Sodium Disorders in Multiple Myeloma: Beyond Pseudohyponatremia to Clinical Pitfalls and Mechanistic Insights

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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)

Corresponding author:
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

Hyponatremia is a relatively frequent finding in multiple myeloma (MM) and may result from either pseudohyponatremia, due to marked hyperproteinemia, or true hyponatremia from genuine sodium-water imbalance. Differentiating between these two entities is essential, as they differ in pathogenesis, clinical relevance, and management.
Pseudohyponatremia, observed in approximately 15–20% of MM patients, is a measurement artifact occurring with indirect ion-selective electrode techniques when plasma water fraction is reduced by high M protein levels. Serum osmolality remains normal, and no sodium correction is required.
True hyponatremia (<135 mEq/L with hypo-osmolality) is less common but clinically significant, often associated with worse prognosis. Mechanisms include renal impairment (cast nephropathy, Fanconi syndrome, light chain deposition), hypervolemia from advanced renal failure, hypovolemia from gastrointestinal losses or diuretics, drug-induced effects (notably bortezomib, cyclophosphamide), and paraneoplastic SIADH. Alterations in electroneutrality and strong ion difference (SID) from highly cationic M protein may further lower sodium, usually mildly. Pseudohyponatremia is managed by controlling the underlying myeloma and reducing paraproteinemia. True hyponatremia treatment is etiology-specific: isotonic saline for hypovolemia, fluid restriction ± solute supplementation for SIADH, careful diuretic adjustment for hypervolemia, and withdrawal of causative drugs when possible. Optimal control of the plasma cell clone, through modern triplet or quadruplet regimens prevents recurrence. A structured diagnostic approach integrating volume status, laboratory evaluation, and medication review is critical to distinguish pseudo from true hyponatremia, prevent inappropriate interventions, and address the underlying disease. Keywords: Multiple Myeloma, Hyponatremia, Pseudohyponatremia

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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  39. Annabelle M Warren, Mathis Grossmann, Mirjam Christ-Crain, Nicholas Russell. Syndrome of Inappropriate Antidiuresis: From Pathophysiology to Management. Endocr Rev. 2023 Sep 15;44(5):819-861. https://doi.org/10.1210/endrev/bnad010

Two Cases of Pseudo-Bartter Syndrome in Childhood: When to Suspect a Rare Onset Pattern of Cystic Fibrosis

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Gianluca Vergine

DOI: 10.69097/41-03-2024-05

Gianluca Vergine1, Giulia Fressola2, Maura Ambroni3, Monica Gessaroli4, Barbara Bigucci1, Martina Mazzocco1, Maria Luisa Conte1

1 UOC Pediatria, Ospedale Infermi, Rimini, ASL Romagna
2 Scuola di Specializzazione in Pediatria, Università degli Studi di Ferrara
3 Centro Regionale Fibrosi Cistica, Ospedale Bufalini, Cesena, ASL Romagna
4 Scuola di Specializzazione in Pediatria, Università degli Studi di Bologna

Corresponding author:
Gianluca Vergine
UOC Pediatria, Ospedale Infermi di Rimini
Via Luigi Settembrini 2
47900 Rimini, Italia
Tel/Fax: 0541/705034
E-mail: gianluca.vergine@auslromagna.it

 

Abstract

Cystic fibrosis is a multisystem disease with extremely variable onset, symptoms and course. One of the onset modality but also a complication of the disease is the pseudo-Bartter syndrome, characterized by hyponatremia, hypochloremic dehydration and metabolic alkalosis in absence of any renal disease. This syndrome occurs more frequently in the first year of life and has a peak in the summer.

In this article, we describe two cases of cystic fibrosis associated with pseudo-Bartter syndrome in childhood. Excluding every possible cause of metabolic alkalosis associated with hyponatremia was crucial for our diagnostic pathway, and the experience gained with the first case helped a lot with the second one.

Keywords: cystic fibrosis, pseudo-Bartter syndrome, metabolic alkalosis, hyponatremia, pediatrics

Sorry, this entry is only available in Italiano.

