subgroup of patients with type I hepatorenal syndrome (HRS) or a MELD score above 30 [20].

 

CPFA (Coupled Plasma Filtration Adsorption)

CPFA is an extracorporeal liver support technique based on plasma separation followed by adsorption of albumin-bound toxins on a hydrophobic resin. The method requires specialized equipment (e.g., Lynda or Amplya machines) and is performed with anticoagulation using heparin or citrate. Plasma is first separated from whole blood and then passed through a resin cartridge with high affinity for bilirubin and bile acids, the main albumin-binding toxins. The purified plasma is subsequently reinfused, completing the circuit. The advantages are effective removal of bilirubin, bile acids, and other albumin-bound toxins, haemodynamic stability, even in septic patients.  This system is well tolerated, with no significant hypotension or major bleeding events, and it offers potentially lower cost and greater technical flexibility compared to other systems such as MARS or Prometheus [21]. However, there are high procedural costs and the need for dedicated equipment, limited clinical evidence, mostly based on small single-centre observational studies and no significant impact on MELD score demonstrated. The HERCOLE (Hepatic Replacement by Coupled Plasma Filtration and Adsorption in Liver Failure) study evaluated the efficacy and safety of CPFA in 12 patients with acute liver failure (ALF) or acute-on-chronic liver failure (AoCLF) treated at S. Orsola Hospital, Bologna (2013-2017). Inclusion criteria were bilirubin >20 mg/dL or MELD score >20. A total of 31 CPFA sessions (6 hours each) were performed. Results showed a mean bilirubin reduction of 28.8% per session (range 2.2-40.5%), with a low rebound effect at 24 hours (median 8.9% after the first session, 6.8% after the second). Resin cartridges demonstrated strong adsorptive capacity, particularly for bilirubin and bile acids. Clinically, one patient underwent liver transplantation, and eight recovered their baseline liver function, with a one-year survival rate of 75%. CPFA was safe, effective in improving biochemical detoxification parameters, and may serve as a bridge to transplantation or recovery. However, due to the small sample size and heterogeneity, further randomized trials are required to confirm its clinical efficacy [21].

 

Dual Plasma Molecular Adsorption System (DPMAS)

Dual Plasma Molecular Adsorption System (DPMAS) is a system that combines plasma filtration and two adsorbent resins: a broad-spectrum resin (HA330-II) for inflammatory mediators and a specific resin (BS330) for bilirubin. This device is easy to use even on standard CRRT machines without the need for dedicated equipment. The advantages of DPMAS are good removal of protein-bound toxins (bilirubin), cytokines and inflammatory mediators, improvements in liver biochemistry, coagulation function and inflammatory and immune indices, good tolerability and safety with citrate anticoagulation. DPMAS in combination with plasmapheresis not only improves bilirubin levels but also 28-day survival in patients with HBV-related ACLF and reduces the need for transplantation in patients with cholestatic hepatitis. The isolated use of DPMAS improves prothrombin activity. Despite promising data, the routine use of DPMAS requires further confirmation through randomised multicentre studies. However, thanks to its ease of use, it appears to be a promising option [22].

Cytosorb

Cytosorb is a whole blood adsorption device designed to eliminate middle-molecular-weight substances, particularly cytokines and inflammatory mediators, and can be easily integrated into any extracorporeal blood circuit, including CRRT, without the need for plasmapheresis, albumin, or plasma replacement. Its main indication is the reduction of inflammatory mediators in sepsis and septic shock, but it is also employed in other critical care settings such as ARDS and ECMO therapy [23], in acute liver failure and rhabdomyolysis for the removal of bilirubin and myoglobin [24], and in cardiac surgery for the elimination of antiplatelet and anticoagulant agents such as ticagrelor and rivaroxaban [25]. In a retrospective comparative study, individual sessions of Cytosorb and MARS were both associated with significant reductions in bilirubin (p = 0.04 and p = 0.04, respectively) and ammonia (p = 0.04 and p = 0.04, respectively), but only Cytosorb achieved additional significant decreases in lactate dehydrogenase (p = 0.04) and platelet count (p = 0.04). After a complete treatment cycle, Cytosorb maintained superiority, showing significant reductions in lactate (p = 0.01), bilirubin (p = 0.01), ammonia (p = 0.02), and lactate dehydrogenase (p = 0.01), while MARS-treated patients did not display significant improvements in liver function parameters. Moreover, only Cytosorb was associated with a significant improvement in the MELD score (p = 0.04), highlighting its superior efficacy over MARS in enhancing liver compensation [26]. Another comparative study assessed detoxification efficiency across several extracorporeal liver support systems and demonstrated that Cytosorb had the highest adsorption capacity for total bilirubin, direct bilirubin, and bile acids when compared with CPFA, MARS, Prometheus, and plasmaperfusion, supporting its potential role as the device of choice in advanced liver failure [27]. Additional real-world evidence will derive from the COSMOS registry, launched in July 2022 and currently enrolling patients in Germany, Spain, Portugal, and Italy, which aims to provide large-scale observational data on the safety and efficacy of Cytosorb in critically ill patients [28].

Experience of our group

ECLSD methods are based on the principles of diffusion, convection, adsorption and phoresis, with the aim of removing water-soluble and hydrophobic toxins bound to albumin that accumulate in acute or acute-on-chronic liver failure. The techniques currently available vary in complexity, effectiveness and accessibility, but none has yet established itself as the absolute standard of treatment. Our group’s experience has included the use of a technique involving the recirculation of albumin without regeneration, RAED (Recirculated Albumin Extended Dialysis), a variant of SPAD that involves the recirculation of albumin without regeneration. In this mode, albumin is used as dialysate in a multi-pass circuit, with the aim of optimising its use and improving the efficiency of removing albumin-bound toxins, while maintaining a simple technical configuration without adsorbent columns. Albumin is circulated through a secondary circuit connected to a high-cut-off dialyzer, facilitating the diffusion of toxic substances from the blood to the albumin dialysate. Although this strategy does not involve the regeneration of the albumin solution using adsorbent cartridges, as is the case with the RHENOB system, it has shown reasonable effectiveness in reducing bilirubin and other toxic markers in patients with acute or acute-on-chronic liver failure. RAED therefore represents an intermediate option between SPAD and more complex systems such as MARS or Prometheus, offering a good compromise between simplicity, effectiveness and low cost, and formed the technological basis for the subsequent development of the RHENOB (Reemplazo Hepático No Biológico) system (Table 2). The system consists (Figure 1) of an albumin recirculation circuit placed in series with a renal circuit (haemodialysis, haemofiltration or haemodiafiltration) and includes albumin regeneration through the use of DPMAS (Double Plasma Molecular Adsorption System; Jafron).

Figure 1.  RHENOB.
Figure 1.  RHENOB.
Feature RAED (Recirculated Albumin Extended Dialysis) RHENOB (Reemplazo Hepático No Biológico)
System type Variant of SPAD with recirculated albumin (multi-pass) RAED circuit combined with albumin regeneration (via DPMAS)
Albumin circuit Uses human albumin (20%) recirculated without regeneration Human albumin (20%) recirculated with regeneration through dual resin cartridges (HA330-II, BS330)
Membrane type High cut-off dialyzer for albumin circuit High cut-off dialyzer for albumin circuit + standard dialysis/hemofiltration membrane for renal circuit
Dialysis configuration Series circuit: blood + albumin dialysate, no adsorbent columns Two circuits in series: renal replacement therapy + albumin recirculation/regeneration
Albumin volume ~300 ml of 20% albumin solution ~300 ml of 20% albumin solution (regenerated by DPMAS)
Flow rates Blood flow: 150–300 ml/min; albumin flow: 15–20 ml/min Blood flow: according to RRT mode (HD/HDF); albumin dialysate flow: ~200 ml/min
Anticoagulation Heparin (standard dialysis dose) Heparin via renal circuit
Technical complexity Moderate – no special equipment needed beyond dialysis machine Higher – requires integration with DPMAS cartridges for albumin regeneration
Main advantage Simple, low-cost, reduces bilirubin; feasible in centres with standard dialysis equipment More efficient toxin clearance (bilirubin, bile acids, cytokines) with lower albumin consumption
Limitation No regeneration → less efficient, higher albumin use over multiple sessions Greater complexity, need for DPMAS system, limited published data
Table 2. Technical comparison of RAED and RHENOB systems.

For the renal circuit, a dialysis membrane is used depending on the method chosen (low-flow haemodialysis, high-flow haemodialysis, haemofiltration or haemodiafiltration); for the albumin circuit, a high-cut-off dialysis membrane is used; 300 ml of 20% human albumin in the albumin circuit acts as dialysate and is passed through the dialysate compartment of the blood-cut dialyzer. The blood and dialysate flow rates depend on the haemodialysis technique used; the albumin dialysate flow rate is 200 ml/min. Heparin is administered through the renal circuit.

Age Gender Etiology Liver Tx MELD Bilirubin Levels (mg/dl) Percentage change in bilirubin after treatment Number of RHENOB sessions performed Outcome
53 F Hepatic failure of unknown cause – AKIN 3 Yes 28 23  56 % 5 Alive
45 M Alcoholic – Acute on Chronic Liver Failure – AKIN 3 Yes 31 18 44 % 4 Alive
42 M Covid Pneumonia – Liver Failure – AKIN 3 No 30 25 52 % 3 Alive
63 F Amiloidosis AL – AKIN 3 No 32 19 47 % 4 Alive
47 F Primary Biliary Cirrhosis No 36 17 43 % 3 Dead
66 F Liver Transplant – Rejection – Cholestasis Yes 40 21 42 % 2 Dead
61 M Hepatitis B – Fulminat Subacute Hepatitis Yes 31 22 50 % 5 Alive
Table 3. Patient characteristics.

Table 3 presents the clinical and biochemical characteristics of each patient, including age, gender, underlying diagnosis, MELD score, baseline total bilirubin levels, number of RHENOB sessions performed, and percentage change in bilirubin after treatment. The mean age of patients was approximately 52 years, ranging from 42 to 66 years; the male prevalence reflects the known distribution of advanced liver disease. Diagnoses included severe alcoholic hepatitis, viral hepatitis, and acute post-transplant graft dysfunction, highlighting the heterogeneity of treatment indications. The MELD score at the start of therapy was high in all cases (median MELD >30), confirming the severity of liver impairment.

Summary table of treatments with comparison of pre- and post-treatment bilirubin
Figure 2. Summary table of treatments with comparison of pre- and post-treatment bilirubin levels for each patient.

All patients showed a significant reduction in bilirubin levels after RHENOB sessions, with an average decrease of between 25% and over 50% in the most severe cases (Figure 2). The therapeutic response was observed after just 1-2 sessions, suggesting that the method is rapidly effective.

In our centre, seven patients with acute liver failure (ALF) or acute-on-chronic liver failure (ACLF) were treated with the RHENOB system. The cohort included heterogeneous etiologies such as severe alcoholic hepatitis, viral hepatitis, acute post-transplant dysfunction, and autoimmune cholestatic disease, with a median MELD score above 30, reflecting advanced liver impairment. All patients experienced a significant reduction in serum bilirubin after treatment, with decreases ranging from 25% to over 50% after only 2-5 sessions. The improvement was evident early, often within the first two sessions, suggesting rapid detoxification efficacy. Treatments were well tolerated in all cases, with no episodes of severe haemodynamic instability, major bleeding, or significant adverse events. Anticoagulation with heparin was sufficient, and no patients required interruption of therapy due to complications. The technique demonstrated good haemodynamic stability, even in patients with concomitant renal failure and critical illness. Among the seven treated patients, three underwent successful liver transplantation after biochemical stabilization, three recovered native liver function, and one patient died due to progression of underlying disease, resulting in an overall survival at hospital discharge of 71%. Importantly, RHENOB allowed stabilization of critical patients awaiting transplantation and facilitated recovery in selected cases, confirming its potential role as an effective “bridge” therapy. Compared to established ECLSD systems, RHENOB provided effective detoxification with lower albumin consumption and without the need for highly specialized infrastructure. These encouraging results support its feasibility in centres without access to advanced extracorporeal liver support devices, although larger prospective studies are needed to confirm its clinical impact on long-term survival and transplant-free recovery. When comparing available non-biological extracorporeal liver support devices (MARS, SPAD, Prometheus, CPFA, DPMAS, Cytosorb, RAED and RHENOB), no single system has yet established itself as the gold standard. MARS and Prometheus remain the most widely studied but are costly and technically demanding, while SPAD and CPFA are simpler yet limited in efficacy or availability. Cytosorb has shown promising detoxification capacity, particularly for bilirubin and bile acids, but requires further validation. Within this landscape, RAED and RHENOB represent pragmatic and innovative approaches: RAED, as a low-cost recirculated albumin method, and RHENOB, as an evolution integrating albumin regeneration with DPMAS, both showing significant bilirubin clearance, good tolerability, and the potential to bridge patients to transplantation or recovery. These techniques, although still supported by limited evidence, offer feasible solutions for centres lacking access to high-cost systems. A call for action is therefore warranted: prospective, multicentre randomized controlled trials should be conducted to consolidate their role, establish standardised protocols, and evaluate their impact on survival and transplant-free outcomes.

 

Conclusions

Several non-biological extracorporeal liver support techniques have been developed with different rationales and performance profiles. MARS and Prometheus remain the most validated, offering effective detoxification but at the cost of complex infrastructure and high resource consumption. SPAD provides a simpler alternative but with limited efficacy and high albumin requirements, while CPFA and DPMAS have shown selective detoxification potential with promising but still preliminary evidence. Cytosorb represents a versatile adsorptive option with encouraging results in bilirubin and cytokine clearance, though standardisation and wider validation are lacking. Within this evolving landscape, our experience with RAED and RHENOB highlights the possibility of achieving clinically meaningful detoxification, particularly bilirubin reduction, with simpler technology and good tolerability. RHENOB, by integrating albumin regeneration, optimises efficiency and reduces costs, while RAED offers an extremely accessible model adaptable to standard dialysis equipment. These approaches may represent valuable opportunities for centres with limited access to high-cost platforms, expanding the applicability of extracorporeal liver support beyond highly specialised units. RAED and RHENOB combine feasibility, tolerability and clinical benefit, potentially filling an important gap in resource-limited settings. Future multicentre randomized controlled trials are warranted to confirm their efficacy, define standardised treatment protocols and establish their role within the broader therapeutic arsenal of extracorporeal liver support.

