Metabolic Kidney Disease: A New Concept in the Interaction Between Obesity, Prediabetes, Diabetes and Liver Dysfunction

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Jorge Rico Fontalvo

DOI: 10.69097/43-01-2026-06

Jorge Rico Fontalvo1,2,6, Rodrigo Daza Arnedo3,6, María Raad Sarabia4, Javier Jiménez5, Juan Montejo-Hernández2,6, Tomas Rodríguez-Yánez7, María José Soler8, Maria Teresa Sciarrone-Alibrandi9, Rodolfo Fernando Rivera10

1. Facultad de Medicina, Departamento de Nefrología, Universidad Simón Bolívar de Barranquilla, Barranquilla, Colombia
2. Departamento médico, IPS Nephromedicall Medellín, Medellín, Colombia
3. IPS Caminos Cartagena, Cartagena, Colombia
4. Facultad de Medicina, Departamento de Medicina Interna, Universidad del Sinú, Cartagena, Colombia
5. Facultad de Medicina, Universidad Militar Nueva Granada, Bogotá, Colombia
6. Asociación Colombiana de Nefrología e HTA (ASOCOLNEF), Bogotá, Colombia
7. Facultad de Medicina, Departamento de Medicina Interna, Universidad de Cartagena, Cartagena, Colombia
8. Servicio de Nefrología, Hospital Universitario Vall de Hebron, Barcelona, España
9. Struttura Complessa Nefrologia e Dialisi, IRCCS Ospedale San Raffaele di Milano, Italia
10. Struttura Complessa Nefrologia e Dialisi, Ospedale Pio XI, Desio, ASST Brianza, Italia

Corresponding author:
Rodolfo Rivera,
E-mail: md.rfrivera@gmail.com

 

Abstract

Metabolic abnormalities such as obesity, insulin resistance, prediabetes, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) increasingly contribute to chronic kidney disease (CKD). Although often treated as separate entities, these conditions share common mechanisms – including glomerular hyperfiltration, adipokine imbalance, chronic low-grade inflammation, endothelial dysfunction and lipid accumulation – that initiate and sustain renal injury long before classical CKD becomes clinically evident.

The concept of Metabolic Kidney Disease (MKD) offers a unified framework that captures the continuum of renal involvement across the metabolic spectrum. Obesity- and prediabetes-related MKD frequently precede diabetic kidney disease, while MASLD – according to updated EASL-EASD-EASO guidelines – is a multisystem disorder with direct renal consequences. Mixed metabolic phenotypes further intensify metabolic stress, accelerating progression toward CKD.

Recognising MKD has important clinical implications. Expanded screening strategies may identify early renal alterations in individuals with metabolic vulnerability who are not targeted by traditional CKD criteria. Integrating metabolic evaluation into nephrology practice may facilitate earlier, more holistic interventions and ultimately improve cardio-renal outcomes.

Keywords: Obesity, Type 2 diabetes, Prediabetes, Chronic Kidney Disease, Liver dysfunction, Cardiorenal metabolic syndrome, Albuminuria, Glomerular hyperfiltration

List of Abbreviations:

ACR – Albumin-to-creatinine ratio
AGEs – Advanced glycation end-products
AKI – Acute kidney injury
CKD – Chronic Kidney Disease
CKM – Cardiovascular-kidney-metabolic syndrome
CRMS – Cardio-renal-metabolic syndrome
DKD – Diabetic kidney disease
eGFR – Estimated glomerular filtration rate
GLP-1 RA – Glucagon-like peptide-1 receptor agonist
HbA1c – Glycated haemoglobin
IL-6 – Interleukin 6
MASLD – Metabolic dysfunction–associated steatotic liver disease
MKD – Metabolic kidney disease
NAFLD – Non-alcoholic fatty liver disease (former term for MASLD)
NF-κB – Nuclear factor kappa-light-chain-enhancer of activated B cells
ORG – Obesity-related glomerulopathy
PKC – Protein kinase C
RAAS – Renin–angiotensin–aldosterone system
ROS – Reactive oxygen species
SGLT2 – Sodium–glucose cotransporter 2
T2DM – Type 2 diabetes mellitus
TGF-β – Transforming growth factor beta
TNF-α – Tumor necrosis factor alpha

 

Introduction

Cardiovascular diseases and other non-communicable conditions remain the leading cause of death worldwide, accounting for nearly 70% of global mortality [1]. Diabetes mellitus, arterial hypertension, obesity, and chronic kidney disease (CKD) constitute the most prevalent chronic conditions contributing to this burden. CKD affects an estimated 9-13% of the population, with prevalence increasingly driven by the global epidemics of diabetes and obesity [2, 3].

In parallel, the prevalence of diabetes has doubled from 1990 to 2022, reaching over 828 million adults globally [4]. Similar trends are observed in Latin America and other regions, where obesity and metabolic dysfunction are now major determinants of cardiovascular and renal risk [5–10]. Importantly, mounting evidence indicates that kidney injury can arise before overt diabetes develops, occurring across the entire spectrum of metabolic disturbances, including obesity, prediabetes, insulin resistance, and metabolic dysfunction-associated steatotic liver disease (MASLD).

These interconnected processes form a continuum in which excess adiposity and adipose-tissue dysfunction induce systemic inflammation, endothelial injury, glomerular hyperfiltration, and neurohormonal activation. This “adipocentric” perspective has led to the recognition of the Cardio-Renal-Metabolic Syndrome (CRMS) as an integrated model encompassing cardiovascular, renal, and metabolic abnormalities [11–13].

Within this framework, the concept of Metabolic Kidney Disease (MKD) emerges as a unifying term describing kidney damage mediated primarily by metabolic dysfunction, even in the absence of sustained hyperglycaemia. MKD encompasses kidney injury associated with obesity, prediabetes, type 2 diabetes, MASLD, and mixed phenotypes. Its early recognition may be essential to interrupt disease progression and reduce cardiovascular and renal complications.

Importantly, metabolic dysfunction precedes and amplifies kidney injury across the entire continuum of adiposopathy, insulin resistance, impaired glucose tolerance, type 2 diabetes and MASLD, highlighting that renal damage often develops before overt hyperglycaemia becomes clinically detectable.

 

Cardio-Renal-Metabolic Syndrome (CRMS)

The Cardio-Renal-Metabolic Syndrome (CRMS) provides the essential pathophysiological context from which Metabolic Kidney Disease emerges. Evidence accumulated over the last decade shows that excess adiposity – particularly visceral and ectopic fat accumulation – drives a systemic inflammatory state that disrupts cardiovascular, renal, and metabolic homeostasis [14]. Rather than isolated diseases, these conditions form an interconnected continuum in which dysfunction in one organ system accelerates injury in the others.

The American Heart Association defines CRMS as a systemic disorder characterized by pathophysiological interactions between metabolic risk factors, CKD, and cardiovascular disease (CVD), leading to multiorgan dysfunction and increased cardiovascular events [12]. This framework emphasizes the bidirectional nature of these interactions: CVD increases the likelihood of renal dysfunction; CKD amplifies cardiovascular risk; and metabolic abnormalities – including adipose-tissue dysfunction, insulin resistance, and subclinical inflammation – drive both processes simultaneously [15–18].

Three major biological pathways underpin CRMS:

  1. Chronic low-grade inflammation, mediated by adipose-derived cytokines such as IL6 and TNFα, promoting endothelial dysfunction, oxidative stress, and vascular injury.
  2. Insulin resistance, contributing to altered podocyte signaling, increased sodium reabsorption, impaired nitric oxide bioavailability, and early glomerular hyperfiltration.
  3. Neurohormonal activation, including heightened activity of the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS), fostering vasoconstriction, hypertension, fibrosis, and progressive organ damage.

To support clinical stratification, the AHA proposes a staging system encompassing the entire spectrum of metabolic and cardiorenal dysfunction [12, 15]:

  • Stage 0: No metabolic risk factors
  • Stage 1: Excess or dysfunctional adiposity, including prediabetes
  • Stage 2: Metabolic risk factors and/or moderate-to-high CKD risk
  • Stage 3: Subclinical CVD with overlapping metabolic or renal risk
  • Stage 4: Established CVD ± CKD (4a: without renal insufficiency; 4b: with renal insufficiency)

Within this continuum, the kidney is both target and mediator of metabolic injury. CRMS thus provides the conceptual foundation for MKD/ERM, clarifying how metabolic dysfunction – independent of glycaemic thresholds – initiates and amplifies renal injury.

 

Definition and Concept of Metabolic Kidney Disease (MKD/ERM)

Metabolic Kidney Disease (MKD), or Enfermedad Renal Metabólica (ERM), is an emerging and evolving concept that seeks to integrate the entire spectrum of renal injury associated with metabolic dysfunction. Rather than representing a single disease or a traditional histopathological entity, MKD reflects a continuum of pathophysiological alterations in which adipose-tissue dysfunction, insulin resistance, and chronic low-grade inflammation converge to drive early and progressive kidney damage. This view departs from classical models focused exclusively on hyperglycaemia or hypertension, and instead places the metabolic milieu – especially dysfunctional adiposity – at the centre of renal injury [13, 19] (Figure 1).

Common pathophysiological mechanisms in metabolic kidney disease (MKD)
Figure 1. Common pathophysiological mechanisms in metabolic kidney disease (MKD). 1. Inflammation: increased cytokine and adipokine signalling leading to endothelial dysfunction, tissue remodelling, and fibrosis. 2. Hyperfiltration: intraglomerular hypertension and haemodynamic stress, contributing to podocyte injury and glomerulosclerosis. 3. Endothelial dysfunction: impaired nitric oxide bioavailability leading to altered autoregulation and vascular stiffness. 4. Insulin resistance: disrupted insulin signalling in target tissues (e.g., podocytes, hepatocytes) promoting metabolic stress, lipotoxicity, and apoptosis.

Adipose-tissue dysfunction plays a pivotal mechanistic role. Excess visceral fat promotes secretion of proinflammatory cytokines (TNF-α, IL-6), dysregulated adipokines (reduced adiponectina, elevated leptina), increased oxidative stress, and activation of the renin–angiotensin–aldosterone system (RAAS). These mechanisms favour afferent arteriolar vasodilation, intraglomerular hypertension, podocyte stress, and alterations in glomerular permeability. Over time, these changes contribute to hypertrophy of glomerular structures, expansion of mesangial matrix, tubulointerstitial inflammation, and ultimately to a decline in glomerular filtration [20–24]. This continuum perspective aligns with current evidence, emphasizing that renal alterations frequently emerge during early metabolic imbalance, well before traditional diagnostic criteria for diabetes or CKD are met.

 

MKD as an Integrative Clinical Framework

The strength of the MKD concept lies in its ability to integrate metabolic phenotypes that traditionally have been described separately. Obesity, prediabetes, type 2 diabetes, MASLD, and their combinations share physiopathological pathways that converge on the kidney. Although the magnitude and temporal sequence of injury may differ, the kidney responds to metabolic stress in a largely stereotyped manner: early glomerular hyperfiltration, podocyte maladaptation, endothelial dysfunction, and progressive fibrosis.

This integrative framework does not negate existing terminology, such as Diabetic Kidney Disease (DKD) or CKD associated with metabolic syndrome, but rather seeks to connect them. DKD remains essential for describing renal injury in established diabetes. However, it does not encompass patients with obesity or prediabetes who show similar physiopathological patterns. Likewise, CKD associated with metabolic syndrome often remains an epidemiological description rather than a mechanistic one. MKD proposes a unifying perspective, highlighting the central role of metabolic dysfunction – whether hepatic, adipose, or pancreatic – in initiating and sustaining renal damage. Given its high prevalence and strong metabolic basis, MASLD should be formally recognised as a key determinant of renal vulnerability within the MKD spectrum, warranting systematic screening even in non-diabetic individuals.

 

Clinical Implications

Recognizing MKD as a distinct and broader clinical construct may help clinicians identify high-risk individuals who would not be screened under current CKD guidelines. It may also encourage early therapeutic interventions targeting adipose-tissue inflammation, insulin resistance, and metabolic stress before overt renal dysfunction becomes evident. Ultimately, MKD promotes a shift from reactive nephrology to a more preventive, metabolically informed approach, consistent with contemporary cardio-renal-metabolic frameworks.
Comparable patterns of early metabolic stress and altered body composition have been reported in kidney conditions characterised by organomegaly, where malnutrition and sarcopenia may develop despite preserved eGFR [25, 26], particularly in women due to the higher prevalence of hepatomegaly [27–29].
Furthermore, persistent inflammatory activation is a hallmark across CKD phenotypes. Evidence from anemia management [30], intravenous iron stewardship [31], and uremic toxin–driven vascular injury [32] highlights how metabolic and inflammatory disturbances can converge to amplify renal vulnerability, mirroring several mechanisms central to MKD.