Introduzione

La fibrosi cistica (FC) è una malattia genetica a trasmissione autosomica recessiva, caratterizzata dalla mutazione del gene che codifica per una proteina (CFTR: cystic fibrosis transmemebrane regulator) coinvolta nel trasporto transmembrana del cloro. Il gene responsabile si trova a livello del braccio lungo del cromosoma 7. Il CFTR è espresso sulle cellule epiteliali delle vie aeree, del tratto digerente, del pancreas, delle vie biliari, nelle ghiandole sudoripare e nell’apparato genitourinario. Le conseguenze del malfunzionamento sono l’incapacità di eliminare secrezioni mucose per lo scarso contenuto di acqua, un elevato contenuto di sali nel sudore e nelle altre secrezioni sierose e infezioni respiratorie croniche. La mutazione più comune del gene è una delezione che determina l’assenza di fenilalanina nella posizione 508 (ΔF508), tuttavia sono state descritte più di 2.000 mutazioni e le conseguenze molecolari di tali mutazioni possono essere raggruppate in 7 classi sulla base del tipo di alterazione (sintesi, maturazione, trasporto, funzionalità) [1].

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Tolvaptan resistance is related with a short-term poor prognosis in patients with lung cancer and syndrome of inappropriate anti-diuresis

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Antonio Lacquaniti1, Susanna Campo1, Alessandro Russo2, Vincenzo Adamo2, Paolo Monardo1

1 Nephrology and Dialysis Unit, Papardo Hospital of Messina, Italy
2 Medical Oncology Unit A.O. Papardo & Department of Human Pathology, University of Messina, Messina, Italy

Corresponding author:
Dr. Paolo Monardo
Nephrology and Dialysis Unit, Papardo Hospital, Messina, Italy
Phone: 00390903993597
Fax: 00390903992337
Mail: pmonardo66@gmail.com

 

Abstract

Purpose: Tolvaptan (TVP), a vasopressin receptor antagonist, represents a therapeutic option in the syndrome of inappropriate anti-diuresis (SIAD). The aim of this study was to evaluate the effect of TVP to treat and solve hyponatremia in oncologic patients.
Methods: 15 oncologic patients who developed SIAD have been enrolled. Patients receiving TVP belonged to group A, whereas group B was characterized by hyponatremic patients treated with hypertonic saline solutions and fluid restriction.
Results: In group A, the correction of serum sodium was achieved after 3.7±2.8 days. In group B, the target levels were obtained more slowly, after 5.2±3.1 days (p: 0.01) than in group A. The hospital stay and incidence of re-hospitalization were higher in group B than in group A. In this latter, 37% of patients had hyponatremic relapses, notwithstanding the progressive increase of doses from 7.5 to 60 mg per day of TVP, revealing a complete lack of response to TVP. In these patients, a growth of tumor mass or new metastatic lesions has been revealed.
Conclusion: TVP improved hyponatremia more efficiently and stably than hypertonic solutions and fluid restrictions. Positive consequences have been obtained about the rate of chemotherapeutical cycles concluded, hospital stay, rate of relapse of hyponatremia, and re-hospitalization.
Our study also suggested potential prognostic information that could be deduced from TVP patients, in whom sudden and progressive hyponatremia occurred, despite TVP dosage increase. A re-staging of these patients to rule out tumor mass growth or new metastatic lesions is suggested.

Keywords: hyponatremia, paraneoplastic syndrome, syndrome of inappropriate anti-diuresis, tolvaptan, vasopressin

Introduction

The prognosis of oncologic patients is often related to the onset of electrolytic disorders, particularly if hyponatremia occurs [1]. The syndrome of inappropriate anti-diuresis (SIAD) represents the main cause of hyponatremia, even though differential diagnosis with concomitant comorbidities (heart failure, nephrotic syndrome, extracellular volume depletion, pulmonary disorders) and drugs (tricyclic antidepressants, selective serotonin reuptake inhibitors, opioids, chemotherapeutic agents and immunotherapy) needs to be carried out [2, 3].

In particular, SIAD is directly associated with malignancy as expression of a paraneoplastic endocrine effect mediated by an ectopic production of vasopressin (AVP) by cancer cells. Moreover, medications, particularly chemotherapic agents, such as vinca alkaloids, alkylating agents, and platinum compounds, which increase the AVP synthesis/release, could induce SIAD. Other drugs, such as cyclophosphamide, could enhance the water permeability of the distal tubule, in the absence of high AVP levels [1].