 

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Ipercolesterolemia e malattia renale cronica: fisiopatologia, diagnosi e trattamento alla luce delle nuove opzioni terapeutiche

Pubblicato il Scarica PDF

Aldo Franculli

DOI: 10.69097/42-05-2025-07

Aldo Franculli1, Luca Di Lullo1, Pasquale Saporito1, Andrea Dello Strologo1, Natascia Miani1, Eleonora Bernabei1, Vincenzo Barbera2, Lorenzo D’Elia2, Antonio Bellasi3, Paola Peverini1

1 UOCA Nefrologia e Dialisi, Azienda USL Roma 6
2 UOC Nefrologia e Dialisi, Ospedale “L. Parodi – Delfino”, Colleferro
3 Dipartimento di Medicina Interna, Ospedale Regionale di Lugano, Ospedale Civico, Ente Ospedaliero Cantonale, Lugano, Svizzera

Corrispondenza a:
Luca Di Lullo
UOC Nefrologia e Dialisi, Azienda USL Roma 6
Email: dilulloluca69@gmail.com
Tel: +39 0693278364

 

Abstract

Con il termine “dislipidemia”, comunemente utilizzato in senso generico, si fa riferimento a una condizione clinica caratterizzata da una alterazione dell’assetto lipidico in tutte le sue componenti: colesterolo totale (TOT-C), colesterolo legato alle lipoproteine ad alta densità (HDL-C), colesterolo legato alle lipoproteine a bassa densità (LDL-C) e trigliceridi (TG). Un disequilibrio di uno o più di questi parametri contribuisce all’incremento del rischio cardiovascolare, determinato in primis dall’accelerazione dei processi aterosclerotici.
Sono attualmente disponibili numerose opzioni terapeutiche per la gestione della dislipidemia, che spaziano da quelle più convenzionali – come gli inibitori della 3-idrossi-3-metilglutaril-coenzima A (HMG-CoA) reduttasi e inibitori selettivi dell’assorbimento del colesterolo – fino ad arrivare a terapie di più recente introduzione, quali gli inibitori della proproteina convertasi subtilisina/kexina di tipo 9 (PCSK9i), i sequestranti degli acidi biliari, gli anticorpi monoclonali, gli integratori alimentari, gli inibitori della sintesi e dell’assorbimento del colesterolo e i promotori dell’escrezione di LDL-C.
L’obiettivo di questa review è fornire una panoramica sistematica dei diversi trattamenti disponibili alla luce di due fattori fondamentali: l’ampio ventaglio di opzioni farmacologiche a disposizione e le recenti novità, in tema di prescrivibilità, che consentono anche allo specialista in nefrologia di prescrivere i farmaci di più recente introduzione.

Parole chiave: inibitori della ANGPTL3, oligonucleotidi antisenso (ASO), inibitori della proteina di trasferimento degli esteri del colesterolo, dislipidemia, inibitori della proproteina convertasi subtilisina/kexina tipo 9 (PCSK9)

Introduzione

Con il termine “dislipidemia” si intende una condizione caratterizzata da livelli anormali di lipidi nel sangue e, più specificamente, da una riduzione dei livelli di colesterolo HDL accompagnata da un contestuale aumento dei trigliceridi, del colesterolo totale e del colesterolo LDL [1]. Questo assetto lipidico si associa significativamente a un aumentato rischio cardiovascolare, in virtù di un incremento del grado di aterosclerosi che, a sua volta, determina un’incidenza più elevata di malattia coronarica e, conseguentemente, una maggiore morbilità e mortalità per cause cardiovascolari, soprattutto nei pazienti con concomitante malattia renale cronica [2].

Interventi farmacologici come gli inibitori del 3-idrossi-3-metilglutaril-coenzima A (HMG-CoA) reduttasi e gli inibitori selettivi dell’assorbimento del colesterolo sono tradizionalmente impiegati nel trattamento della dislipidemia [3]. Tuttavia, pur essendo farmaci efficaci nel migliorare il profilo lipidico, il loro utilizzo è spesso limitato dall’insorgenza di effetti collaterali che possono ridurre l’aderenza del paziente alla terapia.

Alla luce di ciò, l’interesse verso lo sviluppo di nuovi farmaci ipolipemizzanti, caratterizzati da meccanismi d’azione innovativi e da favorevole rapporto costo/beneficio, è cresciuto in maniera esponenziale negli ultimi anni. In questa revisione, verrà presentato un quadro completo dei trattamenti attualmente disponibili, nonché di quelli di prossima introduzione, con particolare attenzione ai diversi meccanismi d’azione, all’efficacia e agli effetti collaterali.

 

Fisiologia, eziologia e fisiopatologia

Il fegato, noto per il suo ruolo centrale nel metabolismo lipidico, è l’organo principale responsabile della sintesi, dell’assorbimento e dell’escrezione di colesterolo e trigliceridi. Svolge una funzione cruciale nel mantenimento dell’omeostasi lipidica, un equilibrio che, se alterato a qualsiasi livello, conduce principalmente a un incremento dei livelli sierici di colesterolo LDL e a una concomitante riduzione di colesterolo HDL, favorendo la deposizione lipidica a livello dell’endotelio vascolare, soprattutto nei vasi arteriosi di calibro maggiore [4].

Nei pazienti con malattia renale cronica (CKD), le alterazioni del metabolismo lipidico presentano caratteristiche peculiari che contribuiscono al rischio cardiovascolare estremamente elevato in questa popolazione. Il pattern tipico di dislipidemia in CKD è caratterizzato da ipertrigliceridemia, riduzione del colesterolo HDL e presenza di particelle LDL piccole e dense, particolarmente aterogene. Queste anomalie derivano da un complesso interplay tra ridotta attività della lipoprotein lipasi (LPL), aumento delle lipoproteine ricche di trigliceridi (VLDL, IDL), stato infiammatorio cronico, stress ossidativo e alterazioni ormonali associate all’insufficienza renale. Inoltre, la ridotta espressione dei recettori LDL a livello epatico e l’accumulo di apolipoproteina C-III e ANGPTL3 favoriscono un rallentamento della clearance lipidica e un progressivo aggravamento del quadro aterogenico.

Il processo di sintesi ha inizio a livello dell’intestino tenue, dove l’assorbimento del colesterolo di origine alimentare, mediato principalmente dalla proteina Niemann-Pick C1-Like 1 (NPC1L1), porta successivamente alla sintesi dei chilomicroni. Queste lipoproteine a bassa densità e ampio diametro incorporano apolipoproteine (ApoB48), trigliceridi e colesterolo di derivazione alimentare. Dopo la sintesi, i cosiddetti “chilomicroni nascenti” vengono riversati nel sistema linfatico e, successivamente, nel circolo sanguigno, dove, grazie all’aggiunta di ApoC2 e ApoE da parte delle lipoproteine HDL, maturano diventando “chilomicroni maturi”.

L’interazione tra la lipoprotein lipasi (LPL) endoteliale dei vasi dei tessuti adiposo e muscolare e ApoC2 consente l’idrolisi dei trigliceridi e la loro incorporazione nei tessuti. Successivamente, i chilomicroni interagiscono nuovamente con le HDL, cedendo a queste ultime ApoC2, colesterolo non esterificato e fosfolipidi, in cambio di colesterolo esterificato. Il prodotto finale di questo processo, i cosiddetti “chilomicroni remnant”, raggiunge il fegato, dove, grazie all’interazione di ApoE con il recettore per le LDL (LDL-R), viene endocitato e smaltito (Figura 1) [5].

Metabolismo esogeno del colesterolo e assorbimento intestinale
Figura 1. Metabolismo esogeno del colesterolo e assorbimento intestinale. Il diagramma rappresenta il processo di assorbimento e trasporto del colesterolo di origine alimentare (dietetico) e biliare nell’organismo. FC (Free Cholesterol): colesterolo libero, presente nelle micelle formate nel lume intestinale; CE (Cholesteryl Ester): colesterolo esterificato, forma in cui il colesterolo viene trasportato all’interno delle lipoproteine; ACAT (Acyl-CoA:Cholesterol Acyltransferase): enzima presente negli enterociti che catalizza l’esterificazione del colesterolo libero (FC) in colesterolo esterificato (CE); Remnants: residui dei chilomicroni (chilomicron remnants) che, dopo aver ceduto trigliceridi ai tessuti, restano ricchi di colesterolo e vengono captati dal fegato; Chilomicroni (Chylomicrons): lipoproteine sintetizzate dagli enterociti per trasportare trigliceridi e colesterolo esterificato attraverso il sistema linfatico e successivamente nel circolo sanguigno; Brush Border: microvilli degli enterociti che aumentano la superficie di assorbimento nel piccolo intestino; Vie biliari: sistema di dotti che trasporta gli acidi biliari e il colesterolo libero sintetizzati nel fegato fino al lume intestinale; Circolo linfatico: via attraverso la quale i chilomicroni entrano nel sistema circolatorio; Formazione della placca: accumulo di CE proveniente dai remnants che può contribuire all’aterosclerosi.

In aggiunta al colesterolo esogeno, di norma non sufficiente a soddisfare le necessità dell’organismo, il fegato svolge una funzione di sintesi endogena. Questa ha inizio con il trasferimento di due atomi di carbonio dal citrato al coenzima A per generare acetil-CoA, un processo catalizzato dall’enzima adenosina trifosfato (ATP)-citrato liasi (ACL). Dalla condensazione di due molecole di acetil-CoA si forma acetoacetil-CoA, che a sua volta reagisce con un’ulteriore molecola di acetil-CoA per produrre 3-idrossi-3-metilglutaril-CoA (HMG-CoA). Quest’ultimo, grazie all’azione dell’enzima HMG-CoA reduttasi, viene ridotto ad acido mevalonico.

L’aggiunta di due gruppi fosfato porta alla formazione del Δ3-isopentenil pirofosfato che, per condensazione di due molecole, genera il geranil pirofosfato. Quest’ultimo, con l’aggiunta di un’ulteriore molecola di Δ3-isopentenil pirofosfato, forma il farnesil pirofosfato che, per condensazione tra due molecole, origina lo squalene. Lo squalene viene poi ciclicizzato in lanosterolo e, successivamente, demetilato per diventare colesterolo (Figura 2).

Il colesterolo così sintetizzato non può essere liberato direttamente in circolo, ma necessita di un trasporto mediato dalle lipoproteine prodotte sempre a livello epatico. Tra queste, le VLDL (lipoproteine a bassissima densità) sono le prime a essere prodotte e immesse in circolo. Le VLDL incorporano apolipoproteine (ApoB100), trigliceridi, fosfolipidi e colesterolo esterificato. Una volta in circolo, seguono un processo simile a quello dei chilomicroni, maturando e interagendo con l’endotelio vascolare dei tessuti adiposo e muscolare per la cessione dei trigliceridi.

A seguito di una seconda interazione con le HDL, le VLDL si trasformano in lipoproteine a densità intermedia (IDL). Le IDL, ricche di colesterolo esterificato, raggiungono il fegato grazie all’interazione di ApoB100 e ApoE con il recettore per le LDL (LDL-R). La restituzione di ApoE a una HDL nascente consente la trasformazione delle IDL in LDL, che vengono in parte endocitate dal fegato e in parte immesse in circolo per fornire colesterolo ai tessuti periferici [6].

Biosintesi epatica del colesterolo
Figura 2. Biosintesi epatica del colesterolo. Schema che rappresenta le principali tappe della sintesi endogena del colesterolo a partire dal citrato nel fegato: Citrato: intermedio del ciclo di Krebs trasportato nel citosol come fonte di acetil-CoA; ATP-citrato liasi: enzima che catalizza la scissione del citrato in acetil-CoA e ossalacetato; Acetil-CoA + A: condensazione di due molecole di acetil-CoA per formare acetoacetil-CoA; Acetil-CoA acetiltransferasi: enzima che catalizza la reazione sopra; HMG-CoA (3-idrossi-3-metilglutaril-CoA): formato dall’aggiunta di una terza molecola di acetil-CoA ad acetoacetil-CoA; HMG-CoA sintasi: enzima che catalizza la formazione di HMG-CoA; Mevalonato: prodotto dalla riduzione di HMG-CoA; HMG-CoA reduttasi: enzima chiave e target delle statine; catalizza la conversione di HMG-CoA in mevalonato; Isopentenil pirofosfato: unità isoprenoide attivata, base per la sintesi di molecole più grandi; Squalene: precursore lineare del colesterolo ottenuto dalla condensazione di sei unità isoprenoidi; Colesterolo: prodotto finale dopo ciclizzazione dello squalene e rimozione di gruppi metilici.

Alla luce di questi complessi meccanismi di regolazione, le alterazioni del metabolismo lipidico possono essere ascritte, da un punto di vista fisiopatologico, sia a fattori ereditari (dislipidemia primaria) sia a fattori ambientali (dislipidemia secondaria). Tra i primi rientrano condizioni ereditarie ormai unanimemente riconosciute, come la sindrome da chilomicronemia familiare (FCS), l’ipercolesterolemia familiare omozigote (HoFH) e l’ipercolesterolemia familiare eterozigote (HeFH) [7] (Figura 3). I meccanismi coinvolti riguardano principalmente difetti di sintesi, trasporto o degradazione delle lipoproteine, con conseguente accumulo di lipidi nel sangue e accelerazione dei processi aterosclerotici.

Figura 3. Fisiopatologia delle sindromi dislipidemiche ereditarie
Figura 3. Fisiopatologia delle sindromi dislipidemiche ereditarie. Sindrome da chilomicronemia familiare (FCS): Malattia genetica rara caratterizzata da un’inibizione dell’attività della lipoprotein lipasi (LPL), enzima coinvolto nell’idrolisi e nell’internalizzazione cellulare (a livello del tessuto adiposo e muscolare) dei trigliceridi contenuti nei chilomicroni e nelle lipoproteine a bassissima densità (VLDL). I sintomi più comuni comprendono dolore addominale, nausea, affaticamento e, nei casi più gravi, pancreatite acuta. Alcuni pazienti possono presentare xantomi eruttivi (lesioni cutanee lipidiche) ed epatosplenomegalia (ingrossamento del fegato e della milza). Nei bambini, la malattia può essere asintomatica o manifestarsi con ritardo della crescita. La diagnosi si basa sull’identificazione di livelli molto elevati di trigliceridi nel sangue e sulla presenza di chilomicronemia. La conferma richiede l’analisi genetica per individuare mutazioni nel gene LPL. Il trattamento ha l’obiettivo di ridurre i livelli di trigliceridi e prevenire complicanze, in particolare la pancreatite. Ipercolesterolemia familiare (FH): Malattia genetica caratterizzata da un’inibizione dell’attività del recettore per le LDL (LDL-R), responsabile del legame e dell’internalizzazione di varie lipoproteine a livello epatico (lipoproteine a bassa densità – LDL; lipoproteine a densità intermedia – IDL; chilomicroni remnants). Può presentarsi in forma eterozigote (HeFH), meno grave e spesso asintomatica, o in forma omozigote (HoFH), molto rara ma anche significativamente più severa. A seconda del genotipo, la patologia si caratterizza per elevati livelli di colesterolo LDL nel sangue, presenza di xantomi, xantelasmi e arco corneale fin dalla giovane età, associati a un alto rischio cardiovascolare e cerebrovascolare. Il trattamento mira a ridurre i livelli di colesterolo LDL per prevenire o rallentare lo sviluppo di malattie cardiovascolari, mediante farmaci, modifiche dello stile di vita e, in alcuni casi, procedure mediche aggiuntive.