 

Clinical Subtypes of Metabolic Kidney Disease

Metabolic Kidney Disease encompasses a spectrum of renal manifestations arising from distinct but interrelated metabolic disturbances. Although these conditions share common physiopathological pathways – such as insulin resistance, adipose-tissue dysfunction, chronic inflammation, and endothelial injury – each metabolic phenotype imprints a characteristic pattern of renal involvement (Figure 2). In the following sections, we describe the major clinical subtypes of MKD, highlighting their specific mechanisms, histopathological features, and implications for early detection and progression.

Figure 2. Proposed classification of metabolic kidney disease (MKD). Subtypes include obesity-related MKD, prediabetes-related MKD, T2DM-related MKD, MASLD-related MKD, and mixed MKD.

Obesity-Related- Metabolic Kidney Disease

Obesity represents one of the most consistent and well-established metabolic risk factors for the development and progression of kidney disease. Far from being a passive -energy storage compartment, adipose tissue – -particularly visceral fat accumulation – functions as an active endocrine and immunometabolic organ capable of modulating systemic inflammation, insulin sensitivity, oxidative stress, haemodynamics, and neurohormonal signalling [33–37]. These perturbations exert direct and indirect effects on renal structure and function, forming the basis of obesity-related- metabolic kidney disease.

From a haemodynamic standpoint, obesity is characterized by increased renal plasma flow, afferent arteriolar vasodilation, and elevated intraglomerular pressure. These early adaptations, largely mediated by hyperinsulinaemia, enhanced tubular sodium–glucose reabsorption, and heightened RAAS and sympathetic nervous system activity, culminate in glomerular hyperfiltration [36–38]. Persistent hyperfiltration contributes to enlargement of glomerular tuft volume and sets the stage for podocyte hypertrophy, detachment, and loss – events central to the initiation of proteinuria and progressive glomerulosclerosis.

Adipokines are central mediators of renal injury in obesity. Elevated leptin levels promote proliferation of mesangial cells, collagen deposition, and activation of profibrotic pathways, whereas reduced adiponectin impairs endothelial integrity and increases susceptibility to inflammation and oxidative stress [22, 37]. In parallel, secretion of cytokines such as IL6 and TNFα from dysfunctional adipose tissue fuels systemic lowgrade inflammation, promoting renal endothelial dysfunction, altered nitric oxide bioavailability, and microvascular injury.
Histopathological studies have described a recognizable phenotype in obesity-related kidney disease, known as obesity-elated glomerulopathy (ORG). Biopsies commonly reveal glomerulomegaly, mesangial expansion, podocyte -foot process widening, increased extracellular matrix deposition, thickening of the glomerular basement membrane, and variable degrees of tubulointerstitial inflammation and fibrosis [38–42]. Although traditionally considered a benign or slowly progressive condition, recent data suggest that ORG may lead to significant proteinuria and decline in kidney function, especially when metabolic risk factors coexist or remain uncontrolled.
Importantly, obesity also amplifies the impact of other metabolic abnormalities – prediabetes, MASLD, dyslipidaemia, and hypertension – enhancing their deleterious effects on the kidney. This synergistic behaviour explains why obesity serves not only as a primary driver of MKD but also as a critical component in mixed metabolic phenotypes.
The recognition of obesity-related MKD underscores the need for early clinical identification of renal stress in individuals with overweight or obesity, even in the absence of diabetes or overt CKD. Given the potential reversibility of early haemodynamic changes and the benefits of weight reduction, pharmacological metabolic modulation, and lifestyle interventions, early detection represents a crucial opportunity for prevention and disease-modifying therapy.

Prediabetes-Related Metabolic Kidney Disease

Prediabetes represents an intermediate metabolic state between normoglycaemia and overt diabetes, characterised by impaired fasting glucose, impaired glucose tolerance, or elevated glycated haemoglobin according to current diagnostic criteria [43]. Although traditionally viewed as a precursor stage with modest clinical implications, accumulating evidence indicates that prediabetes is not a benign condition. Rather, it constitutes a metabolically active and pathophysiologically relevant state capable of inducing early renal injury through mechanisms that parallel, but do not require, sustained hyperglycaemia [44–46].
Several epidemiological studies have demonstrated a consistent association between prediabetes and an increased risk of incident CKD, reduced eGFR, and elevated albuminuria. In a prospective cohort exceeding 7,000 individuals with nearly nine years of follow-up, both impaired glucose tolerance and elevated HbA1c were independently associated with new-onset CKD, with hazard ratios ranging from 1.13 to 1.39 [44]. These findings have been confirmed by larger population-based analyses, including the REACTION study involving more than 250,000 Chinese adults, where prediabetes was identified as an independent predictor of CKD, particularly among men [47]. Meta-analyses reinforce this association, suggesting that even modest elevations in glucose metabolism confer a measurable increase in renal risk [46].
From a mechanistic perspective, renal injury in prediabetes is driven primarily by insulin resistance, hyperinsulinaemia, and intermittent postprandial hyperglycaemia. These alterations impair podocyte insulin signalling, reduce nephrin expression, and promote cytoskeletal instability, rendering podocytes more vulnerable to detachment and apoptosis [45, 48]. Concurrently, increased proximal tubular sodium-glucose reabsorption diminishes sodium delivery to the macula densa, blunting tubuloglomerular feedback and favouring afferent arteriolar vasodilation – enhancing glomerular hyperfiltration in a pattern similar to early diabetic kidney disease [45, 48].
Oxidative stress also plays a central role. Elevated production of reactive oxygen species, accumulation of advanced glycation end-products, and activation of protein kinase C pathways contribute to endothelial dysfunction, mesangial expansion, and increased glomerular permeability [48]. These changes manifest clinically as low-grade albuminuria and may precede overt abnormalities in eGFR.
Despite this growing evidence, prediabetes is not currently included among the recommended indications for CKD screening in most clinical guidelines [49]. Given the substantial prevalence of prediabetes worldwide and its clear association with early renal injury, incorporating individuals with prediabetes into CKD risk stratification strategies could facilitate earlier detection of kidney involvement and prompt implementation of preventive interventions.

Diabetes-Related Metabolic Kidney Disease

Type 2 diabetes mellitus (T2DM) remains the most common metabolic condition associated with chronic kidney disease worldwide, and diabetic kidney disease (DKD) continues to represent a major cause of end-stage kidney disease [50]. However, within the conceptual framework of Metabolic Kidney Disease, diabetes-related renal injury is understood not as an isolated entity, but as the intensification and culmination of metabolic disturbances that often originate much earlier – during obesity, insulin resistance, and prediabetes. This perspective highlights the continuity of metabolic stress across the glycaemic spectrum and underscores the shared mechanisms that unite DKD with other MKD subtypes.
Hyperglycaemia initiates and amplifies several interrelated pathways that contribute to renal damage. Among the earliest alterations is glomerular hyperfiltration, driven by increased proximal tubular sodium-glucose reabsorption mediated by SGLT2. This reduces solute delivery to the macula densa, blunts tubuloglomerular feedback, and promotes afferent arteriolar vasodilation, thereby increasing intraglomerular pressure [51]. Persistent hyperfiltration accelerates podocyte hypertrophy and detachment – lesions central to the development of albuminuria.
Glucotoxicity exerts direct cellular effects. Chronic exposure to elevated glucose levels induces oxidative stress, mitochondrial dysfunction, and accumulation of advanced glycation end-products (AGEs). These processes trigger mesangial expansion, altered extracellular matrix turnover, and thickening of the glomerular basement membrane [52, 53]. Importantly, lipotoxicity – driven by elevated circulating free fatty acids and ectopic lipid accumulation – amplifies these pathways by promoting endoplasmic reticulum stress, inflammation, and apoptosis in podocytes and tubular cells [54].
Inflammatory and fibrotic pathways further contribute to disease progression. Activation of protein kinase C (PKC), nuclear factor-κB (NF-κB), and transforming growth factor-β (TGF-β) promotes epithelial–mesenchymal transition, interstitial fibrosis, and glomerulosclerosis [55]. These processes often evolve silently for years before clinical manifestations appear, explaining why many patients show evidence of renal structural injury even at the time of diabetes diagnosis.
Although DKD has traditionally been described as a distinct clinical entity, MKD emphasizes that diabetes-related renal injury represents a continuum of metabolic renal stress, rather than a binary state emerging only after hyperglycaemia surpasses diagnostic thresholds. This broader view aligns with epidemiological observations showing that albuminuria, reduced eGFR, and microvascular injury can be detected in a significant proportion of individuals with newly diagnosed diabetes or even during the prediabetic phase.
Recognising diabetes-related MKD within this continuum has practical implications: it highlights the importance of early interventions targeting hyperglycaemia, insulin resistance, RAAS activation, and metabolic inflammation. Moreover, therapies such as SGLT2 inhibitors and GLP-1 receptor agonists – initially developed for glycaemic control – have demonstrated significant renal and cardiovascular protection precisely because they modulate many of these shared metabolic pathways.

MASLD-Related Metabolic Kidney Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is now recognised as a multisystem metabolic disorder that extends well beyond the liver. The recent harmonized definitions and clinical practice guidelines issued jointly by EASL, EASD and EASO [56] underline the strong metabolic underpinnings of MASLD and its close association with insulin resistance, visceral fat accumulation, dyslipidaemia and systemic inflammation. This updated framework emphasizes that MASLD frequently coexists with other metabolic conditions and contributes to end-organ damage, including the kidney.
A growing body of evidence indicates that MASLD is independently associated with chronic kidney disease (CKD). A comprehensive and authoritative review by Bilson, [57] summarized epidemiological and mechanistic data supporting a strong association between MASLD and increased CKD risk, even after adjusting for obesity, diabetes and hypertension. These observations confirm that MASLD is not simply a marker of metabolic syndrome but a condition with its own pathophysiological impact on renal structure and function.
Mechanistically, MASLD promotes renal injury through multiple interconnected pathways. Hepatic steatosis triggers the release of hepatokines (e.g., fetuin-A) and other inflammatory mediators, which aggravate insulin resistance, endothelial dysfunction, and oxidative stress. These systemic disturbances impair glomerular autoregulation and increase susceptibility to hyperfiltration and podocyte stress. Disturbances in lipid metabolism characteristic of MASLD facilitate the accumulation of toxic lipid intermediates, contributing to mitochondrial dysfunction and activation of pro-fibrotic cascades within the kidney.
A further layer of complexity arises from genetic predisposition. Variants such as PNPLA3, TM6SF2 and MBOAT7 – well-established determinants of liver disease severity in MASLD – have been associated with increased renal vulnerability, suggesting shared metabolic and inflammatory pathways between hepatic steatosis and CKD [58]. These data reinforce the concept that renal involvement in MASLD is not solely a consequence of coexisting metabolic abnormalities, but reflects intrinsic pathobiological processes linked to the disease itself.
Meta-analytic data continue to support the association between MASLD and kidney dysfunction. The landmark systematic review by Musso and colleagues [59] remains a frequently cited foundational analysis demonstrating increased CKD prevalence and incidence among individuals with NAFLD. While older, its conclusions align with contemporary findings and highlight persistent mechanistic plausibility across diverse populations.
Recognizing MASLD as a distinct subtype within the broader spectrum of Metabolic Kidney Disease has important clinical implications. Given its high global prevalence and frequent underdiagnosis, incorporating MASLD into CKD risk stratification frameworks may facilitate earlier identification of renal involvement. Furthermore, therapeutic strategies targeting hepatic steatosis – such as GLP-1 receptor agonists, weight reduction and lifestyle interventions – may confer renal benefits even in the absence of overt diabetes. As recent guidelines emphasize [60, 61], a comprehensive approach addressing metabolic dysfunction across organ systems represents a crucial step toward improving long-term outcomes.