Fluid restriction remains the mainstay of treatment for acute and moderate hyponatremia associated with SIAD but inefficacy and frequent side effects, such as dehydration and acute kidney injury, often involving patients treated, at the same time with chemotherapy, require pharmacological interventions [4]. Demeclocycline, loop diuretics associated with sodium supplementation, and urea tablets could correct and solve hyponatremia [5]. In particular, the infusion of hypertonic saline (3%) is highly recommended in acute situations with neurological symptoms. The guidelines advise a bolus of 100–150 mL in 10 minutes, which might be repeated 2 to 3 times until serum sodium increase by 5 mmol avoiding overcorrection [6].
No more than 10 mmol in the first 24 hours or 8 mmol if there are risk factors must be reached in order to prevent severe damage to the central nervous system, such as central pontine myelinolysis, ultimately coma and death. The recommendation is to carry on the correction until symptoms’ disappearance, with careful monitoring of patient’s conditions and serum sodium concentration to avoid hyponatremia overcorrection. If the patient is symptomatic but hyponatremia occurred chronically, correction should be performed more gradually (1.5 to 2 mmol/L/h) [7].
Tolvaptan (TVP), an AVP receptor antagonist, represents a therapeutic option in these patients. It induces a net increase in free water excretion, decreasing aquaporin-2 channels in the renal collecting tubules and water re-absorption and consequently increasing serum sodium concentrations. This phenomenon causes a pure aquaresis without a rise of sodium or potassium urinary excretion [8].
Various studies have investigated the usefulness of TVP, revealing its safety and efficacy in hyponatremic patients, with additional benefits in terms of quality of life and reduced hospitalization [9, 10]. The correction of hyponatremia may also improve anti-neoplastic effects of chemotherapies [11], such as the decrease of AVP levels could reflect a neoplastic remission, or conversely, a recurrence [12].
Despite these findings, hyponatremia did not correlate with tumor burden. Although several studies have focused on hyponatremia in cancer patients, only a limited number of case reports of SIAD are available in this setting, and a limited amount of data on SIAD in cancer patients are available in the literature.
This observational, hypothesis generating study aimed to evaluate the efficacy and safety of TVP to treat and solve hyponatremia in oncologic patients with SIAD. Moreover, we compared TVP results with those obtained by intravenous (iv) therapy based on hypertonic solutions. The incidence of re-hospitalization, due to hyponatremia recurrence and consequent prognostic implication of TVP resistance was evaluated.


Patients and methods

15 adult patients, with a histologically confirmed diagnosis of solid pulmonary tumors who have developed SIAD between January 2017 and June 2020, were retrospectively enrolled in the study.
Diagnostic criteria confirmed the SIAD [13] by evaluating the volemic status, serum sodium concentration and serum osmolality, urine sodium concentration and urine osmolality, thyroid function tests, and serum cortisol. Hypovolemic and hypervolemic hyponatremia has been excluded, as well as hyponatremia due to other endocrine causes, including adrenal insufficiency or hypothyroidism.
Patients with transient hyponatremia due to drugs (i.e., antidepressants, anticonvulsants, antipsychotic), who did not feel thirsty or have difficulty drinking water, with urinary tract obstruction, with serum sodium levels <115 mEq/L associated with severe neurologic deficits, such as seizures, have been excluded from the study. Furthermore, heart failure, renal failure with a glomerular filtration rate < 60 ml/min, ascites associated with hepatic cirrhosis, nephrotic syndrome, severe arterial hypotension, evidence of urinary tract obstruction, poorly controlled diabetes mellitus, a recent history of myocardial infarction, and cerebrovascular disorders determined the exclusion from the enrolment.

Hyponatremia correction and follow-up

According to the pharmacological strategy, patients receiving TVP belonged to group A, whereas group B was characterized by hyponatremic patients treated with hypertonic saline solutions and fluid restriction. In particular, group A patients were treated with 7.5 mg/day of TVP on Day 1 and increased to 15 mg/day if no serum sodium increase was revealed. Conversely, an infusion of 1 ml/kg/h of 3% hypertonic saline was administered in group B, with serum sodium checked every 2 hours during the first 12 hours of treatment.

Patients were discharged and managed as outpatients if they met ambulatory criteria, once the maintenance dose of TVP had been determined. In particular, after the hospital discharge, all patients have been followed through a dedicated outpatient clinic system, with different timing according to clinical conditions and sodium levels. “Maintenance criteria” required weekly serum sodium evaluation before TVP administration, with a target of 2 mEq/L of sodium difference if compared with the concentration assessed at the hospital discharge or the last serum assessment. The liver function panel has been also monitored, as well as body weight and vital signs. Moreover, to avoid rapid and potentially dangerous sodium concentration increase, group A patients did not have a fluid restriction.