I fattori ambientali giocano un ruolo determinante nella fisiopatologia della dislipidemia secondaria, influenzando il metabolismo lipidico attraverso meccanismi che coinvolgono la regolazione della sintesi, del trasporto e della clearance delle lipoproteine. Un’alimentazione ricca di grassi saturi e acidi grassi trans riduce l’espressione dei recettori per le LDL (LDL-R) a livello epatico e promuove la produzione di VLDL, favorendo così l’accumulo di LDL circolanti, in particolare delle particelle piccole e dense (sdLDL), notoriamente più aterogene. Un elevato apporto di carboidrati semplici stimola la lipogenesi de novo, mentre una dieta povera di fibre e acidi grassi polinsaturi compromette la clearance del colesterolo LDL.

La sedentarietà, associata a una riduzione dell’attività della lipoprotein lipasi (LPL) muscolare, contribuisce all’aumento dei trigliceridi plasmatici e a un decremento dei livelli di colesterolo HDL, effetti ulteriormente esacerbati dall’accumulo di tessuto adiposo viscerale. Quest’ultimo, attraverso la liberazione di acidi grassi liberi (FFA) e di adipocitochine proinfiammatorie come TNF-α e IL-6, induce insulino-resistenza e un’iperproduzione epatica di VLDL. Anche l’assunzione eccessiva di alcol favorisce l’ipertrigliceridemia attraverso l’aumento della sintesi epatica di trigliceridi, mentre il fumo di sigaretta riduce i livelli di HDL-C e favorisce l’ossidazione delle LDL, potenziandone l’aterogenicità. Il sonno insufficiente e lo stress cronico, attraverso l’attivazione dell’asse ipotalamo-ipofisi-surrene e l’aumento dei livelli di cortisolo, rappresentano ulteriori fattori ambientali che possono influire negativamente sull’equilibrio lipidico.

Anche la malattia renale cronica rappresenta un importante fattore di rischio, poiché associata ad alterazioni del catabolismo delle lipoproteine contenenti ApoB e a una ridotta attività della lipoprotein lipasi e della lipasi epatica, compromettendo l’eliminazione dei trigliceridi e del colesterolo dal sangue.

 

Il ruolo della dislipidemia nell’aterosclerosi e nelle malattie cardiovascolari

La presenza di un quadro dislipidemico innesca una serie di eventi patologici immuno-mediati che portano allo sviluppo dell’aterosclerosi e, di conseguenza, a un incremento del rischio di malattie cardiovascolari su base aterosclerotica (ACVD). Quando il colesterolo in eccesso si accumula nella parete arteriosa, va incontro a ossidazione, stimolando le cellule endoteliali a produrre molecole di adesione intercellulare-1 (ICAM-1) e selectina Endoteliale (E-selectina) [15, 16].

Questa condizione richiama, tramite l’azione della proteina chemioattrattiva 1(MCP-1), i monociti che aderiscono alla parete vascolare. Una volta migrati nell’intima arteriosa, i monociti si differenziano in macrofagi che fagocitano il colesterolo ossidato trasformandosi nelle cosiddette cellule schiumose (foam cells), le quali contribuiscono ulteriormente alla formazione della placca aterosclerotica [17, 18]. Parallelamente, viene rilasciata interleuchina-6 (IL-6), che alimenta il processo infiammatorio e l’ossidazione del colesterolo in un circolo vizioso [19, 20].

Nel tempo, la continua deposizione di foam cells e mediatori immunitari porta a un progressivo restringimento del lume vascolare, aumentando il rischio di infarto del miocardio (IM) ed ictus [21] (Figura 4).

Appare quindi evidente come questa interazione ossidativo-immunitaria rappresenti un target fondamentale per lo sviluppo di nuove terapie mirate al controllo dei livelli sierici di colesterolo e alla prevenzione delle patologie cardiovascolari.

Meccanismi fisiopatologici coinvolti nella formazione di placche aterosclerotiche
Figura 4. Meccanismi fisiopatologici coinvolti nella formazione di placche aterosclerotiche riconducibili ad ipercolesterolemia. Il diagramma illustra il processo mediante il quale la dislipidemia promuove l’aterosclerosi: l’accumulo di colesterolo nelle pareti arteriose porta alla sua ossidazione, stimolando la produzione di citochine proinfiammatorie e molecole di adesione endoteliale. Questo processo favorisce l’ingresso dei monociti attraverso l’endotelio, la loro differenziazione in macrofagi e la formazione di cellule schiumose (foam cells), che si accumulano nella parete vascolare contribuendo alla formazione della placca aterosclerotica. Acronimi: ICAM-1 (Intercellular Adhesion Molecule-1): molecola di adesione cellulare che facilita l’adesione dei leucociti all’endotelio; E-Selectina (Endothelial Selectin): proteina di adesione espressa dalle cellule endoteliali attivate, coinvolta nel reclutamento dei leucociti; IL-6 (Interleuchina-6): citochina proinfiammatoria che amplifica la risposta infiammatoria locale; MCP-1 (Monocyte Chemoattractant Protein-1, qui indicata come proteina chemoattrattiva-1): proteina coinvolta nel richiamo dei monociti verso la zona di infiammazione.

 

Diagnosi

Essendo la dislipidemia una condizione a decorso silente, la diagnosi precoce si basa sull’esecuzione di esami ematochimici di screening, particolarmente raccomandati nelle popolazioni ad alto rischio. È fondamentale un’anamnesi familiare accurata per identificare eventuali condizioni genetiche, nonché un’analisi approfondita dei fattori di rischio per avviare tempestivamente le misure correttive appropriate. Anche l’anamnesi patologica remota riveste un ruolo essenziale per individuare quei pazienti candidabili a terapie di prevenzione primaria o secondaria.

In alcuni pazienti con forme di dislipidemia grave o non adeguatamente trattata, possono manifestarsi segni e sintomi legati alle complicanze, quali xantomi cutanei, aterosclerosi, coronaropatia, arteriopatia periferica, ictus e insufficienza cardiaca. Lo strumento principale per la diagnosi e la valutazione del rischio è rappresentato dagli esami ematochimici, in particolare dall’analisi del profilo lipidico. I valori di riferimento devono essere interpretati in relazione all’età e alla storia clinica del paziente.

 

Opzioni terapeutiche attuali

Le statine

Le statine rappresentano una delle classi di farmaci più conosciute e utilizzate nella pratica clinica per la riduzione dei livelli di colesterolo LDL. La loro azione si basa sull’inibizione competitiva dell’enzima 3-idrossi-3-metilglutaril-CoA- Reduttasi (HMG-CoA-reduttasi) enzima chiave nella via biosintetica del colesterolo. Nello specifico, tale enzima catalizza la conversione dell’HMG-CoA in acido mevalonico, un precursore fondamentale per la sintesi del colesterolo. Inibendo questa reazione, le statine riducono la produzione epatica di colesterolo e aumentano la clearance delle LDL, determinando una significativa riduzione delle concentrazioni plasmatiche di LDL-C (Figura 5) [8].

Sebbene rappresentino la terapia di prima linea per la gestione dell’ipercolesterolemia e per la riduzione del rischio cardiovascolare, il trattamento con statine non è privo di effetti collaterali. Tra questi figurano iperglicemia, aumento dei livelli plasmatici degli enzimi epatici e rischio di rabdomiolisi, con sintomatologia muscolare caratterizzata da mialgie diffuse. Questa sindrome clinica è conosciuta con l’acronimo di SAMS [22, 23].

Studi di genomica hanno inoltre evidenziato una possibile predisposizione genetica allo sviluppo di SAMS, associata alla presenza di varianti del gene TMEM9 (Transmembrane Protein 9) [24, 25]. Tentativi di ridurre il rischio di miolisi mediante l’integrazione di vitamina D hanno prodotto risultati inconcludenti. Inoltre, per il rischio di iperglicemia, i pazienti in terapia cronica con statine presentano un aumento del rischio di sviluppare diabete mellito tipo 2 [26].

Meccanismo d’azione delle statine nella biosintesi del colesterolo.
Figura 5. Meccanismo d’azione delle statine nella biosintesi del colesterolo. Il diagramma rappresenta la via biosintetica del colesterolo e il punto d’azione delle statine. La sintesi del colesterolo parte dall’acetil-CoA, che attraverso una serie di reazioni enzimatiche viene convertito in HMG-CoA (3-idrossi-3-metilglutaril-CoA) e successivamente in acido mevalonico grazie all’enzima HMG-CoA reduttasi, che costituisce il punto di controllo regolatorio della via. Le statine agiscono inibendo competitivamente la HMG-CoA reduttasi, riducendo così la produzione di mevalonato, un precursore essenziale per la sintesi del colesterolo. Ciò comporta una diminuzione della sintesi epatica di colesterolo e un aumento dell’espressione dei recettori per le LDL (LDL-R) sulla superficie degli epatociti, migliorando la clearance delle LDL circolanti.

Ezetimibe

L’ezetimibe esercita la sua azione farmacologica inibendo la proteina Niemann-Pick C1-Like 1 (NPC1L1). Questa proteina, localizzata principalmente sulla membrana plasmatica apicale degli enterociti, è responsabile del trasporto del colesterolo attraverso la membrana per la successiva immissione in circolo. L’inibizione di NPC1L1 da parte dell’ezetimibe determina quindi un blocco dell’assorbimento del colesterolo a livello dell’intestino tenue (Figura 6) [27].

Le linee guida nazionali e internazionali raccomandano la somministrazione combinata di statina ed ezetimibe alla luce dei risultati positivi emersi da diversi trials clinici. Nello studio RACING, circa 3.780 pazienti con malattia cardiovascolare aterosclerotica (ASCVD) sono stati randomizzati a ricevere un regime terapeutico a intensità moderata, costituito dall’associazione ezetimibe/rosuvastatina, oppure una monoterapia con rosuvastatina ad alta intensità. Dopo tre anni di trattamento, nel gruppo trattato con terapia combinata i livelli di LDL-C risultavano inferiori al target di 70 mg/dL nel 72% dei pazienti rispetto al 58% nel gruppo in monoterapia con rosuvastatina (p < 0,0001). Inoltre, la combinazione ha mostrato una migliore tollerabilità: la riduzione del dosaggio o l’interruzione del trattamento per effetti avversi è stata necessaria in 88 pazienti del gruppo combinato, rispetto a 150 pazienti del gruppo in monoterapia, principalmente per una minore incidenza di intolleranza muscolare [28].

Pertanto, si può concludere che l’associazione ezetimibe/statina offre una maggiore riduzione dei livelli di colesterolo LDL e una migliore tolleranza rispetto alla tradizionale monoterapia con statine.

Per quanto riguarda la monoterapia con ezetimibe, gli effetti a lungo termine restano meno definiti e richiedono ulteriori studi. Tuttavia, lo studio EWTOPIA 75 ha mostrato risultati promettenti: i pazienti trattati con 10 mg di ezetimibe hanno registrato una riduzione dei livelli di colesterolo LDL del 25,9% e una diminuzione del rischio di eventi cardiovascolari del 34% [29].

Meccanismo d’azione dell’ezetimibe nell’assorbimento intestinale del colesterolo
Figura 6. Meccanismo d’azione dell’ezetimibe nell’assorbimento intestinale del colesterolo. Il diagramma rappresenta il ruolo della proteina Niemann-Pick C1-Like 1 (NPC1L1) nell’assorbimento intestinale del colesterolo e il punto d’azione dell’ezetimibe. Il colesterolo introdotto con la dieta viene assorbito a livello dell’intestino tenue grazie al trasporto mediato da NPC1L1, situata sulla membrana apicale degli enterociti. Una volta assorbito, il colesterolo viene incorporato nei chilomicroni per l’immissione nel circolo linfatico e sanguigno. L’ezetimibe inibisce selettivamente NPC1L1, bloccando il trasporto del colesterolo alimentare attraverso la membrana enterocitaria e riducendo così la quota di colesterolo assorbito. Questo effetto comporta una diminuzione dei livelli di colesterolo totale e LDL-C nel sangue. Acronimi: NPC1L1 (Niemann-Pick C1-Like 1): proteina trasportatrice del colesterolo localizzata sugli enterociti; LDL-C (Low-Density Lipoprotein Cholesterol): colesterolo associato alle lipoproteine a bassa densità.

Fibrati

L’azione dei fibrati si esplica attraverso l’attivazione dei recettori nucleari PPAR–α (Peroxisome Proliferator-Activated Receptor alpha), localizzati principalmente a livello epatico. Questi recettori regolano l’espressione di geni coinvolti nel metabolismo lipidico. La loro attivazione induce una cascata di eventi molecolari che porta a un’aumentata degradazione dei trigliceridi e a un contemporaneo incremento della sintesi delle HDL.

In particolare, i fibrati stimolano la produzione della lipoprotein lipasi (LPL), enzima che idrolizza i trigliceridi presenti nelle lipoproteine ricche di trigliceridi, come le VLDL (very-low-density lipoproteins). Inoltre, riducono la produzione epatica di VLDL, contribuendo così ad una significativa riduzione dei trigliceridi circolanti (Figura 7).

Questo meccanismo d’azione è cruciale per il miglioramento del profilo lipidico complessivo, determinando la riduzione dei livelli di trigliceridi, del colesterolo lipoproteico ricco di trigliceridi (TRL-C, triglyceride-rich lipoprotein cholesterol) e della Lipoproteina(a) (Lp(a)). Contestualmente, stimolano l’ossidazione degli acidi grassi e aumentano la sintesi di LPL [30].

Meccanismo d’azione dei fibrati sulla regolazione genetica del metabolismo lipidico.
Figura 7. Meccanismo d’azione dei fibrati sulla regolazione genetica del metabolismo lipidico. Il diagramma illustra come i fibrati attivino il recettore nucleare PPAR-α (Peroxisome Proliferator-Activated Receptor alpha), che da stato inattivo passa a uno stato attivo, modulando positivamente l’espressione genica di numerosi target coinvolti nel metabolismo lipidico; Geni coinvolti nella beta-ossidazione: stimolano l’ossidazione degli acidi grassi nei mitocondri, con aumento dell’idrolisi dei trigliceridi, riduzione della sintesi di acidi grassi liberi (FFA, Free Fatty Acids) e trigliceridi (TG, Triglycerides), e maggiore clearance delle particelle ricche di trigliceridi; Gene per LPL (Lipoprotein Lipase): aumenta l’espressione dell’enzima lipoprotein lipasi, potenziando l’idrolisi dei trigliceridi presenti nelle VLDL e nei chilomicroni; Gene per Apo CIII: la soppressione dell’espressione di apolipoproteina CIII riduce la secrezione epatica di VLDL; Geni per Apo AI e Apo AII: stimolano la produzione di apolipoproteine AI e AII, principali componenti delle HDL, contribuendo all’aumento dei livelli di colesterolo HDL. L’effetto finale è una marcata riduzione dei trigliceridi plasmatici, con miglioramento del profilo lipidico complessivo.