Mixed Metabolic Kidney Disease

Mixed Metabolic Kidney Disease represents the convergence of multiple metabolic derangements acting simultaneously on renal structure and function. In clinical practice, this phenotype is increasingly common, reflecting the overlap between obesity, insulin resistance, prediabetes, type 2 diabetes, hypertension, dyslipidaemia and MASLD. Rather than functioning as isolated risk factors, these conditions interact through shared mechanisms that amplify metabolic stress on the kidney, accelerating the transition from early functional changes to established chronic kidney disease [38].
From a pathophysiological standpoint, mixed MKD embodies a state in which haemodynamic, inflammatory, hormonal and lipid-related disturbances reinforce one another. Excess visceral fat accumulation fuels chronic low-grade inflammation and adipokine dysregulation, worsening insulin resistance and promoting hyperinsulinaemia [22]. In parallel, progressive impairments in glucose tolerance intensify tubular sodium-glucose reabsorption, stimulating afferent arteriolar vasodilation and glomerular hyperfiltration [45]. When MASLD coexists, the release of hepatokines and proinflammatory mediators further exacerbates endothelial dysfunction, oxidative stress and microvascular injury [50].
These synergistic mechanisms produce a renal phenotype that is often more severe than the sum of its individual components. Patients with obesity and MASLD, for example, exhibit higher rates of albuminuria and more pronounced declines in eGFR compared with individuals with either condition alone [62]. Similarly, the coexistence of prediabetes or early diabetes with hepatic steatosis and visceral fat accumulation results in more rapid structural changes – mesangial expansion, podocyte stress and tubulointerstitial fibrosis – even when glycaemic abnormalities remain modest [63].
Clinically, mixed MKD is frequently under-recognised. Traditional screening strategies tend to focus on single risk factors – most often diabetes – thereby missing individuals who harbour substantial renal risk due to the cumulative effect of multiple metabolic abnormalities. This oversight is particularly relevant in younger or non-diabetic individuals with obesity and MASLD, in whom early renal involvement may be subtle yet progressive.
Recognising mixed MKD as a distinct and increasingly prevalent phenotype underscores the importance of integrated metabolic assessment in the evaluation of CKD risk. A comprehensive approach – including assessment of adiposity, glycaemic status, hepatic steatosis, blood pressure and lipid profile – allows for earlier identification of individuals at high risk and supports targeted interventions aimed at modulating metabolic stress. Ultimately, the mixed MKD phenotype exemplifies the concept of Metabolic Kidney Disease: a continuum of renal injury shaped not by a single metabolic defect, but by the interplay of multiple overlapping disturbances acting across organ systems. Such multilayered interactions are increasingly documented across metabolic phenotypes, supporting the concept of mixed MKD as a clinically relevant and mechanistically distinct entity.

 

Screening and Clinical Implications

The recognition of Metabolic Kidney Disease (MKD) as a unified conceptual framework has important consequences for screening strategies, particularly in populations traditionally not considered at high risk for chronic kidney disease. Current screening algorithms [64] often prioritise individuals with established type 2 diabetes or long-standing hypertension, overlooking a substantial proportion of patients who exhibit renal involvement driven primarily by obesity, prediabetes, MASLD or combinations thereof. As a result, early stages of metabolic renal stress frequently remain undetected [12] until albuminuria or declines in eGFR become clinically evident.

Integrating MKD-oriented screening into routine nephrology workflows could meaningfully shift clinical practice toward earlier detection, streamlined risk stratification, and more timely initiation of preventive interventions, particularly in metabolically vulnerable individuals.

 

Who Should Be Screened?

Given the burden of metabolic dysfunction in modern populations, screening should extend beyond conventional high-risk groups. Individuals with the following characteristics merit evaluation for possible MKD (Figure 3):

  • Obesity with increased visceral fat accumulation, even in the absence of diabetes or hypertension
  • Prediabetes, particularly in those with impaired glucose tolerance or rising HbA1c
  • MASLD, regardless of glycaemic status, as emphasised by recent international guidelines [56]
  • Family history of type 2 diabetes, CKD or early cardiovascular disease [12]
  • Coexistence of multiple metabolic abnormalities, including dyslipidaemia, hyperuricaemia or elevated liver enzymes

In these individuals, glomerular hyperfiltration and endothelial dysfunction – hallmarks of early MKD – may precede measurable reductions in kidney function, highlighting the importance of timely assessment.

It is important to acknowledge that current CKD guidelines still do not formally recommend routine kidney screening in individuals with prediabetes or MASLD. The evidence supporting such an approach is growing, yet prospective validation and consensus-driven recommendations are still needed to define optimal screening thresholds and intervals.

 

What Tests Should Be Performed?

A pragmatic and clinically accessible initial evaluation may include:

  • Estimated glomerular filtration rate (eGFR) using creatinine or combined creatinine-cystatin C equations
  • Urine albumin-to-creatinine ratio (ACR) to detect early glomerular injury
  • Assessment of metabolic health, including fasting glucose, HbA1c, lipid profile, uric acid and markers of hepatic steatosis
  • Imaging, where appropriate, to evaluate hepatic steatosis or adipose distribution

Importantly, mild elevations in ACR or upward drifts in eGFR (suggesting glomerular hyperfiltration) should not be dismissed as normal variants in individuals with metabolic abnormalities, but rather considered potential markers of MKD.

 

Clinical Integration

Incorporating MKD into routine practice involves adopting a more comprehensive view of metabolic health, recognising that renal involvement can occur long before diagnostic thresholds for diabetes or CKD are reached. Early identification enables timely implementation of therapeutic strategies – such as weight optimisation, dietary interventions, metabolic modulation and blood pressure control – that mitigate renal stress and may alter longterm trajectories.

Screening includes estimated glomerular filtration rate (eGFR)
Figure 3. Recommended screening tests for chronic kidney disease (CKD). Screening includes estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR). These tests are recommended for individuals with obesity, prediabetes, hypertension, T2DM, cardiovascular disease, prior AKI, or age >60 years.

 

Conclusions

Metabolic Kidney Disease represents an important conceptual and clinical evolution in our understanding of the interplay between metabolic dysfunction and renal health. This framework offers clinicians a more actionable understanding of metabolic renal risk, promoting earlier recognition of kidney involvement and more timely implementation of prevention strategies. By integrating obesity, prediabetes, type 2 diabetes, MASLD and mixed phenotypes within a single conceptual framework, MKD offers a more coherent representation of the pathophysiological processes driving early kidney injury in contemporary populations. This approach emphasises the central role of adipose tissue dysfunction, insulin resistance, chronic low-grade inflammation and lipid dysregulation as shared mechanisms across the metabolic spectrum.

Recognising MKD broadens opportunities for earlier diagnosis, particularly in individuals who would not be captured by traditional CKD screening criteria. It also underscores the need for multidimensional management strategies that address metabolic dysfunction across organ systems, rather than focusing solely on glycaemic control or blood pressure.

As the prevalence of metabolic disorders continues to rise globally, incorporating the MKD framework into clinical practice may offer a path toward more effective prevention and improved longterm renal and cardiovascular outcomes. This review highlights the importance of a unified, metabolically informed approach to kidney health – an approach that aligns with modern evidence and reflects the complex, interconnected nature of metabolic disease.

 

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Obesity and Kidney Disease: A Focus on Ciliopathies

Posted on Scarica PDF

Andrea Melluso

DOI: 10.69097/42-04-2025-07

Andrea Melluso1, Alessandra Perna2, Miriam Zacchia2

1 Nephrology and Dialysis Unit, “don Tonino Bello” Hospital, ASL Bari, Molfetta, Italy
2 Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy

Corresponding author:
Andrea Melluso
E-mail: andrea.melluso@virgilio.it

 

Abstract

The prevalence of obesity is progressively increasing on a global scale. Among its negative health consequences, renal damage is also observed. It is due to hemodynamic, metabolic, and inflammatory alterations.
Ciliopathies are a group of disorders caused by dysfunction of the primary cilium; these include autosomal dominant polycystic kidney disease (ADPKD) as well as Alström and Bardet-Biedl syndromes. In ADPKD, obesity accelerates kidney disease progression. In Alström and Bardet-Biedl syndromes, renal disease is likely due to both local and systemic factors; in these syndromes, obesity represents one of the most common clinical manifestations, and studies are currently underway to evaluate its role in the progression of chronic kidney disease.
The management of obesity involves lifestyle interventions, medications, and surgery. Interesting new pharmacological advances are now available for both obesity in the general population and obesity associated with certain genetic disorders; the protective role of many of these drugs in the progression of chronic kidney disease – sometimes even independent of weight loss – is an observation that further highlights the intricate relationship between dysmetabolism and kidney disease.

Keywords: obesity, chronic kidney disease, ciliopathies, ADPKD, Bardet-Biedl syndrome, Alström syndrome

Obesity and Renal Health. Epidemiology

Adult obesity is defined by the World Health Organization (WHO) as a body mass index (BMI) ≥ 30 kg/m², while overweight is defined as a BMI between 25 and 29.99 kg/m². In Europe, the prevalence of obesity is around 20%, with some countries exceeding 30%, and it is projected to reach 24% globally by 2035 [1, 2].
Obesity is more common among individuals with a genetic predisposition, which may be monogenic, oligogenic, or polygenic. Non-syndromic monogenic forms are rare and are typically associated with mutations in genes that regulate the interaction between the brain and adipose tissue, such as those encoding leptin, its receptor, the melanocortin 4 receptor, proconvertase 1, and proopiomelanocortin, which are involved in the leptin-melanocortin pathway. Oligogenic forms account for approximately 3% of cases, while most hereditary obesity has a polygenic basis influenced by epigenetic factors [3].
The detrimental effect of obesity on kidney function is well documented. A systematic review and meta-analysis confirmed that obesity is an independent risk factor for the development of albuminuria (relative risk 1.51, 95% CI 1.36-1.67) and chronic kidney disease (CKD) with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m² (relative risk 1.28, 95% CI 1.07-1.54) [4]. Furthermore, obesity is a risk factor for nephrolithiasis [5].
Epidemiological and observational studies report that 4-10% of obese patients exhibit proteinuria. However, determining the true incidence of obesity-related glomerulopathy is challenging due to variations in the biopsy protocols adopted by different centers [3].
Indices that measure central fat distribution, such as the waist-to-hip ratio, are more closely associated with the risk of end-stage kidney disease (ESKD) than BMI [6, 7]. Although BMI is the most commonly used parameter in clinical practice, it has several limitations, including its inability to differentiate body composition (which is important in the context of potential fluid retention) and fat distribution. An elevated waist-to-hip ratio (≥0.9 in men and ≥0.8 in women) is associated with a higher risk of reduced renal filtration, independent of BMI. This is because central adiposity correlates with diminished renal function even in non-obese individuals. Moreover, advanced techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) can provide more accurate measurements of metabolically active visceral fat [1, 8–10]. The distribution of adipose tissue appears to partly explain the difference in CKD risk between men and women [11].
Another promising index is the weight-adjusted waist index (WWI), calculated as waist circumference in centimeters divided by the square root of body weight in kilograms. The WWI was found to be the best indicator of obesity for predicting CKD and albuminuria compared to other parameters such as BMI, the waist-to-height ratio (WHTR), or waist circumference (WC) [12, 13].
A prospective study of 2,711 Korean participants with normal renal function and an average follow-up of 11 years reported a CKD incidence of 7%. The risk of renal disease was higher in patients with elevated BMI values and, more significantly, with higher waist-to-hip ratios. Moreover, Kaplan-Meier curves demonstrated that reducing obesity improves renal prognosis [14].
A study by Kanda et al. examined the effects of weight loss on renal function in healthy individuals, revealing significant differences based on sex, the rate of weight loss, and baseline BMI [15].
A multivariate analysis of data from the CureGN study did not find an increased risk of renal events in obese patients with glomerulopathies. However, the study had several limitations [16].

 

Renal damage

Renal damage associated with obesity results from both direct effects of adipose tissue on the kidneys and systemic complications related to conditions such as diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, and hypertension. These factors lead to hemodynamic, metabolic, and inflammatory alterations that underlie renal injury [3] (Figure 1).