The current study was undertaken following the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all patients. Clinical data were collected from medical chart reviews and electronic records.

Statistical analysis

Statistical analyses were performed with NCSS for Windows (version 4.0), the MedCalc (version 11.0; MedCalc Software Acacialaan, Ostend, Belgium) software, and the GraphPad Prism (version 5.0; GraphPad Software, Inc., San Diego, CA, USA) package. Data were presented as mean ± SD for normally distributed values (at Kolmogorov-Smirnov test) and median [IQ range] for not normally distributed values. Differences between groups were established by unpaired t-test or by ANOVA followed by Bonferroni’s test for normally distributed values and by Kruskal-Wallis analysis followed by Dunn’s test for nonparametric values. Dichotomized values were compared using the χ2 test. All results were considered significant if p was < 0.05.


Results

Patients baseline characteristics

Total Group A (TVP) Group B (Hypertonic) p
Patients 15 8 7 p > 0.05
Age, y 69.7±5.9 68.6±6.8 67.4±5.2 p > 0.05
WBC, mm3 6.07±2.4 5.24±2.8 6.37±1.9 p > 0.05
eGFR 78.4±12.8 81.2±9.7 77.4±10.1 p > 0.05
Admission [Na], mmol/l 120.4±2.9 119.7±3.8 118.4±2.9 p > 0.05
Admission Serum Osmolality, mOsm/Kg 257±12.3 244.2±9.3 247±11.2 p > 0.05
Admission Urine Osmolality, mOsm/Kg 407±119.8 465±79.2 397±101 p > 0.05
Hospital stay, days 17.9±8.2 17.6±4.7 11.2±3.4 p < 0.01
Δ[Na], mmol/l/24h 7.9±4.4 8.7±3.5 7.4±4.2 p > 0.05
[Na] Target Achievement, days 6.4±3.6 3.7±2.8 5.2±3.1 p: 0.01
[Na] Hospital Discharge 143.8±1.8 143.4±2.6 144.2±2.1 p > 0.05
Hyponatremia recurrence
Outpatients management, days 22.6±10.8 26.5±6.4 11±6.4 p < 0.01
Re-hospitalization, n (%) 8 (53) 3 (37) 5 (72) p > 0.05
[Na] re-admission, mmol/l 122.7±2.8 123.9±3.4 121.4±3.7 p:0.03
Re-admission Serum Osmolality 251±9.4 262±7.9 258±4.5 p > 0.05
Re-admission urine Osmolality 504±104.8 472±93.4 408.5±79 p > 0.05
Disease progression, n (%) 5 (62) 3 (100) 2 (40) p > 0.05
Table 1: Baseline characteristics of the study cohort.

A total of 15 patients (mean age: 69.7±5.9 years) were hospitalized because of SIAD, and the median sodium level at admission was 120.4±2.9 mmol/l (range 117.4-123.2 mmol/l). The median duration of hospitalization was 17.9±8.2 days (range 9.4-22.7 days). All patients underwent chest radiograph evaluation after the admission to the hospital, excluding active findings of pulmonary infection. The mean white blood cell count was 6.07±2.4 mm3.

Hyponatremia management

Eight patients received tolvaptan for SIAD treatment (group A), whereas hypertonic solutions and fluid restriction have been the treatment for the remaining seven patients (group B).

In group A, all patients started tolvaptan at a dose of 7.5 mg/daily, with the next modifications according to sodium and osmolarity levels.

Hyponatremia has been improved in all Group A patients, without toxicity due to the drug, as revealed by normal values of liver function tests.

Serum sodium levels have been monitored over the first 24 h at regular intervals of 4-6 h to check the correction speed. A rapid correction was not observed, with a slow improvement of sodium levels within the range of 8-10 mmol/l/24h (ΔNa: 8.7±3.5 mmol/l/24h). Moreover, the correction of serum sodium, defined at 135 mmol/l, was achieved after 3.7±2.8 days. All patients required a final dose of 7 or 15 mg of TVP, before hospital discharge, as chronic therapy (Figure 1).

Figure 1: Sodium trend during tolvaptan administration.
Figure 1: Sodium trend during tolvaptan administration.

In group B, patients had a similar trend for sodium increase (ΔNa: 7.4±4.2 mmol/l/24h), but the target levels were obtained more slowly, after 5.2±3.1 days (p: 0.01) than group A. Similarly, the hospital stay was longer in group B than in group A (17.6±4.7 vs 11.2±3.4 days; p< 0.01).