Fenofibrato

Nello studio FIELD è stato valutato l’uso del fenofibrato in monoterapia in pazienti non precedentemente trattati con statine. I risultati hanno mostrato una significativa riduzione dei livelli di LDL, trigliceridi (TG) e colesterolo totale. Le donne hanno evidenziato una maggiore riduzione dei livelli di colesterolo totale sia dopo quattro mesi (14% contro 9.9% negli uomini) sia al termine dello studio (9.5% contro 5.2% negli uomini). Analogamente, nelle donne si è osservata una maggiore riduzione dell’LDL a quattro mesi (16,5% contro 9.4% negli uomini) e alla fine dello studio (9.3% contro il 3,3% negli uomini). Complessivamente il fenofibrato ha ridotto la percentuale di pazienti con dislipidemia dal 42,7% al 23,9% nelle donne e dal 34,0% al 20,2% negli uomini [31].

Anche la terapia di combinazione con statina e fenofibrato si è dimostrata efficace nel ridurre i livelli sierici di trigliceridi e colesterolo non-HDL, con una concomitante riduzione dei livelli di proteina C-reattiva [32].

Gemfibrozil

Il gemfibrozil è noto per inibire il metabolismo delle statine attraverso la via della glucuronidazione, agendo sui trasportatori CYP2C8 e OATP1B1. Questo meccanismo aumenta la concentrazione plasmatica delle statine e, di conseguenza, il rischio di effetti collaterali associati, come la SAMS (Statin-Associated Muscle Symptoms) [33]. Le statine con rischio maggiore di interazione sono la simvastatina, lovastatina e pravastatina [34].

Tra gli effetti avversi del gemfibrozil è riportata anche epatotossicità da attivazione cronica del PPAR-α, con alterazione dell’omeostasi dei fosfolipidi e degli acidi biliari. [35]. Per questi motivi, il gemfibrozil è ormai caduto in disuso nella pratica clinica.

Resine sequestranti degli acidi biliari

Le resine sequestranti sono utili nel trattamento della dislipidemia per la loro capacità di legare gli acidi biliari a livello intestinale, impedendone il riassorbimento. Questo legame porta alla formazione di un complesso insolubile che viene eliminato con le feci [39]. La riduzione della circolazione enteroepatica degli acidi biliari stimola il fegato a produrre nuovi acidi biliari dal colesterolo, abbassando così i livelli sierici di LDL-C.

Effetti collaterali comuni includono stipsi ed altri sintomi gastrointestinali (gastro-duodenite). Inoltre, queste resine possono interferire con l’assorbimento di farmaci come digossina, warfarin e ormoni tiroidei [40].

Acidi grassi Omega-3

Gli acidi grassi omega-3 sono polinsaturi presenti in diverse fonti alimentari: il pesce azzurro è ricco di acido eicosapentaenoico (EPA) e acido docosaesaenoico (DHA), mentre fonti vegetali forniscono acido alfa-linolenico (ALA). Questi acidi grassi riducono la sintesi epatica di trigliceridi mediante la diminuzione della produzione di VLDL e ne favoriscono il metabolismo. Inoltre, possiedono proprietà antitrombotiche e antinfiammatorie, con benefici a livello vascolare [47]. L’integrazione è particolarmente utile nei pazienti con ipertrigliceridemia grave e/o ad alto rischio cardiovascolare.

 

Nuove opportunità terapeutiche

Inibitori della proproteina convertasi subtilisina/kexina tipo 9 (PCSK9i)

La PCSK9 è una proteina epatica che si lega ai recettori per LDL (LDL-R) presenti sulla superficie degli epatociti, promuovendone la degradazione lisosomiale. Questo processo riduce il numero di recettori disponibili e aumenta i livelli plasmatici di LDL-C. La sintesi di PCSK9 è stimolata da fattori come dieta, glucagone, insulina, resistina e TNF-α [41].

Gli inibitori di PCSK9 impediscono la degradazione dei recettori LDL, favorendone il riciclo e aumentando la clearance del colesterolo LDL circolante (Figura 8) [11]. Dal 2015 sono stati approvati alirocumab ed evolocumab PCSK9i [42].

Alirocumab

Alirocumab è un anticorpo monoclonale IgG2 umanizzato che si lega alla PCSK9, impedendo l’interazione con i recettori LDL. La sua efficacia è stata valutata in molti studi. I pazienti presi in esame erano diabetici e dislipidemici, quindi a maggior rischio di sviluppo di disturbi metabolici e malattie cardiovascolari per incapacità con le terapie tradizionali di raggiungere i livelli target di LDL, HDL e Apo B [43]. Nello studio ODYSSEY DM-INSULIN, alirocumab è stato in grado di ridurre significativamente i livelli di LDL-C nei pazienti con Diabete Mellito I e II così come i livelli di Apo-B e il colesterolo non-HDL [44]. Come effetti collaterali Alirocumab è stato associato a lievi infezioni respiratorie e reazioni al sito di iniezione in una minoranza di pazienti.

Nello studio ODYSSEY DM-DYSLIPIDEMIA, in cui sono stati messi a confronto pazienti in terapia con alirocumab e pazienti in terapia con fenofibrato, i dati hanno mostrato, nei pazienti diabetici con iperlipidemia mista, una riduzione del 33,3% del colesterolo non-HDL per il gruppo che utilizzava alirocumab rispetto al fenofibrato [45]. La riduzione dei livelli plasmatici di LDL-C è risultata essere immediata e la risposta si è mantenuta nel lungo periodo sia con la somministrazione classica ogni due settimane, sia con la più recente formulazione (300 mg) a somministrazione mensile.

Evolocumab

Evolocumab è un anticorpo monoclonale IgG1 umanizzato che blocca PCSK9, impedendone l’interazione con i recettori LDL, con conseguente incremento dei LDL-R. La sua efficacia è stata valutata nello studio FOURIER in pazienti diabetici e non. Evolocumab si è dimostrato in grado di ridurre i livelli di colesterolo LDL del 57%, di Apo B del 48%, di colesterolo non-HDL del 50% e dei trigliceridi del 16% nei pazienti diabetici. Inoltre, si è osservata una riduzione del 27% del rischio di infarto, del 21% di ictus e del 22% di rivascolarizzazione coronarica [46].

Lo studio Fourier ha, inoltre, evidenziato nella coorte di pazienti con malattia renale cronica – pazienti con valori di filtrato glomerulare compreso tra 30 e 59 ml/min/1.73m2 – una efficacia sovrapponibile a quella nei pazienti con funzione renale normale. Inoltre, dagli studi di farmacocinetica, si è dimostrato come nei pazienti in trattamento emodialitico non vi sia una sovraesposizione alla molecola aprendo, di fatto, all’impiego della molecola anche in questa popolazione di pazienti [46]. Anche nel caso di evolocumab, gli effetti collaterali si sono limitati a delle minime reazioni locali nel sito d’iniezione. Evolocumab prevede una somministrazione a cadenza bisettimanale, garantendo un’ottima compliance da parte del paziente. Inoltre, a differenza delle statine, evolocumab non determina un incremento dei livelli di emoglobina A1C nei pazienti diabetici.

Meccanismo d’azione degli inibitori di PCSK9 (PCSK9i) sulla regolazione dei recettori per LDL
Figura 8. Meccanismo d’azione degli inibitori di PCSK9 (PCSK9i) sulla regolazione dei recettori per LDL. Il diagramma mostra il ciclo dei recettori per LDL (Rec-LDL) negli epatociti e il ruolo della proteina PCSK9 (proproteina convertasi subtilisina/kexina di tipo 9) nel loro turnover. In condizioni normali, i Rec-LDL legano il colesterolo LDL (LDL-C) e, attraverso endocitosi, trasportano le particelle LDL all’interno della cellula. Dopo la liberazione del colesterolo nella cellula, i Rec-LDL vengono riciclati verso la membrana plasmatica per continuare a rimuovere LDL-C dal circolo.Quando PCSK9 si lega ai Rec-LDL, il complesso Rec-LDL–PCSK9 viene invece indirizzato verso i lisosomi, dove è degradato, riducendo così il numero di recettori disponibili per la clearance delle LDL-C. Gli inibitori di PCSK9 (PCSK9i), come alirocumab ed evolocumab, impediscono l’interazione tra PCSK9 e i Rec-LDL, favorendo il riciclo dei recettori e aumentando la rimozione di LDL-C dal sangue. Acronimi: PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9): enzima regolatore dei recettori per LDL; PCSK9i: inibitori di PCSK9, anticorpi monoclonali che bloccano PCSK9; Rec-LDL: recettore per lipoproteine a bassa densità; LDL-C: colesterolo associato alle lipoproteine a bassa densità.

Acido bempedoico

L’acido bempedoico è un agente ipolipemizzante indicato per la riduzione dei livelli plasmatici di colesterolo LDL nei pazienti con ipercolesterolemia familiare eterozigote (HeFH) e malattia cardiovascolare aterosclerotica (ASCVD). Si presenta come un profarmaco, che viene convertito nella sua forma attiva (bempedoil-coenzima-A) dall’enzima acil coenzima A sintetasi a catena molto lunga 1 (ACSVL1). Una volta attivato, il bempedoil-CoA inibisce l’ATP-citrato liasi, un enzima chiave nella via biosintetica del colesterolo che catalizza la conversione del citrato in acetil-CoA (Figura 9).

Questo meccanismo porta a un aumento dell’espressione dei recettori per LDL (LDL-R) e a una riduzione della sintesi epatica di colesterolo, migliorando la clearance delle LDL-C circolanti.

L’acido bempedoico si è dimostrato particolarmente utile nei pazienti intolleranti alle statine o che non raggiungono i target lipidici nonostante la terapia con statine a dosaggio massimo tollerato. Il profilo di tollerabilità è favorevole, con effetti collaterali contenuti tra cui lieve iperuricemia (dovuta a un’interazione con il trasportatore OAT1), infezioni del tratto urinario e un modesto incremento transitorio dei livelli sierici di creatinina [48].

L’efficacia del farmaco è stata valutata nello studio CLEAR HARMONY, studio randomizzato controllato che ha evidenziato una significativa riduzione dei livelli di LDL-C rispetto al placebo. Anche il profilo di sicurezza dell’acido bempedoico è risultato sovrapponibile a quello del placebo [49].

Inoltre, l’acido bempedoico ha dimostrato un effetto nella riduzione dei livelli di colesterolo totale e LDL-C quando somministrato in combinazione con statine o inibitori di PSK9.

Meccanismo d’azione dell’acido bempedoico nella via biosintetica del colesterolo
Figura 9. Meccanismo d’azione dell’acido bempedoico nella via biosintetica del colesterolo. Il diagramma illustra come l’acido bempedoico, un profarmaco, venga convertito nella sua forma attiva bempedoil-CoA dall’enzima ACSVL1 (acil coenzima A sintetasi a catena molto lunga 1). La forma attiva inibisce l’ATP-citrato liasi, un enzima chiave nella biosintesi del colesterolo che catalizza la conversione del citrato in acetil-CoA, precursore indispensabile per la sintesi del colesterolo. L’inibizione dell’ATP-citrato liasi riduce la produzione endogena di colesterolo nel fegato, stimola l’espressione dei recettori per LDL (LDL-R) e aumenta la clearance delle LDL-C circolanti. Questo meccanismo è particolarmente utile nei pazienti intolleranti alle statine o con livelli lipidici non a target nonostante la terapia statinica massimale. Acronimi: ACSVL1 (Acyl-CoA Synthetase Very Long Chain 1): enzima che attiva il bempedoico; ATP-citrato liasi: enzima che catalizza la conversione del citrato in acetil-CoA; LDL-C (Low-Density Lipoprotein Cholesterol): colesterolo associato alle lipoproteine a bassa densità; LDL-R (Low-Density Lipoprotein Receptor): recettore per LDL, responsabile della clearance del colesterolo LDL dal plasma.
Studio, Farmaco N° pazienti Meccanismo d’azione Effetti positivi Eventi avversi
CLEAR Harmony Clinical Trials, Acido Bempedoico 2230

Inibizione della

ATP-Citrato-Liasi

 Controllo della dislipidemia in pazienti intolleranti alle statine o che necessitano di una ulteriore riduzione di LDL-C associato alla massima dose tollerata di statine

Iperuricemia,

Nasofaringite,

Infezioni del tratto urinario,

Gotta
Tabella 1. Studio Clear Harmony.

siRNA PCSK9

Inclisiran

Inclisiran è uno small interfering RNA (siRNA) che agisce interferendo con la sintesi dell’RNA messaggero codificante la proteina PCSK9, bloccandone la produzione. Grazie alla coniugazione con N-acetilgalattosammina, inclisiran viene veicolato in maniera selettiva al fegato, principale sito di sintesi della PCSK9 (Figura 10). Questo meccanismo conferisce al farmaco una maggiore efficacia e una riduzione del rischio di effetti collaterali sistemici [14, 50].

L’efficacia e la sicurezza di inclisiran sono state valutate in diversi studi di fase III: ORION-9, ORION-10 e ORION-11. Nello specifico, lo studio ORION-9 ha incluso pazienti con ipercolesterolemia familiare e livelli di LDL-C ≥100 mg/dL nonostante la terapia con statine al massimo dosaggio tollerato. La somministrazione di inclisiran 284 mg al tempo zero, a 3 mesi e poi ogni 6 mesi ha portato a una riduzione del 48% dei livelli di LDL-C rispetto al placebo (p<0.0001).

Negli studi ORION-10 e ORION 11 sono stati arruolati rispettivamente 1561 e 1617 pazienti con ASCVD e livelli di LDL-C ≥70 mg/dL nonostante terapia ottimale con statine alla massima dose tollerata o con rischio equivalente a ASCVD e valori di LDL ≥100 mg/dL. In entrambi gli studi, i partecipanti sono stati randomizzati 1:1 a ricevere inclisiran 284 mg o placebo, somministrati al momento dell’arruolamento, dopo 90 giorni successivamente ogni 6 mesi per un periodo totale di 540 giorni.

Gli endpoint primari erano la variazione percentuale dei livelli LDL-C rispetto a placebo e rispetto al basale. Al giorno 510, inclisiran ha ottenuto una riduzione del LDL-C del 52% nello studio ORION-10 e del 50% nello studio ORION-11 (p<0.001). La terapia con statine era presente nell’89.2% dei pazienti di ORION-10 e nel 94.7% di ORION-11.

Gli eventi avversi registrati in questi studi sono stati generalmente lievi, prevalentemente reazioni locali al sito di iniezione, senza aumento significativo di eventi avversi gravi [51, 52].

Lerodalcibep

Lerodalcibep è un inibitore di PCSK9 di terza generazione che ha dimostrato di ottenere riduzioni consistenti e sostenute dei livelli di LDL-C in diverse popolazioni di pazienti, inclusi quelli con HeFH, ASCVD e HoFH.

Nello studio LIBerate-HeFH, Lerodalcibep ha determinato una riduzione del LDL-C del 58,6% dopo 24 settimane di trattamento, il 68% dei pazienti ha raggiunto i target raccomandati di LDL-C, accompagnati da una significativa riduzione dei livelli plasmatici di ApoB e Lp(a) [53].

Nello studio LIBerate-HoFH, condotto su pazienti con ipercolesterolemia familiare omozigote, la riduzione di LDL-C è stata più modesta (-4,9% per lerodalcibep vs -10,3% per evolocumab), suggerendo una limitata efficacia del farmaco nei soggetti con ridotta espressione dei recettori per LDL.