Figure 1. Obesity causes hemodynamic, inflammatory, and metabolic alterations that damage the kidney. In addition, intrinsic factors, such as genetic mutations, may compound this damage.
  • Glomerular hyperfiltration and hemodynamic alterations [3, 4, 11, 17] In the presence of insulin resistance, sympathetic nervous system overactivity, and activation of the renin-angiotensin system (RAS), glomerular hypertension and an increased glomerular filtration rate occur.
    The dilation of the afferent arteriole coupled with efferent arteriole vasoconstriction – although initially compensatory – over time leads to glomerular hypertrophy, glomerulosclerosis, and proteinuria (generally subnephrotic, rarely nephrotic). Additionally, visceral fat may exert mechanical compression on the kidneys and vessels, further contributing to RAS activation, while adipose tissue directly produces RAS components (such as aldosterone and angiotensinogen), inducing sodium retention and volume expansion.
  • Adipose Tissue [3, 11, 18] Perirenal fat and renal sinus fat (RSF), located near the renal arteries, compress the renal structures and secrete cytokines and angiogenic factors that influence the vascular wall. Studies have shown that an increase in RSF mass may worsen microalbuminuria, particularly during physical exercise, although available data remains limited.
    Moreover, adipose tissue releases proinflammatory cytokines that promote a state of chronic inflammation and oxidative stress while reducing the production of adiponectin, which has anti-inflammatory and insulin-sensitizing properties. Hyperleptinemia, observed in patients with CKD, exacerbates inflammation, stimulates sympathetic tone, sodium reabsorption, glomerular cell proliferation, and increases type IV collagen synthesis, promoting fibrosis and glomerulosclerosis. Mesangial cells respond to leptin by increasing glucose uptake, undergoing hypertrophy, and, as well as endothelial cells, enhancing the release of extracellular matrix components.
  • Insulin Resistance and Hyperinsulinemia[1, 6, 11] These factors contribute to renal damage through mechanisms such as glomerular hyperfiltration, albuminuria, oxidative stress, and endothelial dysfunction. It is important to note that the predisposition to insulin resistance is not determined solely by BMI; even individuals with normal weight can be at risk for developing complications.

Therefore, adipose tissue is not merely an energy storage depot but an endocrine organ that secretes adipokines, regulating processes such as inflammation, metabolism, appetite, cardiovascular function, and immunity. In fact, the type and amount of adipokines released by adipose tissue depend on several factors, including the type of adipocytes (white or brown), their quantity, location, and interactions with other cells.
Adipocytes are primarily divided into two categories: white adipocytes, which are most abundant in adults and store energy in the form of triglycerides, and brown adipocytes, which are less numerous and more abundant in neonates, storing energy in small lipid droplets. In addition, there is a third type, beige adipocytes – a subtype of white adipocytes – that, in response to cold exposure or specific pharmacological agents, acquire characteristics similar to brown adipocytes. The activation of the beiging process increases energy expenditure and improves carbohydrate and lipid metabolism [19].

Clinically, the earliest sign of obesity-related renal damage is a gradual increase in subnephrotic-range proteinuria [18].
Weight reduction lowers levels of obesity-related proinflammatory cytokines (e.g., TNF-α, MCP-1, and serum amyloid) [11].

 

Histopathological Alterations

The kidneys of obese patients tend to increase in volume [1, 6]. The diagnosis of obesity-related glomerulopathy (ORG) is based on the clinical and histopathological exclusion of other renal diseases in subjects with a BMI ≥30 kg/m². Histopathologically, ORG is characterized by glomerulomegaly, which may be accompanied by secondary focal segmental glomerulosclerosis, often localized in the perihilar glomeruli. Additionally, one may observe a reduction in podocyte density, an increase in the width of foot processes, thickening of the glomerular basement membrane, expansion of the mesangial matrix, and mesangial sclerosis.

Histological studies have also demonstrated that renal tubules can be affected, showing hypertrophy of the proximal tubular epithelial cells. Intracellular lipid vacuoles may occasionally be observed in these epithelial cells, as well as in podocytes and mesangial cells [3, 18].

An important factor in the development of ORG is the presence of predisposing conditions, such as a low nephron number at birth and renal anomalies that, when coupled with compensatory growth, may further promote glomerular hyperfiltration. Frequently associated with visceral obesity, hypertriglyceridemia is another factor that worsens renal outcomes.

 

Treatment of Obesity

The management of obesity includes lifestyle modifications (physical activity, nutrition, behavioral therapy), medications, and bariatric surgery.

Physical activity can reduce mortality risk even in patients with CKD, although there are currently no definitive recommendations regarding frequency, intensity, and duration; therefore, a gradual increase in activity is advised. In polycystic patients, activities that might cause trauma sufficient to rupture cysts should be avoided.

Various dietary interventions have been proposed for patients with ADPKD (e.g., caloric restriction, intermittent fasting, time-restricted feeding, and the ketogenic diet): in these patients, in addition to the benefits related to reduced visceral adiposity, an improvement in nutrient control and cellular energy status is hypothesized, which may influence the mTOR pathway that is abnormally activated in renal cysts [11, 20].

The first-line pharmacological choice for obesity-related hypertension are ACE inhibitors or ARBs because they reduce the risk of obesity-associated glomerulopathy and are associated with a lower incidence of diabetes and favorable effects on left ventricular hypertrophy [17]. Sodium restriction is also important.

When lifestyle interventions are insufficient, a broad range of medications may be used for the treatment of obesity (indicated for a BMI ≥30 kg/m² or ≥27 kg/m² in the presence of weight-related comorbidities). Approved drugs for body weight management include orlistat, extended-release naltrexone/bupropion, controlled-release phentermine/topiramate (a combination of a sympathomimetic and a carbonic anhydrase inhibitor, not approved by the EMA), setmelanotide, GLP-1 receptor agonists (liraglutide and semaglutide), and dual GLP-1/GIP agonists (tirzepatide).

Orlistat is an intestinal lipase inhibitor that reduces fatty acid absorption by up to 30%, leading to approximately 5% weight loss. The most common side effects include flatulence and malabsorption, which can result in reduced levels of vitamin D, vitamin E, and beta-carotene, making supplementation necessary.

The bupropion-naltrexone combination reduces appetite and cravings. Bupropion is a norepinephrine and dopamine reuptake inhibitor that promotes activation of the melanocortin pathway. Naltrexone, a μ-opioid receptor antagonist, mitigates the auto-inhibitory feedback triggered by bupropion on hypothalamic anorexigenic neurons. Common side effects include nausea, vomiting, headache, insomnia, and dry mouth; the potential emergence of suicidal thoughts should be monitored.

Liraglutide is a GLP-1 (glucagon-like peptide) receptor agonist that reduces appetite, slows gastric emptying, and helps balance insulin and glucagon secretion. At a dose of 3 mg/day, liraglutide can reduce body weight by 5-10% and delay the onset of diabetes in obese prediabetic individuals, while also improving glycemic control, blood pressure, and lipid profile. A dose of 1.8 mg is associated with a decreased risk of major cardiovascular events in diabetic patients. Its adverse effects are primarily gastrointestinal (nausea, vomiting, constipation, diarrhea), which can be mitigated by gradual dose escalation. It is contraindicated in patients with a history of pancreatitis, in pregnant women, and in individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN).

Semaglutide, a long-acting GLP-1 agonist, is used either to reduce the risk of major adverse cardiovascular events (MACE) in adults with cardiovascular disease associated with obesity/overweight or for weight loss in obese or overweight patients with related comorbidities. It works by slowing gastric emptying and producing a central anorexigenic effect. Its main adverse effects are gastrointestinal, and similarly to liraglutide, it is contraindicated in pregnancy and in patients at risk for medullary thyroid carcinoma or MEN.

Tirzepatide is a GLP-1 and GIP receptor agonist that, when administered once weekly, reduces appetite, increases insulin sensitivity, and enhances glucose and triglyceride uptake in adipose tissue. The SURMOUNT studies have reported an average weight loss of 20%, with predominantly gastrointestinal side effects and low treatment discontinuation rates.

Setmelanotide is a melanocortin-4 receptor agonist that reduces appetite. Approved for the treatment of certain forms of monogenic obesity and for patients with Bardet-Biedl syndrome, it is administered subcutaneously once daily. The main adverse effects are local injection site reactions, hyperpigmentation, and nausea; there is a manufacturer warning regarding suicidal ideation and depression.

Some drugs, although not specific for obesity management, have beneficial effects on body weight, such as metformin and SGLT-2 inhibitors.

Metformin reduces hepatic glucose production and increases insulin sensitivity. The hypothesized mechanisms for weight reduction include activation of AMPK, an increase in levels of anorexigenic hormones, and enhanced leptin sensitivity. Clinical studies indicate a long-term weight reduction of around 3%, with mainly gastrointestinal side effects and a rare risk of lactic acidosis; prolonged use may cause vitamin B12 deficiency.

SGLT-2 is the protein responsible for reabsorbing most of the glucose in the renal tubules. In patients with diabetes mellitus, SGLT-2 overexpression is often observed during the hyperfiltration phase, exacerbating hyperglycemia and renal stress. This has led to the development of SGLT-2 inhibitors, a class of drugs that block these cotransporters, increasing urinary glucose excretion. SGLT-2 inhibitors improve glycemic control, reduce blood pressure, mortality, and cardiovascular morbidity, slow CKD progression (by reducing hyperfiltration, proteinuria, oxidative stress, and inflammation), and result in an approximate weight loss of 2 kg, although this effect may also be partly due to reduced body water and offset by an increased appetite. The main adverse effects include urinary and genital infections, dehydration, and, in rare cases, diabetic ketoacidosis due to increased lipolysis and free fatty acid release [3, 11, 17, 21, 22].

Several of the aforementioned drugs are known to exert a protective effect against the progression of renal disease, particularly SGLT-2 inhibitors, GLP-1 agonists, and tirzepatide (Table 1).

Class Main Effects
GLP-1 agonists Reduction of proinflammatory cytokines and oxidative stress, improved glycemic and blood pressure control, decreased proteinuria and hyperfiltration (natriuresis) in DKD, weight loss, and RAAS inhibition (likely via an indirect mechanism).
Tirzepatide Similar effects to GLP-1 agonists, with a more pronounced impact on body weight and metabolism due to its action on GIP.
SGLT-2 inhibitors (SGLT2i) Reduction of hyperfiltration, increased natriuresis, decreased proteinuria, and cardiovascular and renal protection independent of glycemic control.
Table 1. Main effects of selected drugs with protective action on renal function.

Regarding bariatric/metabolic surgery, the National Institute for Health and Care Excellence (NICE) guidelines recommend bariatric surgery as a treatment option for individuals with a BMI ≥40 kg/m², or between 35 and 40 kg/m² in the presence of comorbidities (e.g., type 2 diabetes, hypertension) that may benefit from weight loss. Recently, new guidelines from ASMBS and IFSO have significantly expanded the indications for surgery, recommending consideration of surgery for individuals with a BMI between 30 and 35 kg/m² in the presence of metabolic diseases such as type 2 diabetes when non-surgical therapies have yielded insufficient results. In some cases, for patients of different ethnic backgrounds (e.g., Asians with a BMI >27.5 kg/m²) or as a “bridge” to subsequent treatments (such as organ transplantation), bariatric surgery may be indicated [23].

The two most common procedures are laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG). A systematic review found that, one year after the intervention, the LRYGB technique achieved a slightly higher percentage of total weight loss (%TWL) compared to LSG; however, at 5 years the differences between the two techniques were not significant, with mean values of 28.1% for LRYGB and 27.0% for LSG [24].

Weight loss reduces proteinuria and microalbuminuria in CKD patients. The proposed mechanisms include improved blood pressure control, lipid profile, insulin sensitivity, reduced leptin levels, lower activation of the RAAS, decreased glomerular hyperfiltration, and reduced inflammatory processes.

Further larger and longer-term studies will be useful to better understand the effect of weight loss on CKD progression [11].

 

Obesity and Ciliopathies

Cilia are microtubular structures classified, based on the architecture of their axoneme, into motile (9+2) and non-motile (9+0) types. The latter, known as primary cilia, are widely expressed throughout the body and function as sensors and transducers of cellular signals. Through receptors such as Wnt, Hedgehog, TGFβ, and PDGFR, primary cilia participate in the transduction of extracellular signals [25].
The term “ciliopathies” refers to a group of disorders caused by dysfunction of the primary cilium, such as autosomal dominant polycystic kidney disease (ADPKD), Bardet-Biedl syndrome (BBS), Alström syndrome (ALMS), and Senior-Løken syndrome.

ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) affects over 10 million people worldwide and is primarily caused by variants in the PKD1 and PKD2 genes, which encode polycystin 1 (PC1) and polycystin 2 (PC2), respectively. These proteins maintain primary cilium function and preserve the integrity of the renal tubules.
It is noteworthy that there is evidence for a dual ciliary function: in normal renal cells, the primary cilium inhibits cyst formation, whereas in ADPKD – when the polycystin complex is altered – it promotes cystic growth [26–29].