Hyponatremia relapse and re-hospitalization

Serum sodium levels were similar between the two groups during the last assessment in the hospital (143.4±2.6 vs 144.2±2.1; p> 0.05). After discharge, all patients have been followed weekly, to monitor clinical conditions and sodium levels.

Group B was characterized by a higher incidence of re-hospitalization than group A. In particular, 5/7 patients (72%) required hospitalization within 11±6.4 days after the discharge, due to symptomatic hyponatremia (mean serum sodium value at the hospital admission was 121.4±3.7 mmol/l), determining drowsiness, mental confusion or fatigue. This condition was solved by repeating intravenous schemes with hypertonic solutions, with a mean hospital stay of 13.6 ±7.2 days.

In TVP group A, only 3/8 patients (37%) had hyponatremic relapses. These three patients were managed in the outpatient clinic after 26.5±6.4 days (vs 11±6.4 days; p < 0.01) since the last hospital discharge. During this period, serum sodium was maintained between 140 and 145 mmol/l, administering 7.5 or 15 mg of TVP, daily or every other day. In these three patients, severe, sudden and detrimental hyponatremia was observed (123.9±3.4 mmol/l), requiring re-hospitalization. Notwithstanding the progressive increase of doses of TVP, from 7.5 or 15 mg to 60 mg per day hyponatremia did not improve, revealing a complete lack of response to TVP.

Behind planned protocols, the unscheduled oncologic and radiologic staging was early performed. In all three patients, a growth of tumor mass or new metastatic lesions has been revealed, requiring a re-scheduling and modification of chemotherapy cycles. Only after some chemotherapy administration, sodium levels slowly increased. Figure 2 synthetizes the events occurred in a patient with TVP resistance.  

Figure 2: Management of hyponatremia and oncologic restaging in a patient with tolvaptan resistance.
Figure 2: Management of hyponatremia and oncologic restaging in a patient with tolvaptan resistance.

In the remaining five patients (63%) of group A, hyponatremic episodes were often acutely and temporarily related to chemotherapy administration, with sodium correction after adjustment of TVP dose. These patients have been managed in outpatients clinic for more than six months, without the requirement of re-hospitalization and with no progression of cancer disease revealed after scheduled follow-up. All patients completed the planned chemotherapy.

No patients discontinued the TVP treatment due to adverse events, liver dysfunction, or serum sodium concentration exceeding 145 mEq/L.


Discussion

TVP represents a safe and valid therapeutic option to treat hyponatremic oncologic patients who developed SIAD, with no rapid sodium increase observed during the study period and without side effects TVP-related, such as sodium overcorrection or hepatic toxicity. Moreover, the aquaretic approach immediately increased serum sodium concentration, reducing the length of hospitalization, if compared to alternative methods, such as hypertonic solutions, reaching sodium normalization, but in fewer patients and in a longer time.

TVP also reduced the incidence of relapse of hyponatremia and re-hospitalization rate in outpatient follow-up, with obvious positive consequences on quality of life and costs.

These positive data also derived from specific clinical management of these patients, requiring multidisciplinary approaches and strategies, through a dedicated outpatient clinic system after the hospital discharge. Our patients have been evaluated with different timing, according to sodium levels and, consequently, TVP dosage adjustment.

A specific focus on these patients determined various supplementary effects, behind the issue “natremia”. During the follow-up, no TVP patients experienced acute kidney injury in concomitance with chemotherapeutical cycles, probably due to the diminished incidence of dehydration, secondary to fluid restriction, which could be usually prescribed in patients with low sodium levels. The maintenance of serum sodium within the normal range allowed the precocious start of chemotherapeutic agents, without chemotherapy-related hyponatremia, due to the intravenous fluid overload and drug-associated AVP secretion. Behind these positive effects, related to the quick start of chemotherapy, TVP treatment facilitated the administration of chemotherapy cycles constantly and promptly, avoiding delays. Moreover, the efficacy of anticancer treatment is notably improved in patients with normal sodium levels or after its correction, as recently stated by Berardi who revealed an optimal sodium correction, an improvement of the hospitalization length and quality of life during TVP treatment [14].

Our study also suggested potential prognostic information that could be deduced from TVP patients, in whom sudden and progressive hyponatremia occurred, despite TVP dosage increase. A re-staging of these patients highlighted tumor mass growth or new metastatic lesions, suggesting cancer AVP production, requiring modification of chemotherapy cycles.