Lo studio LIBerate-CVD ha mostrato una riduzione significativa di LDL-C del 62% a 52 settimane e un tasso di raggiungimento del target LDL-C<55 mg/dL superiore al 90%, evidenziando un’efficacia sostenuta nel tempo nei pazienti con ASCVD [54].

Il profilo di sicurezza di lerodalcibep è stato eccellente in tutti gli studi, con effetti avversi limitati a lievi reazioni cutanee al sito di iniezione e nessuna segnalazione di eventi avversi gravi.

Meccanismo d’azione di Inclisiran (siRNA PCSK9)
Figura 10. Meccanismo d’azione di Inclisiran (siRNA PCSK9). Il diagramma mostra come Inclisiran, uno small interfering RNA (siRNA), inibisca la sintesi della proteina PCSK9 a livello epatico. Inclisiran è coniugato con N-acetilgalattosammina (GalNAc), che consente il legame selettivo al recettore asialoglicoproteina (ASGPR) presente sugli epatociti, favorendo l’endocitosi del complesso. All’interno della cellula, Inclisiran viene caricato nel complesso proteico RISC (RNA-Induced Silencing Complex). Qui, il filamento antisenso guida il RISC al target, cioè l’mRNA di PCSK9, che viene degradato. La degradazione dell’mRNA impedisce la sintesi della proteina PCSK9, determinando una maggiore espressione dei recettori LDL (LDL-R) sulla superficie degli epatociti. Questo incrementa l’assorbimento di LDL-C dal sangue e riduce i livelli plasmatici di colesterolo LDL.  Acronimi: siRNA (small interfering RNA): piccolo RNA interferente che silenzia specifici mRNA; GalNAc (N-acetilgalattosammina): molecola che media il targeting epatico; ASGPR (Asialoglycoprotein Receptor): recettore epatocitario per glicoproteine desialate; RISC (RNA-Induced Silencing Complex): complesso proteico che degrada l’mRNA target; PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9): proteina che regola il turnover dei recettori LDL; LDL-C (Low-Density Lipoprotein Cholesterol): colesterolo associato alle lipoproteine a bassa densità.
Prospetto degli studi clinici riguardanti Inclisiran e Lerodalcibep.
Tabella 2. Prospetto degli studi clinici riguardanti Inclisiran e Lerodalcibep.

 

Farmaci in fase di sperimentazione

Apolipoproteina C-III (apoC-III) siRNA

L’apolipoproteina C-III (ApoC-III) è una proteina prodotta principalmente a livello epatico, la cui azione consiste nell’inibire l’attività della lipoprotein lipasi (LPL), riducendo così il catabolismo delle lipoproteine ricche di trigliceridi, come chilomicroni e VLDL. Inoltre, ApoC-III ostacola la captazione epatica dei remnants di queste lipoproteine, inibendo l’interazione con i recettori epatici, e stimola la secrezione epatica di VLDL. Un’aumentata espressione di ApoC-III si osserva sia nelle dislipidemie primarie che in quelle secondarie.

La riduzione dell’espressione epatica di ApoC-III rappresenta quindi un target terapeutico strategico per il controllo della dislipidemia. In questo contesto, la terapia con siRNA anti-ApoC-III emerge come una delle novità più promettenti.

Questa classe farmacologica utilizza un meccanismo simile a quello di Inclisiran per raggiungere selettivamente gli epatociti: un filamento di RNA interferente (siRNA) silenzia l’espressione genica di ApoC-III a livello epatico, determinando: riduzione della sintesi di ApoC-III; maggiore attività della LPL (grazie alla ridotta inibizione); un incremento della clearance di chilomicroni e VLDL; una conseguente riduzione dei livelli sierici di trigliceridi [55].

Plozasiran

Plzasiran è un agente interferente basato sul silenziamento genico che ha come bersaglio ApoC-III. È stato studiato in pazienti con iperlipidemia mista in uno studio di fase 2b che ha coinvolto un totale di 353 partecipanti randomizzati.

Alla settimana 24, plozasiran ha determinato riduzioni significative dei livelli di trigliceridi a digiuno, con variazioni percentuali medie di LDL-C rispetto al placebo pari a: -49,8% con dose trimestrale da 10 mg, -56,0% con dose trimestrale da 25 mg, -62,4% con dose trimestrale da 50 mg; -44,2% con dose semestrale da 50 mg. Il trattamento ha inoltre ridotto significativamente i livelli di APOC-III: -57,3% a 10 mg, -72,5% a 25 mg, -78,5% a 50 mg, accompagnati da riduzioni del colesterolo non-HDL e dell’Apo-B rispettivamente del 16.7 e 24.2%.

In termini di sicurezza, non sono stati osservati aumenti degli enzimi epatici né alterazioni della conta piastrinica. Tuttavia, un peggioramento del controllo glicemico è stato riportato nel 10% del gruppo placebo rispetto al 12% del con 10 mg trimestrali, 7% con 25 mg trimestrali, 20% con 50 mg trimestrali, 21% con 50 mg semestrali [56].

Un altro studio di fase 2b (SHASTA-2) ha confermato l’efficacia di plozasiran nei pazienti con ipertrigliceridemia grave, mostrando riduzioni dei livelli di trigliceridi del 74% e di ApoC-III del 78%. Anche in questo caso non sono stati segnalati eventi avversi significativi, e nessun paziente ha interrotto il trattamento [57].

Alla luce di questi dati, plozasiran si configura come una promettente opzione terapeutica, capace di ottenere riduzioni acute e sostenute dei livelli di trigliceridi e un miglioramento complessivo dei profili lipidici aterogenici. Restano tuttavia necessari studi di fase III per confermare la sicurezza e l’efficacia a lungo termine.

Inibitori della proteina 3 simile all’angiopoietina (ANGPTL3i)

L’ANGPTL3 (proteina 3 simile all’angiopoietina) è una glicoproteina secreta principalmente dal fegato. La sua funzione consiste nell’inibire l’attività della lipoproteina lipasi (LPL) della lipasi endoteliale (EL) attraverso il legame della sua forma attiva con questi enzimi, causando la loro denaturazione e inattivazione. Questo effetto, analogo a quello dell’ApoC-III, comporta una riduzione del catabolismo delle lipoproteine ricche di trigliceridi, con conseguente aumento dei loro livelli plasmatici.

Un’aumentata espressione di ANGPTL3 è stata associata a condizioni dislipidemiche sia primarie che secondarie. Al contrario, studi di popolazione hanno evidenziato che nei pazienti portatori di una mutazione loss of function (LOF) di ANGPTL3 vi è una riduzione del rischio cardiovascolare. In particolare, i portatori eterozigoti di mutazioni LOF hanno mostrato: una riduzione del 34% del rischio di malattia coronarica (CAD) rispetto ai non portatori; una diminuzione del 17% dei livelli di trigliceridi; una riduzione del 12% dei livelli di LDL-C [66].

Evinacumab

Sulla base del ruolo regolatorio di ANGPTL3, sono stati sviluppati inibitori di questa proteina come potenziali agenti terapeutici. Evinacumab è un anticorpo monoclonale che si lega e inibisce ANGPTL3, risultanto efficace nel trattamento dell’ipercolesterolemia familiare [12, 67]. Studi di fase 3 hanno dimostrato che evinacumab è in grado di ridurre i livelli di LDL-C del 47,1% dell’LDL-C nei pazienti con ipercolesterolemia familiare; ridurre i livelli plasmatici di trigliceridi dell’88.2% nei pazienti con ipertrigliceridemia [12]. Inoltre, non sono stati segnalati eventi avversi gravi associati al trattamento.

Inibitori della diacilglicerolo aciltransferasi (DGATi)

La diacilglicerolo aciltransferasi (DGAT) è un enzima chiave nella sintesi dei trigliceridi e nella regolazione dell’omeostasi lipidica. DGAT catalizza l’ultimo passaggio della sintesi dei trigliceridi, favorendo la reazione tra diacilglicerolo (DAG) e acil-CoA per la formazione di trigliceridi e CoA libero. L’inibizione di DGAT rappresenta quindi un target terapeutico per ridurre la sintesi di trigliceridi e migliorare i profili lipidici nei pazienti con dislipidemia.

Pradigastat

Pradigastat è un inibitore selettivo di DGAT1 che ha dimostrato un effetto dose-dipendente nella riduzione dei livelli plasmatici di trigliceridi, chilomicroni e ApoB-48. Questa molecola si è rivelata potenzialmente utile per il trattamento di specifici sottotipi di dislipidemia, come la chilomicronemia familiare (FCS) [37]. Dal punto di vista della tollerabilità, pradigastat ha mostrato un buon profilo di sicurezza, con effetti collaterali limitati principalmente a lievi disturbi gastrointestinali.

Ervogastat

Ervogostat è un inibitore della diacilglicerolo aciltransferasi-2 (DGAT2i) che agisce bloccando la fase finale della sintesi dei trigliceridi. A differenza degli inibitori di DGAT1, ervogastat riduce i livelli di trigliceridi plasmatici senza indurre effetti collaterali gastrointestinali significativi [38]. Questo profilo lo rende un candidato interessante per future applicazioni terapeutiche nei disordini metabolici caratterizzati da ipertrigliceridemia.

Inibitori della proteina di trasferimento dei trigliceridi microsomiali

La proteina di trasferimento dei trigliceridi microsomiali (MTP) è un complesso eterodimerico situato nel lume del reticolo endoplasmatico di epatociti ed enterociti. È costituita da una subunità catalitica di 97 kDa e dalla proteina disolfuro isomerasi (PDI). La funzione principale di MTP è trasferire trigliceridi, esteri del colesterolo e fosfolipidi sulle apolipoproteine B nascenti (apoB-48 nell’intestino e apoB-100 nel fegato), facilitando così l’assemblaggio iniziale delle lipoproteine ricche di trigliceridi, come chilomicroni e VLDL.

Durante la biogenesi di queste lipoproteine, MTP fornisce il core lipidico essenziale che stabilizza le molecole di apoB, prevenendone la degradazione precoce tramite il sistema ubiquitina-proteasoma. La sua attività è quindi fondamentale per la secrezione efficiente delle lipoproteine contenenti apoB nel circolo sanguigno.

L’inibizione o la carenza di MTP, come osservato in condizioni genetiche rare quali l’abetalipoproteinemia (causata da mutazioni nel gene MTTP), compromette profondamente l’assemblaggio e la secrezione di chilomicroni e VLDL. Ne conseguono una marcata riduzione dei livelli plasmatici di colesterolo e trigliceridi, accumulo intracellulare di lipidi (steatosi) e sindromi da malassorbimento con deficit di vitamine liposolubili (A, D, E, K).

Per queste ragioni, MTP rappresenta un target farmacologico strategico per il trattamento di dislipidemie severe. L’inibizione controllata della sua attività è alla base dell’efficacia di farmaci come lomitapide, impiegato nella gestione dell’ipercolesterolemia familiare omozigote (HoFH), grazie alla sua capacità di ridurre la sintesi e la secrezione di VLDL e LDL-C.

Lomitapide

Lomitapide è un inibitore selettivo della proteina di trasferimento dei trigliceridi microsomiali (MTTPi), essenziale per l’assemblaggio e la secrezione delle lipoproteine contenenti ApoB, come chilomicroni e VLDL. È indicato per il trattamento di pazienti con gravi dislipidemie, tra cui la sindrome da chilomicronemia familiare (FCS) e l’ipercolesterolemia familiare omozigote (HoFH), con l’obiettivo di ridurre i livelli plasmatici di colesterolo LDL.

Il suo meccanismo d’azione consiste nel legarsi e inibire MTTP, bloccando così la formazione e la secrezione delle lipoproteine contenenti apolipoproteina B (ApoB) sia a livello intestinale che epatico.

Lo studio LOCHNES ha evidenziato che lomitapide è in grado di ridurre significativamente i livelli di trigliceridi (TG) e ApoB nei pazienti con FCS e HoFH. Inoltre, è stato osservato un incremento dei livelli di HDL-C. Il farmaco presenta un profilo di tollerabilità generalmente buono, con effetti collaterali modesti, prevalentemente di natura gastrointestinale [36].

Inibitori delle proteine di trasferimento degli esteri del colesterolo (CETPi)

La proteina di trasferimento degli esteri del colesterolo (CETP) è una glicoproteina plasmatica che media lo scambio di lipidi tra le lipoproteine plasmatiche. In particolare, trasferisce gli esteri del colesterolo dalle particelle di HDL-C alle lipoproteine contenenti apolipoproteina B (ApoB), come LDL-C e VLDL-C, in cambio di trigliceridi. Questa attività di scambio “scambio lipidico” riduce i livelli di HDL-C e favorisce l’arricchimento di LDL e VLDL con colesterolo, promuovendo la formazione di particelle LDL più piccole e dense (sdLDL), notoriamente più aterogene.

Alla luce delle funzioni, un’iperattività della CETP è stata associata a un aumento del rischio di aterosclerosi e malattie cardiovascolari (CVD). Gli inibitori della CETP (CETPi), bloccano questa proteina, determinando un incremento dei livelli plasmatici di HDL-C e una concomitante riduzione dei livelli di LDL-C. Tra i principali CETPi attualmente studiati vi sono CKD-519, obicetrapib, evacetrapib, torcetrapib e anacetrapib [58].

CKD-519

CKD-519 è un potente inibitore della CETP che ha dimostrato di ridurre l’attività della proteina del 63-83% con un conseguente incremento di HDL-C del 25-48%. Nonostante questi risultati promettenti, il profilo di sicurezza ha sollevato alcune preoccupazioni, con effetti avversi riportati come  cefalea, ipertrigliceridemia, diarrea, nausea, vertigini, malattia parodontale, rinite allergica e aumento della creatinchinasi  (CPK). Questi dati indicano la necessità di ulteriori studi per confermare la tollerabilità a lungo termine [59].

Obicetrapib

Obicetrapib rappresenta un altro promettente candidato tra i CETPi. In studi di fase 2 l’associazione di 10 mg di obicetrapib con 10 mg di ezetimibe ha prodotto una riduzione significativa dei livelli di LDL-C: 63,4% nel gruppo di terapia combinata, 43,5% in monoterapia, contro un 6,35% del gruppo placebo [60]. La combinazione ha inoltre migliorato in maniera marcata l’assetto lipidico aterogenico. In termini di sicurezza, non sono stati segnalati eventi avversi significativi, suggerendo un profilo di tollerabilità favorevole.

Evacetrapib e Torcetrapib

Studi clinici hanno mostrato che la somministrazione di evacetrapib e torcetrapib aumenta i livelli HDL-C rispettivamente del 125% e del 29% e quelli di apolipoproteina A1 (apoA1) del 99% e 50%. Tuttavia, è stato osservato un incremento della lipoproteina ApoC-III, con una maggiore percentuale di HDL contenenti ApoC-III (16,5% con torcetrapib e 18,4% con evacetrapib). Questo sottotipo di HDL-C è stato associato a un rischio cardiovascolare più elevato, suggerendo un possibile effetto controproducente [61]. Inoltre, torcetrapib è stato ritirato dallo sviluppo clinico a causa di effetti off-target, tra cui un aumento della pressione arteriosa e un incremento del rischio cardiovascolare.