The accumulation of adipose tissue can exacerbate the metabolic defects associated with ADPKD by influencing various cellular signaling pathways.
In the HALT-PKD A study, a high BMI was associated with a greater increase in total kidney volume (TKV) and a more rapid decline in eGFR. In obese patients, the risk of rapid TKV progression (annual variation rate ≥7% versus <5%) was approximately four times higher, and the annual percentage increase in TKV was more than 50% greater compared to normal-weight patients.
In the TEMPO 3-4 study, the association between BMI and TKV increase was confirmed, whereas the decline in eGFR correlated with BMI only in women. To avoid bias due to the weight contribution of the cysts, in both cited studies TKV was calculated by subtracting the estimated cyst weight. Discrepancies in the results may be attributable to the lack of consideration of body fat distribution or other factors.

The TEMPO 3:4 study demonstrated that the efficacy of Tolvaptan, a drug used to slow the progression of ADPKD, was independent of BMI. However, a subsequent retrospective cohort study revealed that an increase in visceral fat more accurately predicts renal volume expansion than BMI in lean subjects, and that the drug’s efficacy decreases with increasing visceral fat [11, 30–32].

Obesity affects hormone and cytokine levels, leading to increased activation of the PI3K/Akt pathway, which promotes cell survival and growth. Adiponectin – whose levels are reduced in obesity – activates AMPK, which in turn inhibits the mTOR pathway and reduces cellular proliferation. Concurrently, cytokines released from visceral fat, such as IL-6 and TNF-α, stimulate inflammation and cell proliferation, while insulin activates the PI3K-Akt, mTOR, and MAPK pathways. Moreover, saturated fatty acids bind to fetuin, an endogenous ligand for TLR2/TLR4 receptors, triggering a chronic low-grade inflammatory response.

Weight loss in obese subjects with ADPKD represents a potential therapeutic target to improve metabolic status, reduce TKV increase, and the pro-inflammatory response [11].

Syndromic ciliopathies characterized by obesity and kidney disease: Bardet-Biedl syndrome and Alström syndrome

Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS) present a clinical spectrum that includes early-onset obesity and renal dysfunction.

Bardet-Biedl syndrome is a rare autosomal recessive genetic disorder with an estimated prevalence of 1 in 120,000 to 160,000 in North America and Europe, while in some isolated communities, the frequency is significantly higher. Diagnosis, based on Beales’s criteria, requires the presence of at least four primary features or three primary and two secondary features. Early diagnosis can be challenging, as clinical signs manifest progressively over time, and genetic testing can be useful for confirmation [33].

Obesity is one of the primary clinical features of BBS and manifests early: although birth weight is normal, 90% of patients experience weight gain within the first year of life, with obesity becoming evident by age three. A study by Feuillan et al. showed that BBS patients have greater visceral adiposity than BMI-matched controls, even after adjusting for covariates (age, sex, race, and total body fat percentage measured via DEXA). However, after further adjusting for age, sex, race, total body fat percentage, free testosterone, and estradiol, the difference in visceral fat adiposity becomes non-significant (p = 0.06). Leptin levels are higher than in controls relative to the degree of adiposity, suggesting resistance to this hormone.
In a comparison between groups with BBS10 and BBS1 mutations, the former showed higher BMI Z-scores and greater visceral obesity than the latter. Other genotype-phenotype studies suggest that BBS1 mutations are linked to a milder obesity phenotype compared to other BBS genotypes (a difference that seems to diminish in adolescence), while BBS9 and BBS4 mutations are associated with higher BMI. Children with loss-of-function mutations have a higher risk of developing severe obesity [33–35].

The prevalence of kidney disease in BBS patients varies across studies, partly due to differing definitions. A study by Forsythe et al. on 350 patients found that 31% of children and 42% of adults had CKD at stages 2-5, while CKD stages 4-5 were present in 6% of pediatric subjects and 8% of adults. Meyer et al., analyzing 607 BBS patients from the Clinical Registry Investigation of BBS (CRIBBS), identified an end-stage renal disease (more accurately termed ‘Kidney Failure’) stage in 44 individuals (7.2%).

Renal abnormalities arise from both anatomical and functional causes, and the pathogenesis of kidney disease remains partially understood. The expression of BBS proteins in the kidney suggests a local contribution to renal damage. A study on 54 patients found that hyposthenuria was associated with a more rapid decline in eGFR. This reduced urine concentration capacity may indicate a tubulointerstitial disorder. Furthermore, the observation that even patients with preserved eGFR exhibit abnormalities on functional magnetic resonance imaging, particularly in the medullary region, strengthens the hypothesis of a primary tubulointerstitial disorder.

The frequent presence of factors such as obesity, diabetes, and hypertension highlights the need for in-depth analyses to quantify their contribution to kidney damage. Our recent observational study of 65 patients with BBS demonstrated that reduced eGFR correlates with hypertension and truncating mutations in any BBS gene; moreover, in multivariate analysis, BMI was independently associated with eGFR decline (β = –2.45; p < 0.0001). The presence of significant phenotypic discordance in 50% of patients with the same pathogenic variants supports the hypothesis of an interplay between intrinsic and secondary factors [33, 36, 37].

The etiopathogenic mechanisms underlying obesity in certain ciliopathies are not yet fully understood and appear to derive from multiple factors involving energy metabolism regulation at both central and peripheral levels. Neurons and glial cells also possess cilia, and the hypothalamus plays an essential role in energy homeostasis. In the hypothalamic arcuate nucleus, two neuronal populations – AgRP and POMC neurons – regulate appetite and energy expenditure: AgRP neurons activate under energy deficit conditions and are inhibited by insulin and leptin, whereas POMC neurons activate under energy surplus conditions, reducing food intake and increasing energy expenditure [2, 38].

Studies on obesity in BBS have primarily focused on the role of BBS proteins in intracellular trafficking to the primary cilium or plasma membrane. The primary cilium is crucial for leptin signal transduction in the hypothalamus, and its alteration has also been observed in BBS patients, who exhibit higher plasma leptin levels than controls. Additionally, anomalies in the trafficking of neuropeptide Y and serotonin (5-HT2C) receptors have been proposed as potential contributors to obesity development.
Another aspect concerns adipogenesis dysfunction: during differentiation, preadipocytes express a primary cilium that hosts receptors for Wnt and Hedgehog signaling pathways, essential for proper adipocyte development. Finally, BBS1 and BBS2 proteins are indispensable for the correct trafficking of the insulin receptor to the plasma membrane [33, 39].

Regarding Alström syndrome, studies on murine models with Alms1 gene mutations show a reduction in the percentage of ciliated hypothalamic neurons, associated with a significant decrease in energy expenditure. The molecular details of this mechanism remain unclear [2].

Alström syndrome is an autosomal recessive condition characterized by a broad range of clinical manifestations, including obesity, insulin resistance or type 2 diabetes mellitus, hypertriglyceridemia, hearing loss, cardiomyopathy, retinal dystrophy, progressive kidney, and liver disease. Its estimated prevalence ranges from 1 to 10 cases per million people. Obesity and insulin resistance typically begin to develop during the first year of life. A study by Waldman et al. on 38 patients with Alström syndrome found that among 25 observed children, only 20% had a normal weight, while 8% were overweight and 72% were obese. In the adult population (13 patients), 15% were overweight, and 85% were obese, with insulin resistance present in 100% of cases.
While BBS can be caused by mutations in over 20 genes, Alström syndrome is caused by mutations in the ALMS1 gene [33, 40, 41]. Patients with ALMS, but not all individuals with BBS, are predisposed to type 2 diabetes, suggesting a complexity in the regulation of ciliary function, with some alterations potentially even providing protection against metabolic disorders (interestingly, the absence of BBS12 in mice increases adipogenesis but, paradoxically, also enhances insulin sensitivity) [42, 43].

Renal function tends to deteriorate with age, as evidenced by Waldman’s study and previous studies by Marshall et al.
In Waldman et al.’s study, about 20% of patients aged 20 to 38 years met the criteria for chronic kidney disease (CKD) diagnosis, with renal impairment likely linked to the absence of the ALMS1 protein, although the contribution of associated conditions such as metabolic dysfunction cannot be excluded [41].

The therapeutic approach for obesity in ciliopathies is based on lifestyle modifications, which include a hypocaloric diet and aerobic physical activity tailored to the patient’s clinical condition. In addition, improving sleep hygiene and increasing sleep duration may contribute to obesity management. An optimal strategy involves the support of a multidisciplinary team composed of physicians, dietitians, psychologists and physical therapists. In high-risk obese patients, bariatric surgery may be considered, although its long-term effects remain under investigation. A review has highlighted less durable benefits in subjects with hyperphagic disorders [2, 33].

In diabetic patients, treatments that improve insulin sensitivity without causing weight gain should be prioritized (e.g., metformin, incretins, SGLT2 inhibitors) [36].

Obesity is one of the clinical features of Bardet-Biedl and Alström syndrome, for which there are promising therapeutic developments. Setmelanotide, an agonist of the melanocortin-4 receptor (MC4R), was approved in the United States in 2020 and in Europe in 2021 for the treatment of obesity caused by mutations in POMC, PCSK1, and LEPR in individuals over 6 years of age [33]. In 2022, the FDA extended the therapeutic indication of setmelanotide to patients with Bardet-Biedl syndrome (BBS), based on a phase 3 study that demonstrated, after 52 weeks of treatment, that approximately 30% of participants (aged over 12 years) achieved a ≥10% reduction in body weight, with an average BMI reduction of over 9% within one year [44, 45].

A recent study investigated the efficacy of setmelanotide in children under 6 years of age and, in the BBS group, observed an average percentage reduction in BMI of 10% at week 52 [44, 46]. An abstract reporting the extension of the phase 3 study indicated sustained clinical benefits after 3 years of continuous treatment with the drug, with average weight losses of approximately 20 kg in adults and a 19.4% reduction in BMI percentiles in pediatric patients [47].

Ganawa et al. reported a case of GLP-1 agonist use in a young woman with BBS, who had childhood-onset obesity and hyperphagia. Due to weight regain upon dose reduction, it was necessary to maintain the medication. Similarly, in Alström syndrome data suggest that GLP-1 receptor agonists are not inferior in these forms of obesity compared to polygenic forms [48].

Several beneficial metabolic effects of these drugs have been observed independently of BMI reduction [48, 49].

Currently, there are no specific interventions to prevent kidney damage. Kidney transplantation is the treatment of choice for end-stage uremia. An increase in the median BMI has been reported in the cohort of transplant patients compared to non-transplanted individuals, so it is advisable to employ immunosuppressive regimens that allow for reduced steroid use and, in particular, to carefully evaluate the use of tacrolimus, considering the higher risk of post-transplant diabetes (NODAT) in obese patients [33, 36, 50].

 

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Renal Damage and Obesity: a Silent Pairing

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Paola Nazzaro

Paola Nazzaro1, Alessandra Amatuzio1, Silvana Baranello1, Marcellino Corvinelli1, Giuseppe Di Cienzo1, Francesco Principe1, Paolo Trucillo1, Antonio Buondonno2, Caterina Vitagliano1, Filippo De Stefano3

1 U.O.C. Nefrologia e Dialisi, P.O. “A. Cardarelli”, Campobasso
2 U.O.C. Chirurgia Generale, P.O. “A. Cardarelli”, Campobasso
3 U.O.S. Dialisi, P.O. Veneziale, Isernia

Corresponding author:
Paola Nazzaro
U.O.C Nefrologia e Dialisi
Ospedale “Antonio Cardarelli”
Contrada Tappino
86100 - Campobasso
Tel/Fax 0874.409275
Email: p.nazzaro@live.it

 

Abstract

Obesity is recognized as a true chronic disease and an independent risk factor for kidney disease. In particular, a correlation was observed between obesity and the development of focal segmental glomerulosclerosis. The clinical consequences of obesity on the kidney can include albuminuria, nephrotic syndrome, nephrolithiasis, and increased risk of development and progression of renal failure. Conventional therapy, which includes low-calorie diet, exercise, lifestyle changes, and drug therapy, including GLP1-RA, phentermine, phentermine/topiramate, bupropion/naltrexone, orlistat, is not always able to achieve the desired results and above all does not guarantee stabilization of body weight over time. On the other hand, bariatric surgery is giving excellent results in terms of efficacy and duration. Bariatric surgery techniques that are generally divided into restrictive, malabsorptive, and mixed are not free from possible metabolic complications such as anemia, vitamin deficiency, and stones. However, they are able to ensure a good maintenance of weight loss obtained with disappearance or reduction of the incidence and severity of comorbidities related to obesity.

Keywords: obesity, renal failure, bariatric surgery, sleeve gastrectomy

Sorry, this entry is only available in Italiano.