However, notwithstanding all this available evidence, the use of TVP remains limited in daily clinical practice, around 5%, according to the hyponatremia registry [15].

Adequate management of natremia is crucial due to the well-known correlation with overall survival, both in the general population and in cancer patients. Many studies revealed a close link between low sodium levels and poor prognosis, not only in small cell lung cancer [14] but also in other types of non-pulmonary tumors, including renal cell carcinoma and gastrointestinal cancer [16–19].

We cannot analyze potential relationships between survival and sodium correction, acutely or during a long follow-up period, by TVP administration due to the small cohort of patients.

The present study has some limitations that should be mentioned. First, the retrospective nature of this study could result in unwanted methodological biases. The therapy choices were not randomized; therefore, conclusions about the relative efficacy of the treatments, including TVP, are limited. Confirmation in wider cohorts is indispensable to attribute general validity to our results.

These limitations did not allow us to strengthen the prognostic role of TVP failure to improve sudden hyponatremia or to evaluate the impact of TVP therapy and sodium maintenance on patients’ survival. However, our study generating hypotheses could be a starting point for further studies.

 

Conclusions

Our data demonstrated that TVP improved hyponatremia more efficiently and stably than hypertonic solutions and fluid restrictions, with a high rate of chemotherapeutical cycles concluded. Positive consequences have been obtained about the hospital stay, rate of relapse of hyponatremia, and re-hospitalization. TVP exerted its potential benefit of long-term use in an outpatient setting, improving the quality of life of SIAD oncologic patients.

 

Acknowledgments

The authors acknowledge the Nephrology nurses Carmelo Saterno and Caterina Ragno for their clinical work during the outpatient clinic management and for participating in the study collecting data.

 

Bibliography

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  2. Doshi SM, Shah P, Lei X et al. Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes. Am J Kidney Dis 2012; 59:222–228. https://doi.org/1053/j.ajkd.2011.08.029.
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The pathway of vasopressin as a pharmacological target in nephrology: a narrative review

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Michi Recupero

Recupero Michi, Fulignati Pierluigi, Naticchia Alessandro, D'Alonzo Silvia, D'Ascenzo Francesca, Costanzi Stefano

Autore corrispondente:
Dott. Recupero Michi
Scuola di Specializzazione in Nefrologia,
U.O.C.  Nefrologia, Università cattolica del sacro cuore
Fondazione  Policlinico Universitario A. Gemelli IRCCS, Roma, Italia
tel: 3299314372.
e-mail: m.recupero@hotmail.it

 

Abstract

ADH is a hormone secreted by neurohypophysis that plays different roles based on the target organ. At the renal level, this peptide is capable of causing electrolyte-free water absorption, thus playing a key role in the hydro-electrolytic balance. There are pathologies and disorders that jeopardize this balance and, in this field, ADH receptor inhibitors such as Vaptans could play a key role. By inhibiting the activation pathway of vasopressin, they are potentially useful in euvolemic and hypervolemic hypotonic hyponatremia. However, clinical trials in heart failure have not given favourable results on clinical outcomes. Even in SIADH, despite their wide use, there is no agreement by experts on their use.

Since vaptans inhibit the cAMP pathway in tubular cells, their use has been proposed to inhibit cystogenesis. A clinical trial has shown favourable effects on ADPKD progression.

Because vaptans have been shown to be effective in models of renal cysts disorders other than ADPKD, their use has been proposed in diseases such as nephronophthisis and recessive autosomal polycystic disease. Other possible uses of vaptans could be in kidney transplantation and cardiorenal syndrome.

Due to the activity of ADH in coagulation and haemostasis, ADH’s activation pathway by Desmopressin Acetate could be a useful strategy to reduce the risk of bleeding in biopsies in patients with haemorrhagic risk.

 

Keyword: vasopressin, vaptans, hyponatremia, ADPKD, biopsy

Sorry, this entry is only available in Italiano.

Introduzione

La vasopressina, nota anche come adiuretina o arginin-vasopressina (AVP) o ormone antidiuretico (ADH), è un ormone neuropeptidico prodotto a livello dei nuclei sopraottico e paraventricolare che viene secreto dall’ipofisi posteriore in risposta ad un aumento della tonicità plasmatica o alla diminuzione del volume plasmatico (1).

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