Anacetrapib

Lo studio HPS3/TIMI55-REVEAL, che ha coinvolto 30.449 partecipanti con malattia aterosclerotica, ha valutato l’efficacia di anacetrapib (100 mg/die) rispetto al placebo in un follow-up medio di 4.1 anni. Anacetrapib ha ridotto l’incidenza di eventi coronarici maggiori del 9%, con un effetto ancora più marcato nel periodo post-studio (riduzione del 20%). Inoltre, ha aumentato i livelli medi di HDL-C di 43 mg/dL e ridotto il colesterolo non-HDL-C di 17 mg/dL. Il profilo di sicurezza è risultato buono, senza effetti avversi significativi sulla mortalità per cause non cardiovascolari [62].

Presi nel loro insieme, gli inibitori della CETP hanno mostrato risultati promettenti in termini di aumento di HDL-C e riduzione di LDL-C. Tuttavia, non tutti i CETPi hanno mantenuto queste promesse nella pratica clinica. Torcetrapib ed evacetrapib sono stati abbandonati a causa di effetti collaterali significativi e risultati clinici deludenti. Al contrario, anacetrapib e obicetrapib appaiono più promettenti, con un miglior equilibrio tra efficacia e sicurezza. Resta fondamentale comprendere meglio la qualità funzionale delle particelle HDL-C aumentate dai CETPi, poiché un incremento quantitativo di HDL-C non sempre si traduce in protezione cardiovascolare.

Terapie con oligonucleotidi antisenso (ASO)

Gli oligonucleotidi antisenso (ASO) sono brevi sequenze sintetiche di acidi nucleici a singolo filamento progettate per legarsi in modo complementare all’mRNA target. Questo legame porta alla formazione di un ibrido DNA-RNA che attiva l’enzima RNasi H1, il quale degrada selettivamente l’mRNA bersaglio. In questo modo viene impedita la traduzione dell’mRNA e la successiva sintesi proteica, riducendo l’espressione di specifiche proteine coinvolte nel metabolismo lipidico [13, 63].

AKCEA-APO(a)-LRx

AKCEA-APO(a)-LRx è un ASO mirato contro l’mRNA della lipoproteina(a) [Lp(a)], una lipoproteina contenente apolipoproteina(a) associata a un aumentato rischio di malattie cardiovascolari, tra cui infarto miocardico e stenosi valvolare aortica. In uno studio di fase 2 AKCEA-APO(a)-LRx ha ottenuto riduzioni significative dei livelli di Lp(a): 80% con una dose settimanale di 20 mg, 56% con una dose bisettimanale di 40 mg, 72% con una dose mensile di 60 mg. Tuttavia, gli outcome clinici cardiovascolari (MACE, Major Adverse Cardiovascular Events) sono ancora in fase di valutazione in studi di fase avanzata [64].

Olezarsan

Olezarsan è un ASO che agisce sul silenziamento dell’mRNA dell’apolipoproteina C-III (ApoC-III), una proteina chiave che inibisce la lipoprotein lipasi (LPL) e favorisce la produzione epatica di VLDL, contribuendo all’ipertrigliceridemia. Lo studio BRIDGE-TIMI 73a ha dimostrato che olezarsan è un candidato promettente per la riduzione dei trigliceridi e di ApoC-III nei pazienti con ipertrigliceridemia moderata o grave. A sei mesi di trattamento, i risultati principali sono stati: riduzione dei trigliceridi: -49,3% (dose 50 mg) -53,1% (dose 80 mg); riduzione di ApoC-III plasmatico: -64,2% (dose 50 mg) -73,2% (dose 80 mg); riduzione del colesterolo non-HDL e di ApoB: non-HDL-C: -18,2% (50 mg), -25,4% (80 mg) ApoB: -9,9% (50 mg), -9,8% (80 mg).

In termini di sicurezza lo studio ha evidenziato riduzioni significative della conta piastrinica, pur senza casi gravi di trombocitopenia. Incrementi transitori degli enzimi epatici si sono verificati nel 47% dei pazienti trattati con 50 mg e nel 37% con 80 mg di olezarsan. Sono pertanto necessari studi di fase 3 per confermare la sicurezza a lungo termine e valutare l’impatto sugli outcome cardiovascolari [65].

 

Discussione e conclusioni

Negli ultimi anni, i progressi nella terapia della dislipidemia sono stati straordinari, grazie allo sviluppo di agenti farmacologici innovativi che offrono una maggiore efficacia e un miglior profilo di sicurezza rispetto alle terapie tradizionali. La disponibilità di molecole come lerodalcibep, plozasiran, pemafibrato e inclisiran sta trasformando radicalmente l’approccio al trattamento delle dislipidemie, permettendo una personalizzazione sempre più precisa della terapia in base al profilo lipidico e al rischio cardiovascolare individuale.

Lerodalcibep, un inibitore di PCSK9 di terza generazione, mostra una notevole versatilità nella gestione di pazienti con ipercolesterolemia familiare omozigote (HoFH), eterozigote (HeFH) e malattia cardiovascolare aterosclerotica (ASCVD). La sua capacità di ridurre i livelli di LDL-C in modo sostanziale e sostenuto, unita a un ottimo profilo di tollerabilità, lo rende un promettente candidato per l’uso clinico, anche in combinazione con altre terapie ipolipemizzanti.

Plozasiran, un siRNA mirato all’APOC-III, ha già dimostrato un’efficace riduzione dei trigliceridi e dei profili lipidici aterogenici, con eventi avversi minimi. Questo farmaco potrebbe rappresentare una svolta nel trattamento delle ipertrigliceridemie, in particolare in quelle forme associate a un elevato rischio di pancreatite e complicanze cardiovascolari.

Inclisiran, grazie alla tecnologia siRNA, consente una riduzione marcata e prolungata di LDL-C con somministrazioni semestrali, migliorando l’aderenza terapeutica e mostrando un profilo di sicurezza favorevole anche nei pazienti con comorbidità multiple.

Queste terapie emergenti, alcune già disponibili nella pratica clinica, aprono la strada a regimi terapeutici combinati che potrebbero non solo integrare, ma anche sostituire le opzioni tradizionali in determinate categorie di pazienti. La varietà di meccanismi d’azione e la possibilità di combinazione consentono di affrontare in modo più mirato i diversi aspetti della dislipidemia, dalla riduzione di LDL-C e ApoB alla gestione dell’ipertrigliceridemia e dei livelli di Lp(a).

Nei pazienti con malattia renale cronica, la gestione della dislipidemia riveste un ruolo ancora più cruciale, poiché l’aterosclerosi accelera con la progressione della CKD e rappresenta la principale causa di morbilità e mortalità cardiovascolare in questa popolazione. Il tipico pattern lipidico aterogenico della CKD, caratterizzato da ipertrigliceridemia, HDL-C ridotte e particelle LDL-C piccole e dense, è difficile da correggere con le terapie convenzionali. Le statine hanno dimostrato benefici significativi nei pazienti CKD non dializzati, ma la loro efficacia nei pazienti in dialisi è controversa. Ezetimibe, grazie al meccanismo d’azione intestinale, rappresenta un’opzione utile e ben tollerata.

Tuttavia, è con l’arrivo delle nuove molecole che si aprono possibilità concrete per affrontare il rischio cardiovascolare residuo nella CKD avanzata. Gli inibitori di PCSK9, come alirocumab ed evolocumab, hanno mostrato efficacia anche nei pazienti con moderata riduzione del filtrato glomerulare (eGFR 30-59 ml/min/1,73 m²) senza evidenza di accumulo del farmaco nei soggetti in dialisi. Inclisiran, con somministrazione semestrale, potrebbe favorire l’aderenza nei pazienti fragili e politrattati tipici della CKD. Plozasiran offre una nuova strategia per la gestione dell’ipertrigliceridemia, frequente nei pazienti con CKD e correlata al rischio di pancreatite e di progressione della malattia renale stessa. AKCEA-APO(a)-LRx, mirato a ridurre i livelli di Lp(a), potrebbe avere un impatto significativo sul rischio cardiovascolare residuo, considerando l’associazione tra Lp(a) elevata e calcificazione valvolare, particolarmente rilevante nei pazienti uremici.

Con l’ampliamento dell’arsenale terapeutico, il nefrologo acquisisce un ruolo sempre più centrale nella gestione del rischio cardiovascolare associato alla CKD. La recente possibilità di prescrivere inibitori di PCSK9 e siRNA offre l’opportunità di intervenire in modo decisivo su uno dei principali determinanti di morbidità e mortalità nei pazienti nefropatici. La capacità di personalizzare le terapie ipolipemizzanti in base al profilo lipidico individuale e alle comorbidità (es. diabete, malattia cardiovascolare preesistente) rappresenta un elemento chiave per ottimizzare gli outcome clinici.

In futuro, la combinazione di questi nuovi agenti con approcci tradizionali potrebbe consentire di raggiungere target lipidici finora difficilmente conseguibili nei pazienti con CKD avanzata e dializzati. Inoltre, i buoni profili di sicurezza di queste terapie, associati alla possibilità di dosaggi ottimizzati e di una gestione costo-efficacia più favorevole, potrebbero rivoluzionare l’approccio al rischio cardiovascolare in CKD, riducendo non solo la mortalità cardiovascolare ma anche potenzialmente rallentando la progressione della malattia renale.

 

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Gene Therapies: Any Merit in Nephrology?

Pubblicato il Scarica PDF

DOI: 10.69097/42-05-2025-06

Emre Leventoğlu1, Sevcan A. Bakkaloğlu2, Fatih Süheyl Ezgü3

1 Department of Pediatric Nephrology, Konya City Hospital, Konya, Turkey
2 Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
3 Department of Pediatric Genetics, Faculty of Medicine, Gazi University, Ankara, Turkey

Corrispondenza a:
Emre Leventoğlu, MD
Department of Pediatric Nephrology, Konya City Hospital, Konya, Turkey
Phone: +90 312 202 52 26, +90 506 608 66 86
E-mail: dremrelevent@gmail.com

 

Abstract

Gene therapy is an innovative medical approach that involves altering or replacing defective genetic material to treat or potentially cure genetic disorders. This technique primarily uses viral or non-viral vectors to deliver genetic material into cells, aiming to restore normal gene function. The therapy has the potential to address a wide range of diseases, including genetic, cardiovascular, and neurodegenerative disorders. In this review, the focus will be on gene therapies related to kidney diseases. Topics to be covered include the use of messenger ribonucleic acid (mRNA) therapies for conditions such as hypertension and kidney cancer, as well as targeted gene therapies using small interfering RNA (siRNA) and adeno-associated viruses to treat glomerular diseases and prevent kidney damage. The application of gene therapies in treating well-known genetic conditions, such as Alport syndrome and cystinosis, will also be discussed. Additionally, the review will explore the progress of RNA interference (RNAi) therapies in acute kidney injury (AKI) and chronic kidney disease (CKD). Finally, the challenges and risks associated with gene therapy, including immune responses, insertional mutagenesis, and the high costs of treatment, will be examined. 

Keywords: Gene Therapy, Kidney Diseases, Molecular Nephrology, Nephrogenetics

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction to Gene Therapy

Gene therapies represent a cutting-edge approach in modern medicine, offering the potential to treat or even cure a range of genetic disorders by altering or replacing the genetic material within the cells. Gene replacement therapies generally use viral (adenovirus, or lentivirus) or non-viral vectors to transfer the new genetic material. These therapies aim to reconstitute the expression of the mutant genes responsible for recessively or dominantly inherited genetic disorders, such as cancer, cardiovascular, and neurodegenerative diseases. Some therapies are based on delivering genetic material without integrating into the patient’s genome. On the other hand, some therapies including Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 (CRISPR-Cas9) can provide long-lasting or permanent potential therapeutic effects by inserting, removing, or altering genetic sequences [1].

 

Gene Therapy in Kidney Diseases

Chronic kidney disease (CKD) is a major global health problem, affecting approximately 10-15% of the adult population worldwide. Beyond its impact on morbidity and mortality, CKD significantly impairs patients’ quality of life and imposes a substantial economic burden on healthcare systems due to the high costs of long-term medical care and renal replacement therapies [2, 3]. While acquired causes remain prevalent, a growing body of evidence highlights the important role of genetic factors in the etiology of kidney diseases [4]. Advances in genetic sequencing technologies have dramatically increased the recognition of inherited kidney diseases, revealing that up to 20-30% of early-onset or familial cases have an identifiable genetic basis [5, 6]. Becherucci et al. developed a multi-stage diagnostic approach consisting of patient selection based on specific referral criteria, whole exome sequencing (WES), reverse phenotyping and multidisciplinary board evaluation to make the diagnosis of genetic kidney diseases more efficient and cost-effective. This method achieved a 67% diagnosis rate, confirming the clinical prediagnosis in 48% of cases and changing the diagnosis in 19%. Genetic diagnosis was achieved in 64% of children and 70% of adults. Cost analysis showed that early genetic testing resulted in cost savings of 20-41% per patient. Thus, a model of genetic diagnosis with high diagnostic success and economic advantage is possible [7]. However, current management strategies for many genetic kidney diseases remain largely symptomatic, aiming to slow disease progression and address complications rather than correct the underlying genetic defects. In this context, gene-based therapies have emerged as a promising frontier in nephrology, offering the potential to directly target the molecular causes of disease.

Messenger ribonucleic acid (mRNA) therapies for kidney diseases are still largely experimental, with preclinical studies showing promising results [8]. For instance, a study on hypertension showed that zilebesiran, a ribonucleic acid (RNA) interference (RNAi) drug, effectively lowers blood pressure by targeting hepatic angiotensinogen [9]. mRNA vaccines have also been explored for treating kidney cancer, showing promising results in early studies [10].

A targeted gene therapy using small interfering RNA (siRNA) may be delivered via specialized nanoparticles to treat kidney diseases. The nanoparticles, made of siRNA and cationic liposomes coated with PAI-1R, specifically target glomerular cells. When tested in a nephritic rat model, the therapy effectively reduced transforming growth factor-β1 (TGF-β1) levels in the glomeruli, improving glomerulosclerosis without affecting other organs. This approach shows promise for treating kidney diseases by specifically silencing mutant genes in the glomeruli [11]. Additionally, thymosin β4 (TB4), an actin-sequestering peptide, plays a crucial role in maintaining podocyte cytoskeleton integrity. A lack of endogenous TB4 exacerbates podocyte injury. Administration of an adeno-associated viral vector (AAV) encoding TB4, increased circulating TB4 levels, preventing adriamycin-induced podocyte loss and albuminuria. TB4 gene therapy also restored the disorganized actin cytoskeleton in vitro. These findings suggest that systemic gene therapy with TB4 expression could prevent podocyte injury and maintain glomerular filtration, offering a novel treatment strategy for nephrotic syndrome [12].