Introduzione

L’obesità è ormai riconosciuta una vera malattia e un fattore di rischio indipendente per lo sviluppo di malattia renale cronica [1]. Si stima che al mondo ci siano circa 600 milioni di persone affette da obesità [2]. Secondo il Rapporto Osservasalute del 2016 che fa riferimento ai risultati dell’Indagine Multiscopo dell’Istat “Aspetti della vita quotidiana” emerge che nel 2015, in Italia, più di un terzo della popolazione era in sovrappeso (35,3%) e una persona su dieci era obesa (9,8%). Complessivamente il 45,1% dei soggetti di età superiore ai 18 anni era in eccesso ponderale [3].

In epoca più recente, il 9° Rapporto sull’obesità in Italia [4], curato dall’Istituto Auxologico Italiano, ha evidenziato come, secondo una stima provvisoria per il 2020, su 10 uomini adulti 6 sono in sovrappeso, su 10 donne invece 4 sono in sovrappeso. In entrambi i sessi la prevalenza è maggiore nella fascia d’età compresa tra i 65 e i 74 anni. Anche per quanto riguarda l’obesità, come per il sovrappeso, la popolazione maggiormente colpita è quella maschile: l’11,7% tra gli uomini e il 10,3% tra le donne. Se invece si considera la grave obesità (caratterizzata da un BMI superiore a 35) dal rapporto si evince che ne risultano colpite in Italia oltre un milione di persone, pari al 2,3% degli adulti e in questi casi le donne sono maggiormente interessate [4].

Il gradiente geografico è chiaramente a sfavore delle regioni meridionali. Complessivamente, nel Nord-ovest e nel Centro Italia la prevalenza dell’obesità si attesta al 10% mentre nel Nord-est e nelle isole il valore raggiunge l’11,4%; al Sud sale al 12,4%. Le percentuali non sono migliori quando spostiamo l’attenzione dagli adulti ai bambini e agli adolescenti. In Italia tra i giovani la prevalenza di obesità è del 18% nei bambini e del 19% negli adolescenti. Anche in questo caso c’è una grossa differenza tra nord e sud. Al Sud il 34,1% della popolazione 3-17 anni è obesa, al Nord-ovest il 20,0%; il 22,4% al Nord-est, il 23,9% al Centro e il 28,4% nelle isole. Le percentuali maggiori riguardano la Campania (37,8%), il Molise (33,5%), la Basilicata (32,4%), Abruzzo e Puglia (31,2%) [4].

L’obesità è ormai riconosciuta come un fattore di rischio indipendente di malattia renale cronica e di progressione verso l’End-Stage Renal Disease (ESRD). In particolare, è stata osservata una correlazione tra obesità e sviluppo di glomerulosclerosi focale segmentale (GSFS). Le conseguenze cliniche dell’obesità sul rene possono includere albuminuria, sindrome nefrosica, nefrolitiasi, aumentato rischio di sviluppo e di progressione dell’insufficienza renale.

La terapia convenzionale dell’obesità, che include dieta ipocalorica, esercizio fisico, modifiche dello stile di vita e terapia farmacologica, non è sempre in grado di ottenere i risultati sperati e soprattutto non garantisce una stabilizzazione del peso corporeo a distanza di tempo. La chirurgia bariatrica sta dando, invece, risultati ottimi in termini di efficacia e durata.

 

Misurazione dell’obesità: il concetto di “obesity paradox”

In medicina la definizione di obesità è sempre stata in evoluzione: molto spesso è stato necessario ricorrere a strumenti di misurazione indiretta per definire un paziente obeso o misurare il suo grado di obesità.

Dal punto di vista metabolico e soprattutto in correlazione con il rischio cardiovascolare, è molto importante classificare l’obesità in funzione della distribuzione del grasso (Tabella 1).

Tipo Obesità Localizzazione
Obesità viscerale Omento – Mesenteri -Retroperitoneo
Obesità centrale – addominale (androide) Omento – Mesenteri – Retroperitoneo e sottocutaneo addominale
Obesità periferica sottocutanea (ginoide) Fianchi – Cosce
Obesità generalizzata –
Tabella 1: Classificazione dell’obesità in funzione della distribuzione del grasso.

Esistono diversi strumenti che possono essere impiegati per la misurazione indiretta dell’obesità o meglio della massa grassa di un soggetto:

  • il Body Mass Index (o BMI)
  • la plicometria
  • la bio-impedenziometria (o BIA)
  • la circonferenza addominale
  • il rapporto vita-fianchi

Body Mass Index

In base al Body Mass Index (BMI), indice rappresentato dal rapporto tra il peso del soggetto (kg) e il quadrato dell’altezza (m), l’OMS classifica l’obesità in tre gradi: obesità di I° grado (BMI tra 30 e 34,9 kg/m2), obesità di II° grado (BMI tra 35 e 39,9 kg/m2) e obesità di III° grado (BMI maggiore di 40 kg/m2). Il BMI è un dato biometrico ottenuto dalla deduzione del matematico e statistico belga Adolphe Quetelet. Egli condusse studi antropometrici sulla crescita umana ottenendo come conclusione dei suoi dati che il peso cresce con il quadrato dell’altezza, denominando il rapporto tra questi come indice di Quetelet [5], sostituito poi nel 1972 dal Body Mass Index introdotto dal fisiologo Ancel Keys.

Plicometria

La plicometria permette di stimare attraverso validate equazioni la densità corporea, la massa grassa e la massa magra grazie all’uso di un plicometro che consente di rilevare lo spessore delle pliche sottocutanee: le pliche interessate nella metodica sono quella tricipitale, sottoscapolare, sovrailiaca, pettorale, ascellare, addominale, quadricipitale [6].

Bioimpedenziometria

La bioimpedenziometria è una metodica utilizzata per studiare la composizione corporea, misurando l’impedenza del corpo al passaggio della corrente elettrica a bassa potenza e ad alta frequenza: essa viene impiegata anche per lo studio del paziente in emodialisi per valutare la TBW (Total body water) e la quota di ECW (extracellular-water) in eccesso.

Circonferenza addominale

La circonferenza della vita o circonferenza addominale invece è un parametro che correla indirettamente con l’obesità: i valori normali devono essere inferiori a 94 cm negli uomini e 80 cm nelle donne e viene misurata appena sopra l’ombelico (precisamente appena al di sopra della porzione superiore del bordo laterale della cresta iliaca). Una circonferenza superiore ad 88 cm nelle donne e 102 cm negli uomini viene definita obesità viscerale.  La circonferenza addominale riflette l’accumulo del grasso totale e addominale e rispecchia prevalentemente la presenza del grasso sottocutaneo addominale e non proprio il grasso viscerale.

Rapporto vita-fianchi

Il rapporto tra la circonferenza della vita e la circonferenza dei fianchi (o delle anche) definito anche WHR (waist/hip ratio) è il metodo maggiormente utilizzato per la valutazione della distribuzione del grasso corporeo negli studi epidemiologici. Quando il rapporto è maggiore di 0,92 nell’uomo e 0,82 nella donna si parla di obesità centrale: tali valori corrispondono all’85° percentile della distribuzione di tale indice nella popolazione generale.

Negli studi sull’obesità il parametro più impiegato è quello del BMI. Tuttavia, in alcuni trial sull’obesità i risultati talvolta possono essere inattesi o addirittura non previsti: in tali casi si parla di “paradigma del paradosso dell’obesità (Obesity Paradox)”, un fenomeno del tutto inaspettato osservato in alcune patologie. L’obesity paradox si osserva in tutti quei trial che si sono conclusi indentificando il BMI o l’obesità come fattori protettivi per la popolazione. È ovvio che tali risultati contrastino parecchio con i dati oggettivi e con i dati di rischio di mortalità dell’obesità nella popolazione generale in tutta la letteratura scientifica (concetto di “reverse epidemiology”): tale fenomeno tuttora non ha trovato una valutazione conclusiva che ne possa spiegare l’insorgenza.  Questo paradosso, secondo il quale sovrappeso e obesità migliorano la prognosi di alcune patologie di cui favoriscono l’insorgenza, è stato ampiamente documentato in corso di malattie cardiovascolari, insufficienza renale cronica, neoplasie, diabete e in altre patologie. Mentre secondo alcuni il fenomeno, sebbene non ancora chiaramente spiegato, esprime una realtà biologica, secondo altri esso è il risultato statistico di bias di selezione, di diversi fattori interferenti e principalmente dell’impiego del BMI come misura del grado di adiposità (BMI paradox).

Le ipotesi biologiche in merito al fenomeno dell’Obesity Paradox, vengono delineate in questa Review di Donini et al. [7] e sono influenzate da:

  • Struttura corporea e composizione corporea: l’aumento del peso corporeo e della massa grassa può alterare le conseguenze metaboliche delle malattie nei pazienti obesi e delle cure, a causa dell’aumento della massa muscolare e adiposa;
  • Metabolismo lipidico: alti livelli di colesterolo e lipoproteine possono migliorare l’effetto scavenging delle endotossine a differenza di quelli con livelli molto più bassi di colesterolo (più inclini all’endotossinemia) e alle sue conseguenze infiammatorie;
  • Rilascio di NT-proBNP dai cardiomiociti (per aumentata tensione di parete) dopo infarto del miocardio, è significativamente più basso nei pazienti obesi rispetto alla popolazione generale.
  • Produzione di fattori protrombotici (Trombossano B. et al.) che sono correlati negativamente con BMI e leptina: il rilascio di questi mediatori è mediato dall’endotelio e paradossalmente questi valori risultano nella norma nei soggetti con obesità rispetto ai non obesi proprio per un miglioramento paradossale della funzione endoteliale;
  • Aumentata sintesi di ghrelina (o grelina): ha un meccanismo compensatorio nell’ostacolare l’evoluzione dello scompenso cardiaco. La sintesi di ghrelina è aumentata nei pazienti obesi in quanto riduce il senso di sazietà e aumenta la fame e l’assunzione di cibo, favorendo l’insorgenza di obesità.
  • Produzione di citochine: il rischio cardiovascolare è incrementato dall’aumentata produzione di citochine infiammatorie come il TNF-alfa che si lega a recettori solubili del TNF-alfa tipo I e II che sono prodotti proprio dal grasso corporeo. Nei pazienti con scompenso cardiaco si osserva un’abnorme produzione di queste molecole infiammatorie che risulta altresì inferiore ai pazienti con obesità: l’elevata concentrazione di queste citochine dovrebbe determinare effetti negativi sul miocardio, che non si hanno nei pazienti con obesità [8]. Inoltre diverse adipochine (es: adiponectina, leptina, omentina, etc.) prodotte dal tessuto adiposo hanno dimostrato effetti protettivi sul rischio cardiovascolare, nonostante questo sia un paradosso [9].
  • Aspetti endoteliali e vascolari: una maggiore mobilizzazione delle cellule progenitrici endoteliali può proteggere i pazienti con obesità dall’aterogenesi attraverso la promozione di processi di rigenerazione del miocardio danneggiato e la neoangiogenesi. Questi processi favoriscono la riduzione delle resistenze del post-carico (dilatazione flusso-mediata e riduzione spessore medio-intima dei vasi) e al potenziamento della funzione contrattile del miocardio e dei processi metabolici dei cardiomiociti, alla riduzione dell’apoptosi e della fibrosi del miocardio. Pertanto si assiste ad un paradossale mantenimento della fisiologica struttura vascolare, cosa che in realtà non avviene [10].

Ad esempio, mentre nello studio di Clark et al. [11] l’elevato BMI sia un fattore riconosciuto per HF (Heart Failure), in parecchi altri trial l’analisi di coorte ha evidenziato come il BMI elevato risulterebbe un fattore protettivo contro lo scompenso cardiaco. Anche per ciò che concerne la coorte di pazienti con malattia renale o in emodialisi nello studio di Johansen et al. si è osservato come sia un effetto protettivo l’eccesso ponderale sulla sopravvivenza [12] mentre nello studio di Postorino et al. condotto su 537 pazienti in cui è stata utilizzata la misura della circonferenza della vita invece del BMI si è osservato che l’obesità rappresenta un fattore di rischio importante [13]. Il fenomeno dell’obesity paradox nei pazienti in emodialisi può essere spiegato sia per il fatto che l’obesità riduce in questi l’incidenza dello stato catabolico sia sulla maggiore incidenza di ipotensioni intradialitiche.