Gene therapies may be useful in Alport syndrome, a disease with a well-known genetic mechanism. It is caused by mutations in the genes for alpha 3, alpha 4, and alpha 5 chains of type IV collagen. This condition leads to symptoms such as hematuria, proteinuria, progressive kidney dysfunction, hearing loss, and eye problems. The mutation results in an abnormal collagen network in the glomerular basement membrane, impairing kidney function. Current conservative treatments, like angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) or mineralocorticoid receptor antagonists have limited effectiveness. Gene therapy offers a potential solution by aiming to correct the mutations and restore normal collagen production. Advances in recombinant AAVs are making progress in kidney gene therapy, with ongoing research focused on developing effective treatments for Alport syndrome [13].

Investigational gene therapies can also be used to treat some clinical conditions that do not have a clear genetic basis. Acute kidney injury (AKI) is a serious condition with significant morbidity, even mortality and no definitive treatment. The RNAi is a potential solution by using engineered red blood cell-derived extracellular vesicles (REVs) to deliver therapeutic siRNAs to injured kidneys. The REVs, tagged with a peptide that binds to kidney injury molecule-1 (KIM-1), specifically targeted damaged kidney tubules in mouse models. They successfully delivered siRNAs targeting the transcription factors P65 and snail family transcriptional repressor 1 (Snai1), which are involved in inflammation and fibrosis. Therefore, anti-inflammatory and anti-fibrotic effects of this treatment lead to an improvement in kidney function and prevention of progression to chronic kidney disease (CKD) [14]. However, some patients may develop CKD despite all interventions. CKD is primarily driven by progressive fibrosis, making it essential to target and reverse the profibrotic processes in affected tissues. Nanoparticles offer a new method for delivering antifibrotic treatments directly to the kidneys. Chitosan nanoparticles coated with hyaluronan can deliver plasmid DNA encoding bone morphogenetic protein 7 (BMP7) or hepatocyte growth factor/NK1 (HGF/NK1) to the kidneys. These nanoparticles promote cellular growth and reduce fibrosis by inhibiting fibrotic gene expression. When administered to mice with unilateral ureteral obstruction, the nanoparticles successfully delivered about 40-45% of the genetic material to the kidneys. This treatment reduced fibrosis, improved kidney function, and either reversed fibrosis and regenerated tubules or halted CKD progression and reduced collagen deposition [15].

Kidney transplantation is the best option among kidney replacement therapies in patients who develop kidney failure. However, ischemia-reperfusion injury can sometimes lead to adverse outcomes [16]. Normothermic machine perfusion (NMP) is a state-of-the-art method of organ preservation that overcomes the limitations of traditional hypothermic techniques in solid organ transplantation. It allows for the assessment and recondition of organs prior to transplantation and enables the delivery of therapeutic agents to organs. In a recent study, an oligonucleotide-based therapy, antagomir targeting microRNA-24-3p was successfully delivered to human kidneys during NMP. This treatment localized to the endothelium and proximal tubular cells of the kidney, showed specific interaction with the microRNA target and increased the expression of associated genes. It demonstrated a potential to target and block harmful microRNAs prior to transplantation [17]. Thus, it may be beneficial in increasing graft survival in kidney transplantation.

Investigational gene therapies have also been used in certain systemic diseases affecting the kidney such as cystinosis. Cystinosis, a lysosomal storage disorder caused by mutations in the CTNS gene, leads to cystine buildup due to the loss of cystinosin function. The kidneys are the most affected organs, with damage progressing to kidney failure. While cysteamine is the current treatment, it only lowers cystine levels without restoring kidney function and has significant side effects [18]. In a study, synthetic mRNA can successfully restore cystinosin expression in CTNS-/- kidney cells and zebrafish following delivery via lipofection. A single dose of CTNS mRNA reduced cellular cystine for up to 14 days in vitro and improved kidney function in zebrafish, enhancing tubular reabsorption, reducing proteinuria, and restoring key receptor functions. That study provides early evidence that mRNA-based therapies could offer a new approach to treating cystinosis by restoring cystinosin expression and improving kidney function [19]. In another study, hematopoietic stem cell (HSC) transplantation shows potential for treating cystinosis by delivering a functional CTNS gene to various organs. A clinical trial of allogeneic HSC transplantation in a cystinosis patient led to improved symptoms but severe complications, underscoring the risks. As a safer alternative, a Phase I/II trial is exploring autologous HSC transplantation, where a patient’s HSCs are genetically modified to express CTNS, potentially reducing risks and offering new treatment options [20].

As can be seen, gene therapies are being tested in the treatment of various diseases in the field of nephrology. However, so far, gene therapy has only been approved for the treatment of primary hyperoxaluria [21]. Primary hyperoxaluria (PH) type 1 (PH1) is a rare autosomal recessive genetic disorder caused by mutations in the AGXT gene. This condition impairs the enzyme alanine glyoxylate aminotransferase (AGT), leading to oxalate overproduction and subsequent kidney damage, including nephrocalcinosis, nephrolithiasis, chronic kidney disease, kidney failure. Systemic oxalosis may also be seen. Conventional medical treatments for PH1 are generally inefficacious except for pyridoxine in cases with pyridoxine-sensitive mutations. Current strategies mainly involve targeting the liver to block oxalate production. Lumasiran is the first RNAi therapy approved for PH1, receiving approval from the US Food and Drug Administration and the European Union in November 2020. The phase III trials demonstrated that lumasiran effectively lowers oxalate levels in urine and plasma across various patient groups, including children, adults, and those with advanced kidney disease with a good safety profile [22, 23]. Nedosiran, another RNAi therapy, reduces hepatic lactate dehydrogenase activity, a key factor in all genetic forms of PH. In a double-blind study with 35 participants with PH1 or PH 2 (PH2) received either nedosiran or placebo monthly for 6 months, nedosiran significantly reduced plasma oxalate in PH1 and was generally well tolerated [24]. It was first approved in the USA in 2023 for PH1 patients aged 9 years and older with relatively preserved kidney function [25].

 

Challenges and Risks of Gene Therapy

Gene therapy has made remarkable progress over the past 50-60 years, with new treatments now available for previously untreatable diseases. While advancements in gene editing technologies have significantly improved the precision and feasibility of these treatments, their clinical application is still carefully regulated due to potential risks. The immune system may react to the viral vector used in therapy, causing inflammation, fever, or more serious reactions [26]. Another potential side effect is called insertional mutagenesis, where the therapeutic gene integrates into the wrong part of the genome. This can disrupt the function of other genes and lead to cancer or other disorders [27]. Additionally, the therapy may affect non-target cells or tissues, resulting in unintended tissue damage [28]. Even if the therapeutic gene is placed in the right position, overproduction can lead to inflammation or tissue damage may occur [29]. Despite its effectiveness, there might be serious adverse events, such as thrombotic microangiopathy or immune hepatitis, associated with viral vector-based gene therapies [30]. The long-term effects of gene therapies are not yet fully understood. Factors such as the impact on future generations or the long-term presence of the therapeutic gene are still under investigation [31]. From an economic perspective, high costs for these therapies pose significant barriers to access. This issue may be exacerbated by complex health insurance systems. Recent discussions highlight the need for solutions to make these therapies more affordable and accessible, ensuring that advancements in gene therapy benefit all patients equally and fairly [32].

 

Conclusion

Gene therapy has made remarkable progress in recent years, offering promising therapeutic potential for a variety of genetic and acquired kidney diseases. However, despite the scientific progress, the high costs and limited accessibility of these therapies present significant challenges to widespread adoption. Moving forward, ongoing research is essential to refine the safety and efficacy of gene therapies, while addressing economic and logistical barriers to ensure equitable access for all patients. The future of gene therapy holds great promise, with the potential to transform the treatment landscape for kidney diseases, offering hope where conventional therapies have been limited.

 

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Realizzazione per via endovascolare della fistola artero-venosa per emodialisi: esperienza di un singolo centro

Pubblicato il Scarica PDF

Valentina Pistolesi

DOI: 10.69097/42-05-2025-05

Valentina Pistolesi1, Pierleone Lucatelli2, Laura Zeppilli1, Mario Barile1, Laura Pedata1, Mario Corona2, Santo Morabito1

1 Hemodialysis Unit, Azienda Ospedaliero-Universitaria Policlinico Umberto I, “Sapienza” Università̀ di Roma, Rome, Italy
2 Interventional Radiology Unit, Azienda Ospedaliero-Universitaria Policlinico Umberto I, “Sapienza” Università di Roma, Rome, Italy

Corrispondenza a:
Valentina Pistolesi, MD, PhD
UOSD Dialisi, Azienda Ospedaliero-Universitaria Policlinico Umberto I,
“Sapienza” Università di Roma
Viale del Policlinico, 155
00161 Rome, Italy
E-mail: valentina.pistolesi@uniroma1.it
Phone: +39 06 49974263

 

Abstract

I sistemi endovascolari rappresentano una tecnica interessante per la creazione non chirurgica della fistola artero-venosa (FAV) per emodialisi. L’obiettivo era valutare efficacia e sicurezza dell’applicazione di un sistema endovascolare per la creazione di FAV nei pazienti con ESRD trattati nel nostro centro.
Metodi. Il controllo ecografico con Color Doppler è stato utilizzato per valutare i criteri anatomici di idoneità del paziente. È stato effettuato un accurato follow-up clinico e strumentale post-procedura.
Risultati. La FAV endovascolare (endoFAV) è stata creata con successo in 7 pazienti in assenza di complicanze perioperatorie. Nel corso di alcune procedure sono state eseguite embolizzazione della vena brachiale (n = 4) e angioplastica (n = 1) per deviare una maggiore quantità di flusso attraverso la vena perforante verso le vene superficiali (vene cefalica, cubitale mediana e/o basilica). Il controllo ecografico con Color Doppler ha mostrato flussi ottimali a 24 ore, 7 giorni, 30 giorni, 6 e 12 mesi. Tutte le endoFAV hanno soddisfatto i criteri di maturazione entro il primo mese e sono state incannulate con successo. I tassi di pervietà primaria a 4, 6 e 18 mesi sono stati rispettivamente 100%, 85.7% e 71.4%. Il tasso di pervietà cumulativa durante il follow-up (mediana 16 mesi) è stato del 100%. Durante il follow-up, 2 pazienti hanno richiesto interventi correttivi con un tasso di reintervento di 0.21 procedure per paziente/anno.
Conclusioni. Lo studio conferma la sicurezza e l’efficacia di questa tecnica alternativa per la creazione della FAV. L’implementazione di un team ben preparato, che includa nefrologi e radiologi interventisti, è fondamentale per confezionare e mantenere una endoFAV ben funzionante.

Parole chiave: fistola arterovenosa, endovascolare, emodialisi, percutaneo, accesso vascolare

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

The choice of the optimal hemodialysis vascular access is part of the “action plan” that should be proposed and individualized for each patient with progressive chronic kidney disease (CKD) and/or with estimated glomerular filtration rate (eGFR) between 15 and 20 ml/min/1.73 m2 (End-Stage Kidney Disease Life-Plan) [1]. Timely planning and performing vascular access are crucial to obtain a functional hemodialysis access, essential for delivering adequate dialysis, and to avoid the risk of complications related to the use of temporary central venous catheters (CVC), thus limiting the need for subsequent interventions [1, 2].

In recent years a promising option for the creation of the arteriovenous fistulas (AVF) for hemodialysis derives from the implementation of 2 innovative techniques: percutaneous (Ellipsys) or endovascular (WavelinQ) [3, 4].

By using these systems, the site of AVF creation is in the proximal forearm. Indeed, both methods take advantage of the perforating vein as a connection between the deep venous circulation and the superficial venous circulation. Although the 2 techniques use a different approach to create an AVF, both have shown promising results in terms of maturation rate and subsequent use [3, 5–11]. The WavelinQ device (BD Medical, previously EverlinQ TVA) is a system of specific 4Fr arterial and venous catheters (Figure 1) guided inside the vessel under fluoroscopy that, by using radiofrequency (RF) energy, creates an arteriovenous communication in the deep circulation of the proximal forearm. The arterialization of the superficial veins occurs through the perforating vein [7, 12]. The choice of the WavelinQ technique includes a preliminary phase of careful evaluation of the patient aimed at assessing his eligibility to endovascular AVF (endoAVF) creation with this specific system. For this purpose, an accurate mapping through color Doppler ultrasound is crucial to ensure that the anatomical criteria essential for creating the endoAVF are met [6, 7].

The aim of the study was to evaluate the preliminary data about the feasibility, the efficacy, and the safety of the application of the WavelinQ technique to perform an endovascular AVF (endoAVF) in patients with end-stage kidney disease (ESKD) undergoing hemodialysis at the Dialysis Unit of the Policlinico Umberto I Hospital, Rome, Italy.

Figure 1. Main components of venous and arterial catheters of the WavelinQ device.
Figure 1. Main components of venous and arterial catheters of the WavelinQ device.

 

Patients and Methods

We performed a single-center retrospective analysis of ESKD patients who underwent endoAVF creation with the WavelinQ system between May 2023 and September 2024 at the Interventional Radiology Unit of the Policlinico Umberto I Hospital (Rome, Italy). Main data were prospectively recorded and retrospectively analyzed.

The technical success was defined as the successful completion of the procedure, as well as the intraoperative control of the AVF blood flow by ultrasound. EndoAVF maturation was defined according to KDOQI 2019 criteria [1]. Perioperative complications have been defined as hand ischemia, bleeding, and infections.

The study was approved by the Territorial Ethical Committee of Lazio Area 1, Italy (No. 293/2025) on March 26, 2025. All participants provided written informed consent prior to participating.

Vascular mapping and procedure planning

To evaluate the eligibility of the patients for the creation of endoAVF, the vessels of both arms were accurately studied through a color Doppler ultrasound examination.

In particular, the potential access sites for the devices, the target vessels for the creation of the fistula, the presence and the adequacy of the perforating vein as a connection between the deep circulation and the superficial circulation, were carefully studied. Essential anatomical characteristics for WavelinQ system application are summarized in Figure 2. The patency and the depth with respect to the skin plane of any venipuncture sites (cephalic vein and/or basilic vein) were also evaluated. The WavelinQ system also requires that the distance between the ulnar or radial artery and their concomitant veins at the target fistula creation site is less than or equal to 2 mm. Finally, the presence of central venous stenosis and/or upper extremity venous occlusion on the same side as the planned AVF creation have been excluded. Depending on the access site considered suitable at color Doppler ultrasound examination, the parallel (same direction) or antiparallel (opposite direction) approach for the introduction of the 2 catheters has been scheduled.

Figure 2. Main eligibility criteria for endoAVF creation.
Figure 2. Main eligibility criteria for endoAVF creation. 