 

Meccanismi fisiopatologici di danno renale correlati all’obesità

Nel 1974 Weisinger descrisse per la prima volta l’associazione tra obesità e sindrome nefrosica, con remissione di quest’ultima in seguito a perdita di peso e recidiva dopo nuovo incremento ponderale [14]. Istologicamente si trattava di una glomerulosclerosi focale segmentale, dando origine al termine glomerulonefrite obesità-relata per indicare le forme di GSFS secondarie ad obesità. Oltre alla GSFS, istologicamente possono riscontrarsi ingrandimento glomerulare dovuto alla ialinosi e alla fibrosi, depositi di lipidi nelle cellule tubulari e mesangiali e adesione alla capsula di Bowman [15, 16]. L’accumulo di lipidi nel rene induce alterazioni strutturali e funzionali delle cellule mesangiali, dei podociti e delle cellule tubulari prossimali [17]. L’obesità aumenta, inoltre, la massa renale e il diametro glomerulare.

I meccanismi fisiopatologici alla base del danno renale secondario ad obesità sono diversi e complessi. Schematicamente distinguiamo alterazioni emodinamiche, attivazione del sistema renina-angiotensina, iperinsulinemia e resistenza all’insulina, infiammazione (effetti di adipochine).

Alterazioni emodinamiche

In caso di obesità aumentano il filtrato glomerulare, il flusso plasmatico renale, la frazione di filtrazione e il riassorbimento tubulare del sodio [18]. Diversi studi hanno evidenziato una chiara correlazione tra i diversi marker di obesità (BMI, circonferenza addominale e rapporto vita-fianchi) e il filtrato glomerulare [19, 20]. La vasodilatazione dell’arteriola afferente è la principale causa di aumentato flusso plasmatico renale.

L’iperfiltrazione glomerulare probabilmente provoca un danno podocitario con conseguente sviluppo della glomerulosclerosi spesso osservata in questi pazienti [21, 22]; inoltre, aumenta il riassorbimento tubulare del sodio come effetto dell’attivazione di trasportatori del sodio. La conseguente ridotta concentrazione di sodio nel tubulo distale attiva il feedback tubulo glomerulare e stimola la secrezione di renina da parte dell’apparato iuxtaglomerulare, con un meccanismo simile a quello dell’iperfiltrazione presente nella nefropatia diabetica [23, 24]. In seguito all’ipertensione intraglomerulare si verifica un aumentato stress meccanico sulla parete capillare sia circonferenziale che assiale che si trasmette ai podociti danneggiandoli [25]. Sono stati ritrovati nelle urine di adulti obesi con normoalbuminuria elevati livelli di mRNA associato ai podociti, tra cui nefrina, alfa-actina-4, alfa3beta1 integrina, TGF-beta suggerendo in questi soggetti un precoce danno podocitario [26].

Attivazione del sistema Renina-Angiotensina (RAA)

L’angiotensinogeno, normalmente prodotto dal fegato ma anche da altri tessuti tra cui il grasso viscerale, è aumentato nei soggetti obesi [27]. Il tessuto adiposo è anche in grado di convertire l’angiotensinogeno in angiotensina II (ATII) potenziando l’attivazione del sistema RAA [28]. Gli elevati livelli di ATII e l’aumentata espressione del suo recettore AT1 causano vasocostrizione arteriolare e aumento della filtrazione glomerulare contribuendo alla ritenzione di sodio e allo sviluppo di ipertensione [29].

Iperinsulinemia ed insulino-resistenza

Diverse evidenze suggeriscono che la resistenza insulinica, caratteristica dell’obesità, contribuisce al danno renale in quanto induce iperfiltrazione glomerulare, disfunzione endoteliale, aumentata permeabilità vascolare, angiogenesi [30]. L’insulina agisce direttamente sui podociti: studi in vitro hanno dimostrato che in seguito allo stimolo insulinico i podociti raddoppiano il trasporto di glucosio attraverso la trasposizione dei trasportatori GLUT1 e GLUT2 dai vacuoli intracellulari alla superficie di membrana podocitaria. I substrati 1 e 2 del recettore dell’insulina (IRS1/2) sono espressi sulle cellule epiteliali renali [31, 32]. Il legame a IRS 1/2 stimola la produzione di ossido nitrico [33]. Inoltre, l’insulina agisce sulle cellule tubulari prossimali promuovendo la formazione di TGF-b e collagene di tipo IV che contribuiscono alla fibrosi tubulointerstiziale.

Infiammazione

Alterati livelli di adipochine, citochine prodotte e rilasciate dal tessuto adiposo tra cui si annoverano leptina, adiponectina, resistina, visfatin, sono associati con lo sviluppo di GN correlate all’obesità. In particolare, la leptina aumenta l’espressione della metalloproteinasi-2 (MMP-2) nelle cellule renali mesangiali [34], stimola la produzione di TGF-b1 da parte dell’endotelio e causa ipertrofia mesangiale. A livello mesangiale agirebbe anche per via paracrina stimolando la produzione di collagene di tipo IV e la proliferazione delle cellule endoteliali glomerulari innescando la glomerulosclerosi [35, 36]. In aggiunta, la leptina aumenta lo stress ossidativo e la secrezione di citochine pro-infiammatorie come l’MPC-1 [37].

L’adiponectina, invece, è presente a livelli ridotti nei soggetti obesi. Bassi livelli di adiponectina sono correlati ad insulino-resistenza e allo sviluppo di malattia renale [38]. Nei ratti adiponectina-knockout è stata riscontrata albuminuria che regredisce con la somministrazione di adiponectina esogena [39].

Aumentati livelli di leptina e bassi livelli di adiponectina sono responsabili, nei soggetti obesi, anche dell’attivazione del sistema nervoso simpatico [40], contribuendo ulteriormente alla ritenzione di sodio [41].

 

Obesità e calcolosi

Nel 2005 Taylor et al. [42] hanno studiato l’associazione tra obesità e aumento di peso con il rischio di nefrolitiasi e la formazione di calcoli renali e del tratto urinario, osservando tre grandi coorti per un tempo di quarantasei anni e dimostrando che è la stessa condizione di obesità e di aumento del peso a predisporre a un aumentato rischio di nefrolitiasi. Il rischio risulta più alto nelle donne rispetto agli uomini. Un altro importante studio condotto da Powell et al. [43] ha usato dati di 5942 pazienti da un laboratorio di calcolosi renale valutando le differenze nell’escrezione urinaria delle 24 ore di metaboliti nei soggetti obesi. Hanno osservato che l’escrezione di calcio, ossalato e acido urico era essenzialmente aumentata nelle 24 ore. Inoltre, all’esame chimico fisico delle urine il pH era sempre su valori acidi, favorendo la precipitazione urinaria dei metaboliti urinari. Questa condizione ovviamente era più frequente nei soggetti obesi in cui non si osservavano elevati livelli di citrato urinario e alto flusso urinario, che contrastano la precipitazione urinaria. Inoltre si osservavano nei pazienti obesi elevati valori di solfato e sodio urinario, direttamente correlati all’elevato intake di sodio alimentare ma soprattutto di proteine di origine animale. Un ruolo significativo nei soggetti obesi è inoltre determinato dall’assunzione di cibi e bibite ricche di fruttosio: il fruttosio oltre a favorire l’aumento del peso corporeo, determina resistenza alla leptina, un ormone che da sempre influenza in maniera preponderante il rischio di obesità. Lo stesso fruttosio ad elevate concentrazioni nei pazienti obesi favorisce non solo l’aumentata escrezione urinaria di calcio, ma anche l’aumentata produzione di acido urico sierico favorendo quindi la cristallizzazione urinaria con calcolosi uratica e calcolosi ossalatica [44]. L’aumentato rischio di nefrolitiasi, associato all’ormai già noto rischio cardiovascolare, può accelerare o peggiorare il rischio di peggioramento della funzionalità renale.

 

Obesità e albuminuria

L’obesità quindi è un fattore riconosciuto che determina un danno renale: l’aumento della massa corporea induce iperfiltrazione glomerulare con modifiche della struttura glomerulare e tubulare, a causa dell’alterato riassorbimento di sodio; inoltre il rimodellamento del nefrone a causa del rilascio di citochine e adiponectine con rilascio di TGF beta ed attivazione di MMP con formazione di collageno, può sensibilmente peggiorare la prognosi dei pazienti obesi [45]. La concomitante diagnosi di diabete e ipertensione nei pazienti obesi aumenta largamente il rischio di albuminuria e proteinuria, ma i pazienti obesi presentano una prevalenza maggiore di proteinuria/albuminuria rispetto alla popolazione generale, anche in assenza di diabete mellito ed ipertensione, come valutato dal report di Chang [46]. In questo trial di reclutamento di pazienti obesi (n=218) da sottoporre a chirurgia bariatrica è stato osservato come la prevalenza dell’albuminuria e della proteinuria fosse sensibilmente maggiore rispetto alla popolazione generale nei pazienti con diabete mellito ed ipertensione (proteinuria 33,3% negli obesi e 22,6% negli ipertesi; albuminuria 41,5% nei diabetici, 17,7% negli ipertesi) mentre nei pazienti obesi in assenza di ipertensione e diabete mellito, sussisteva una prevalenza di proteinuria del 13,3% e di albuminuria dell’11% [47]. Nei pazienti obesi si è osservato che oltre alla perdita di peso e alla restrizione dell’introito di sale, la terapia anti-proteinurica con ACE-i /ARBs, riduce la pressione intraglomerulare, rallentando la progressione del danno renale [48]. La proteinuria nei pazienti obesi tendenzialmente si presenta in assenza di anomalie del sedimento urinario e soprattutto quasi sempre inferiore a 300 mg/die: in alcune eccezioni è possibile un riscontro di proteinuria in range nefrosico (talvolta associato anche a cilindri ialini-granulosi e lipidici) [19]. Nei soggetti obesi con sindrome nefrosica, talvolta potrebbe non presentarsi una condizione di ipoalbuminemia con edema tale da far pensare ad una sindrome nefrosica, pertanto l’esame delle urine risulta dirimente: una proteinuria in range nefrosico deve sempre far sospettare una sottostante nefropatia glomerulare [49].

 

Terapia non chirurgica dell’obesità

Nel 2013 una revisione sistematica di letteratura ad opera di Bolignano e Zoccali [50] ha incluso sei RCT che prevedevano modifiche dello stile di vita, un RCT sull’impiego di strategie farmacologiche e 24 studi osservazionali per esaminare gli effetti di queste strategie terapeutiche sui parametri renali nei pazienti obesi con alterata funzione renale. Negli RCT selezionati, le modifiche dello stile di vita prevedevano almeno una delle seguenti modifiche dietetiche combinate con l’esercizio fisico: dieta vegana ipocalorica, dieta ipocalorica (1000-1400 Kcal/die), dieta a basso contenuto di carne, dieta a restrizione di carboidrati; in questi gruppi si è dimostrato rispetto al gruppo controllo una riduzione del 31% della proteinuria ed un declino del filtrato glomerulare nel follow-up più lento. Nel Trial Look ARG [51] che è stato condotto successivamente al Trial Look AHEAD per valutare l’effetto delle modifiche dello stile di vita nella popolazione con obesità e diabete, si osservava come nel braccio dello studio comprendente le modifiche intensive dello stile di vita (i cui obiettivi erano: perdita di peso maggiore del 7%, dieta di 1200-1800 Kcal/die; riduzione della quota di grassi del 30%/die e aumento del 15%/die di proteine; oltre 175 minuti a settimana di esercizio fisico moderato) l’incidenza cumulativa a dieci anni per il rischio di peggioramento della funzionalità renale risultava sensibilmente minore del 31%. A sostegno di questo studio, l’analisi di Ibrahim e Weber [52] approfondiva proprio come nei pazienti obesi, la perdita di peso associata a strategie farmacologiche (tra cui ARBs e ACEi) favoriva non solo la stabilizzazione della perdita del filtrato glomerulare ma riduceva l’albuminuria (intesa come parametro ACR<300 mg/g/die).

Per quanto concerne la prima strategia farmacologica, ossia l’approccio dietetico, l’analisi di Tirosh et al. [53] ci è sembrata suggestiva: un RCT randomizzato di 322 pazienti obesi (99 con CKD stadio III, 23 con ACR > 30 mg/g) seguiti per un periodo di due anni inclusi in uno dei tre regimi dietetici associati (dieta low-fat, dieta mediterranea, dieta low-carb) in cui si è osservato che la dieta mediterranea e quella low-carb favorivano una perdita di peso maggiore (oltre i 4 kg in media) rispetto a quella low-fat (<3 kg in media). In un’analisi post hoc è stato appunto osservato che in tutti e tre i regimi dietetici associati si osservava un’incremento dell’eGFR rispetto al basale del 7,1% e una riduzione dell’ACR di circa 25 mg/g rispetto al basale. Ovviamente nell’analisi post-hoc non sono stati inclusi i pazienti in trattamento emodialitico cronico [54].