EndoAVF creation procedure

The procedure was performed in supine position and under local or brachial plexus block anaesthesia. The arm, which was designated for the endoAVF creation, was immobilized on a side table with the palm facing upward. Under ultrasound guidance, the arterial and venous catheters were percutaneously inserted. In the case of “parallel approach”, percutaneous access was obtained through the cannulation of the radial artery and its concomitant vein at the wrist or the brachial artery and its concomitant vein at the upper arm; in the case of “antiparallel approach”, the access was gained through the radial artery at the wrist while the brachial vein was accessed from the upper arm. By using fluoroscopy, the catheters advanced until the target creation site was reached (Figure 3a). Once placed in proximity, the magnets of the 2 catheters attracted each other, pulling the arterial and venous vessels closer together. After evaluating the correct alignment of the magnets (Figure 3b), it was possible to deliver the burst of RF energy (60 Watts for a duration of 0.7 seconds) through the electrode in the venous catheter, thus obtaining the communication between the artery and the vein. Then, an intraoperative arteriography was performed to verify the actual creation of the fistula (shunt of blood flow from the artery to the venous system) and to exclude any immediate complications such as blood extravasation or pseudoaneurysm formation. Moreover, the need to divert more flow through the perforator to the superficial veins (cephalic, median cubital and/or basilic veins) by embolization of the brachial vein (positioning of a coil) or by angioplasty of the outflowing veins (perforator vein, cephalic vein and/or basilic vein) was also assessed. Hemostasis after endovascular catheters removal was achieved through manual compression of the puncture sites (15 minutes for arterial access, 5 minutes for venous access).

Catheters advancement to the target creation site under fluoroscopic guidance
Figure 3 a) Catheters advancement to the target creation site under fluoroscopic guidance. In this case the “antiparallel approach” has been used (arterial access gained through the radial artery at the wrist, venous access obtained through the brachial vein from the upper arm). b) Fluoroscopic control of the correct alignment of the 2 magnets (yellow dashed rectangle). In both figures, the blue and red arrows indicate the venous and arterial catheter, while the blue and red asterisks indicate the venous and arterial rotational indicators, respectively.

Follow-up

The next phase involved short-term follow-up (24 hours, 7 days, 30 days) including blood flow rate measurement of the endoAVF by using color Doppler ultrasound, and medium- and long-term clinical/instrumental follow-up. Furthermore, timing of maturation and of venipuncture with 1 or 2 fistula needles were evaluated and recorded.

 

Results

The procedure was performed in 7 patients (6 male, 1 female) with ESKD. Main patients’ clinical characteristics are reported in Table I. Mean age was 53.9±21.6 years. Mean BMI was 28.3±6. Regarding timing for referral to the nephrologist, 3 (43%) patients were early-referral and 4 (57%) late-referral. Only one early-referral patient met clinical indications to begin renal replacement therapy before the creation of the endoAVF and thus a temporary vascular access (jugular CVC) was placed. All late-referral patients already had temporary or tunnelled CVC at the time of endoAVF creation.

The selected arm was non-dominant in 6 patients and dominant in 1 patient, due to the absence of anatomical eligibility criteria for the WavelinQ technique in the non-dominant arm. In only one case the AVF was performed on the side where the jugular CVC had previously been positioned; however, imaging confirmed the absence of central stenoses at the time of the procedure.

Table II shows the main anatomical characteristics recorded during pre-operative vascular mapping. Local anaesthesia was performed in 3 patients (43%), while brachial plexus anaesthesia was performed in 4 (57%). In 5 patients the approach was parallel (4 retrograde, 1 antegrade); in the remaining 2 patients an antiparallel approach was necessary (Table III). In all cases, the radial artery was chosen, and the anastomosis was created between the proximal radial artery and the lateral concomitant vein. The intraoperative arteriography confirmed the actual creation of the fistula in all patients. During the procedure, 4 patients (57%) underwent coil placement in the brachial vein, while intraoperative angioplasty was performed in 1 patient. No intra- or post-operative complications were observed (Table III). Mean duration of the procedure was 146 ± 35 minutes.

EndoAVF flows were monitored with color Doppler ultrasound over the brachial artery 24 hours, 7 days, 30 days, 6 and 12 months after the procedure (Table IV).

All patients met KDOQI maturation criteria within 1 month. EndoAVF venipuncture times were 53.6 ± 19 days (median 51) from the date of endoAVF creation (n = 5). In 2 early-referral patients on conservative therapy, the endoAVF was mature and adequate for venipuncture when the indication to start hemodialysis treatment was made. After the first month from the start of cannulation all endoAVF was deemed successfully used for hemodialysis (FUSH) [13].

The average follow-up time was 12.6 ± 6.2 months (median 12, range 5-21). Primary patency rates at 4, 6 and 18 months were 100%, 85.7%, and 71.4%, respectively. Cumulative patency rate during the entire follow-up period was 100%. During follow-up, 2 patients (29%) required corrective interventions with a re-intervention rate of 0.27 procedures per patient year (Table IV). In one case, due to the excessive flow dispersion in the deep circulation, embolization of the lateral brachial concomitant vein was needed approximately 15 months after endoAVF creation. The second patient underwent thrombectomy along with simultaneous percutaneous transluminal angioplasty (PTA) for venous side stenosis approximately 5 months after the endoAVF was performed (Table IV).

Age, years 53.9 ± 21.6
Male gender 6 (86%)
Smokers 2 (29%)
BMI 28.3±6
Diabetes mellitus 3 (43%)
Hypertension 5 (71%)
Patients on conservative medical therapy 2 (29%)
Patients already undergoing hemodialysis 5 (71%)
Early-referral 3 (43%)
Late-referral 4 (57%)
Previous vascular access
– Temporary contralateral trans-jugular CVC 2 (29%)
– Long-term ipsilateral trans-jugular CVC 1 (14%)
– Long-term contralateral trans-jugular CVC 1 (14%)
– Femoral CVC 1 (14%)
– No previous vascular access 2 (29%)
Table I. Main clinical characteristics of the patients (n=7). Continuous variables expressed as mean±SD; categorical variables expressed as n (%). CVC: central venous catheter.
PATIENT ID 1 2 3 4 5 6 7
Cephalic vein (mm)
Diameter/depth		 D d D d D d D d D d D d D d
· Proximal <2.5 n.a. 3.4 2.4 <2.5 n.a. <2.5 n.a. 3 4.8 2.5 6 <2.5 n.a.
· Middle <2.5 n.a. 3.6 2.3 <2.5 n.a. <2.5 n.a. 2.7 2.7 2.5 6 <2.5 n.a.
· Distal <2.5 n.a. 3.8 2.2 <2.5 n.a. 3.5 3.5 3.2 2.9 2.5 1.9 <2.5 n.a.
Basilic vein (mm)
Diameter/depth		 D d D d D d D d D d D d D d
· Proximal 6 6.7 7 14 2.5 6 6 11 5.2 1.5 2.5 6 4.1 6
· Middle 5.8 5.9 7 10 3.2 7.7 5.5 2.8 2.9 6 2.5 6 4 6
· Distal 6.7 4.1 5 11 3 2 4 3.8 3 3.2 3.2 4.1 4 4
Brachial artery
· Diameter (mm) 3.7 5 5.3 5.8 4.7 5 5
· Bifurcation
(above/below elbow)		 below below below below below below below
· Triphasic flow Yes Yes Yes Yes Yes Yes Yes
Perforating vein
Patency Yes Yes Yes Yes Yes Yes Yes
Diameter (mm) 2.8 2.4 2.9 3.3 3.5 3.6 3.8
Connection L.R.V. L.R.V./M.R.V. L.R.V. L.R.V. L.R.V. L.R.V./M.R.V. L.R.V./L.U.V.
Table II. Anatomical characteristics resulting from pre-operative vascular mapping. L.R.V.: Lateral radial vein; M.R.V.: Medial radial vein; L.U.V.: Lateral ulnar vein. n.a.: not applicable (depth not assessed in the case of inadequate vessel diameter).
PATIENT ID 1 2 3 4 5 6 7
Devices access sites
Radial artery diameter (mm) wrist 2.4 2.6 3.2 2.8 2.2 2 2.5
Lateral radial vein diameter (mm) <2 <2 <2 <2 2.2 2.1 2
Medial radial vein diameter (mm) <2 <2 <2 <2 2.2 2 <2
Brachial artery diameter (mm) 3.7 5 5.3 5.8 4.7 5 5
Lateral brachial vein diameter (mm) 3.7 3.5 <2 4.8 2.5 5 5
Medial brachial vein diameter (mm) 2 2.2 3.4 4.8 <2 <2 2.5
Creation site
Radial artery diameter (mm) 2.5 3 3.5 2.2 2.2 2.9 3.2
Lateral radial vein diameter (mm) 2.5 3.1 2.4 3.5 2.6 2.3 3
Medial radial vein diameter (mm) 4.8 <2 <2 3.6 <2 2.9 2
Intraoperative variables
Parallel/Antiparallel approach A A P P P P P
Intraoperative embolization No No Yes No Yes Yes Yes
PTA No Yes No No No No No
Complications No No No No No No No
Table III. Anatomical characteristics of endoAVF devices access sites, creation site, and intraoperative variables. PTA: percutaneous transluminal angioplasty
Blood flow rates (ml/min) measured at brachial artery
PATIENT ID 1 2 3 4 5 6 7 N=7
24 hours 550 600 800 750 360 450 450 566±163
7 days 1000 750 950 900 1200 600 450 836±254
30 days 1100 850 1000 900 1200 650 600 900±222
6 months 1000 700 1000 700 1100 1000 800 900±163
12 months 1200 700 1000 800 1100 1100 n.a. 983±194
Need for corrective interventions and timing from endoAVF creation
PATIENT ID 1 2 3 4 5 6 7
Procedure No Yes Yes No No No No
Coiling – 15 months – – – – –
PTA – – 5 months – – – –
Thrombectomy – – 5 months – – – –
Table IV. Blood flow rates and need for corrective interventions during the follow-up period. Data expressed as mean ± SD. PTA: percutaneous transluminal angioplasty. n.a.: not applicable

 

Discussion

The arteriovenous fistula represents the vascular access of first choice for ESKD patients requiring hemodialysis [1, 2]. In recent years, two different techniques have been proposed to create a fistula in the proximal forearm percutaneously without the need for a surgical incision [3, 4]. Among these non-surgical AVF creation options, the WavelinQ EndoAVF System is indicated to perform an arteriovenous connection between the radial artery and its concomitant vein or the ulnar artery and its concomitant vein in patients with well-defined anatomical characteristics. From the anastomosis the blood flows through the perforating vein into the superficial circulation, thus allowing the arterialization of cephalic and/or basilic vein.

Our preliminary experience allows to confirm the efficacy and safety of the endovascular procedure by using the WavelinQ System. Indeed, in the first 7 patients who underwent the procedure of endoAVF creation at our center the technical success was 100%. During the observation period (>12 months in 4 cases and >5 months in the remaining patients) primary and cumulative patency rates were 71.4% and 100%, respectively. Moreover, no peri-operative complications such as vascular lesions or arm ischemia occurred. Although obtained in a limited sample of patients, these findings agree with literature data [8, 11, 14, 15]. For example, in a study of pooled data from three prospective, multicenter, single-arm trials procedural success was achieved in 116 patients (96.7%), while the primary and secondary patency rates were 71.9% and 87.8% at 6 months, respectively [8]. More recently, in a prospective, single-center study including a total of 20 patients, technical success was 100% in absence of serious adverse events; at 6-month follow-up, the primary and cumulative patency rates were 65% and 75%, respectively [11]. Moreover, Inston et al, comparing a single-center series of WavelinQ endoAVF with a matched series of surgically created radiocephalic AVF, reported a significantly greater mean primary patency in the endoAVF group (362 ± 240 vs 235 ± 210 days, p<0.05) [14].

Pre-operative vessel mapping is an important step in identifying patients who can successfully undergo an endoAVF procedure. Thus, an accurate ultrasound examination plays a key role to assess the presence of the specific anatomical characteristics required to create a well-functioning fistula by using this system. For this purpose, we have implemented a well-trained specialized team including nephrologist and interventional radiologist to take advantage of their specific skills in the crucial phase of patient’s selection. Moreover, it is well recognized that this collaboration is also essential to achieve and maintain a functional AVF. Starting from this assumption, at our hospital, during the intraoperative phase nephrologists and interventional radiologists together evaluate the need for further intraprocedural interventions aimed at diverting greater blood flow towards the superficial veins. Thus, in our experience, 5 out of 7 patients underwent coil placement in the brachial vein or intraoperative angioplasty. These procedures facilitated the maturation of the endoAVF and possibly contributed to limit the need for subsequent re-interventions. In our patients, procedures aimed at maintaining the patency of the access and strengthening the inflow and outflow, were necessary in only 2 cases. In this regard, the need for subsequent procedures to facilitate the maturation of the AVF, intended as PTA or coiling on deep circulation veins, has been reported in few cases also by other authors. Indeed, data published so far seems to show that, compared to the surgical approach, the WavelinQ technique requires fewer re-interventions, thus compensating potential higher initial costs [16–18]. In particular, in a propensity score study matching 60 endoAVF with 60 surgical AVF patients, Yang et al found that the endoAVF group required significantly fewer post-creation procedures with consequently lower mean costs within the first year [16]. Furthermore, a cost-effectiveness and budget impact analysis, conducted in hemodialysis patients from the prospective of the Italian Healthcare Service, suggested that endoAVF could be a cost-saving strategy compared to surgical AVF creation [18].

Post-procedure follow-up is an essential component in access management. Indeed, regular follow-up makes it possible to verify that the endoAVF is properly working to deliver adequate dialysis and to timely identify the need for corrective measures, thus allowing to significantly increase the AVF lifespan. The follow-up phase involves careful routine monitoring even in the period following the start of endoAVF venipuncture. The role of the nephrologist become central when maturation is completed and endoAVF can begin to be used. To minimize the failure risk of the first venipunctures, the right approach is to identify possible sites for correctly positioning the needles through ultrasound evaluation. A good practice is to assign an experienced operator (physician or nurse) to perform the first cannulations. In our experience, within the first 4 weeks from the start of venipuncture, all endoAVF were considered successfully used for dialysis, that is, they were used with two-needle cannulation for two-thirds or more of all dialysis runs for 1 month, delivering the prescribed dialysis within the prescribed time frame [13].

In our opinion, endoAVF appears to offer an interesting opportunity among vascular access creation options. The use of the deep circulation expands the anatomical options for the creation of AVF, preserves the patient’s venous circulation without precluding any subsequent endovascular or surgical approach [14]. It should also be considered that the anastomosis is performed without dissection and traumatism of the vessels and surrounding tissues, with a possible lower predisposition to a subsequent development of aneurysms and venous stenosis [15, 19]; the former are often a cause of discomfort for patients. Moreover, the minimally invasive technique does not produce surgical scarring that could disfigure the arm. In this regard, an aspect that should not be overlooked is patient satisfaction [20]. In fact, in the examined cases the endoAVF had minimal aesthetic impact and no patient complained of symptoms (e.g., pain, paresthesia) or functional limitation of the affected arm.

 

Conclusion

This study, although it includes a limited number of patients and it is characterized by a relatively short follow-up period, confirms that the WavelinQ technique, if performed by operators well-trained in performing and monitoring of endoAVF, could be considered safe and effective. This innovative and constantly evolving technique adds a further option in the choice of optimal vascular access for the hemodialysis patient with the aim of ensuring ever greater personalization of therapeutic choices.

 

Bibliography

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