In aggiunta al cambiamento dello stile di vita alimentare e all’aumento dell’esercizio fisico settimanale, l’impiego di alcuni farmaci potrebbe sensibilmente favorire la perdita di peso: tra questi ricordiamo i GLP1-RA, fentermina, fentermina/topiramato, bupropione-naltrexone, orlistat. Nella Tabella 2 è possibile osservarne le caratteristiche e la prescrivibilità in base al filtrato glomerulare.

Farmaco Meccanismo di azione Effetti collaterali Effetti Renali Dosaggio
LIRAGLUTIDE

 

0,6 mg; 1,2 mg; 1,8 mg; 2,4mg; 3 mg.

 Agonista recettoriale GLP-1: stimola secrezione insulina e inibisce glucagone. Regola appetito ed intake calorico. Ipoglicemia, aumento lipasi, nausea, vomito, diarrea. Escrezione 60% renale (metaboliti). Nessun aggiustamento di dosaggio. Dati limitati per l’uso in dialisi.
NALTREXONE/

BUPROPRIONE

 

8mg/90mg fino a 32mg/360mg die

Anoressizzante (esatto meccanismo non conosciuto).

Bupropione: inbitore reuptake dopamina e norepinefrina;

Naltrexone: antagonista oppioide.

 Vertigini, nausea, mal di testa, secchezza delle fauci. Ipertensione e palpitazione. Incremento creatinina (inibizione OCT2). Escrezione urinaria: 87% buproprione, 79% naltrexone.

8mg/90mg fino a 32mg/360mg.

In caso di peggioramento della funzione ridurre dosaggio.
ORLISTAT

 

60 mg; 120 mg

 Inibitore delle lipasi pancreatiche (azione nello stomaco e nel tenue). Perdita di feci dal retto, incontinenza fecale, flatulenza. Ridotto assorbimento delle vitamine liposolubili. Calcolosi ossalatica. Escrezione fecale (<2% nelle urine).

Somministrare Ciclosporina 3 ore dopo Orlistat.

Nessun aggiustamento di dose.

60 mg/die dose iniziale, fino a 120 mg/die
FENTERMINA

 

15 mg; 30 mg; 37,5 mg

 Anoressizzante simpaticomimentico (esatto meccanismo non conosciuto). Palpitazioni, vertigini, turbe della libido, insonnia, secchezza delle fauci, nausea, vomito. Ipertensione, aumenta la pressione glomerulare.

 

Escrezione urinaria: controllare pH urinario.

Nessun aggiustamento di dose con eGFR > 30 ml/min (15-30 mg/die);

eGFR 15-29 ml/min: 15 mg/die.

Non consentito in dialisi.
FENTERMINA/

TOPIRAMATO

 

3,75/23 mg

7,5/46 mg

11,25/69 mg

15/92 mg

 Anoressizzante,

modulatore GABA-r con effetto sipaticomimetico.

 Parestesie, disgeusia, secchezza delle fauci, insonnia, costipazione. Tachicardia e palpitazioni. Acidosi metabolica. Nefrolitiasi. Incremento creatininemia, ipokalemia. Teratogenicità.

Nessun aggiustamento di dose fino ad

eGFR < 50 ml/min: dosaggio max 7,5/46mg/die.

Non raccomandato in dialisi.
Tabella 2: Farmaci prescrivibili per il trattamento dell’obesità ed effetti renali correlati [55].

Tra questi l’impiego del GLP-1 RA ha dimostrato effetti cardioprotettivi e nefroprotettivi come descritto in parecchi trial: nel RCT LEADER del 2018 l’impiego della liraglutide nei pazienti con DM II ha dimostrato una riduzione del rischio per eventi compositi renali e cardiovascolari (riduzione albuminuria e raddoppiamento della creatinemia) rispetto al placebo [56]. Anche il trial di Le Roux pubblicato nel 2017 su Lancet [57] ha preso in considerazione l’impiego del liraglutide per favorire la riduzione del peso corporeo nei pazienti in pre-diabete con BMI > 30 kg/m2 oppure < 27 kg/m2 ma con comorbidità: il trial ha avuto una durata di 3 anni (160 settimane) con un numero di 2254 partecipanti, ma solo 1128 hanno terminato lo studio e hanno preso in considerazione la somministrazione giornaliera di 3 mg rispetto al placebo dimostrando che si otteneva una perdita di peso di circa il 6% rispetto al placebo (1,9%), riducendo sensibilmente il rischio cardiovascolare e migliorando la tolleranza glucidica periferica, rallentando l’incidenza di diabete e in maniera correlata il rischio di obesità.

Per quanto concerne l’impiego del bupropione-naltrexone, un trial che indagava sugli effetti cardio-vascolari a lungo termine nei pazienti obesi che assumevano quest’associazione di farmaci e che ha selezionato in maniera randomizzata una coorte di pazienti in sovrappeso o obesi per valutare la probabilità di comparsa di MACE (Major Adverse Cardiovascular Events) a lungo termine, è stato interrotto prima del termine e prima di ottenere dati significativi [58]. Viene riportato sui dati forniti dalla FDA che la terapia a base di bupropione-naltrexone in un RCT non citato, riportava un incremento della creatinina sierica rispetto al follow-up e un rischio dello 0,6% di raddoppiamento della creatinina rispetto al gruppo placebo (0,1%) dopo un anno. L’incremento della creatinina sierica sembrerebbe dovuto al rilascio di metaboliti che interferiscono con la proteina OCT 2 (organic cationic transporter type 2): pertanto nessuno studio ne supporta l’impiego in CKD [59].

L’impiego dell’orlistat come farmaco anti-obesità è inusuale: inibitore delle lipasi gastriche e pancreatiche, che determina un malassorbimento nel tratto intestinale, causando una perdita di peso e riducendo il senso della fame. Non richiede aggiustamento di dose per malattia renale cronica, ma sono stati riportati alcuni casi di calcolosi ossalatica secondaria [60]. Altri dettagli in Tabella 2.

 

Tecniche di chirurgia bariatrica

Nel 2004 Christou [61] ha pubblicato i risultati al lungo termine della chirurgia bariatrica, mettendo a confronto pazienti operati e non. I pazienti operati presentavano una minore incidenza di cancro (2,0 vs 8,49%), una minore incidenza di accidenti cardiovascolari (4,73 vs 26,69%) ed una minore incidenza di disturbi endocrinologici (9.47 vs 27.25%), muscoloscheletrici (4,83 vs 11,90%), psichiatrici (4,35 vs 8,20%) e respiratori (2,71 vs 11,36%). La mortalità registrata nel corso dell’osservazione è stata dello 0,68% nel gruppo dei pazienti operati e del 6,17% nel gruppo dei pazienti non operati.

Numerosi altri lavori successivi [62, 63] hanno riportato analoghi risultati.

Le tecniche di chirurgia bariatrica vengono generalmente distinte in: restrittive, malassorbitive e miste.

Le procedure restrittive, che si basano sulla riduzione del volume gastrico, sono il bendaggio gastrico (o pallone gastrico), la gastroplastica verticale, la sleeve gastrectomy e la Bariclip.

L’idea di usare un pallone endogastrico (BIB: Bioenterics Intragastric Ballon) per il trattamento dell’obesità nacque dall’osservazione dei pazienti psichiatrici portatori di bezoari gastrici [64]. Si tratta di un dispositivo espansibile in silicone di forma sferica posizionato per via endoscopica. Una volta introdotto nel lume gastrico, il BIB viene riempito con soluzione fisiologica sterile (circa 500-600 ml) oppure con aria; in tal modo si riempie parzialmente lo stomaco inducendo un prematuro senso di sazietà. Il meccanismo d’azione è multifattoriale, includendo sia fattori fisiologici che neurormonali. Si tratta di un dispositivo temporaneo che può essere tenuto per sei mesi e che preserva l’anatomia dello stomaco. È indicato nei pazienti che presentano controindicazioni all’intervento o che rifiutano la chirurgia [65].

La sleeve gastrectomy è l’intervento maggiormente eseguito in Italia. Consiste in una gastrectomia verticale subtotale con conservazione del piloro e tubulizzazione dello stomaco residuo [66]. Quindi, a differenza della tecnica precedente, questo è un intervento irreverisibile che altera la normale anatomia dello stomaco. Si ottiene generalmente una perdita di circa il 60% del peso corporeo [67]. Presenta un minore tasso di mortalità rispetto al bypass gastrico e in generale un minor numero di complicanze post-operatorie [68]. La plicatura gastrica è un’evoluzione meno invasiva della sleeve gastrectomy in cui la riduzione di volume dello stomaco si ottiene ripiegandolo su se stesso e suturandone una parte.

La Bariclip, o gastroplastica con clip, consiste in una gastroplastica verticale ottenuta mediante una clip realizzata in titanio e rivestita in silicone che viene posizionata parallelamente alla piccola curvatura dello stomaco in modo da dividerlo in due parti: la parte più grande è esclusa [69].

Le procedure malassorbitive sono più invasive di quelle restrittive ma presentano maggiori probabilità di calo ponderale. Appartengono a questa categoria la diversione biliopancreatica secondo Scopinaro e Duodenal Switch, la diversione biliopancreatica con conservazione dello stomaco e il mini bypass gastrico.

La diversione biliopancreatica si ottiene eseguendo prima una gastrectomia subtotale e una resezione dell’ileo a 250 cm dalla valvola ileo-cecale; successivamente si connette il tratto distale al moncone gastrico mentre il tratto prossimale viene riconnesso a 50 cm dalla valvola ileocecale [70].

Il mini bypass gastrico consiste, invece, nella creazione di una tasca gastrica verticale di circa 60 ml che viene poi anastomizzata con un’ansa digiunale, bypassando in tal modo circa 180-250 cm di duodeno. In confronto al bypass gastrico Roux-en-Y, il mini bypass è una procedura tecnicamente più semplice e reversibile [71].

Tecnica mista è appunto il bypass gastrico, in cui si crea una piccola tasca nella parte superiore dello stomaco che viene collegata direttamente all’intestino tenue mediante un’ansa digiunale a forma di Y.

Nella Tabella 3 sono riassunte le caratteristiche delle principali tecniche chirurgiche.

Nel 2017 un trial pubblicato sul New England Journal of Medicine ha confrontato pazienti diabetici con BMI compreso tra 27 e 43 kg/m2 randomizzati a ricevere per il trattamento dell’obesità terapia medica intensiva, terapia medica intensiva combinata a bypass gastrico Roux-en-Y o sleeve gastrectomy: sono stati arruolati 150 pazienti per un follow-up di 5 anni in cui si è osservato che i pazienti arruolati nel braccio che comprendeva l’approccio terapeutico con terapia medica e chirurgia bariatrica presentavano un cambiamento nella percentuale di riduzione del BMI e un miglioramento dell’emoglobina glicata maggiore rispetto al braccio con solo terapia medica; inoltre i dati inerenti l’impiego della Roux-en-Y o della sleeve gastrectomy sul BMI erano sovrapponibili [72].

BENDAGGIO GASTRICO REGOLABILE SLEEVE    GASTRECTOMY BYPASS GASTRICO DIVERSIONE BILIOPANCREATICA
Calo ponderale 45% 55% 60% 65%
Rischio di recupero peso +++ ++ ++ +
Mortalità operatoria 0,1% 0,15% 0,54% 0,8%
Complicanze perioperatorie 1,9% 8,3% 14,2% 12,4%
Complicanze tardive 10,3% 3,7% 2,9% 6%
Complicanza metabolico-nutritive – + ++ +++
% di reinterventi 7,6% 5,3% 3,3% 5,8%
% di miglioramento DM 50% 70% 84% 99%
Tabella 3: Caratteristiche delle principali tecniche chirurgiche (tratta da LG di Chirurgia Bariatrica della SICOB).

 

Effetti benefici della chirurgia bariatrica sulla funzione renale e sulla proteinuria

Diversi autori hanno riferito di effetti benefici della riduzione di peso ottenuta con la chirurgia bariatrica sulla funzione renale e sull’albuminuria.

Nel 2014 Chang et al. hanno riportato i risultati di uno studio condotto su 3134 soggetti sottoposti a chirurgia bariatrica e seguiti per una media di 2,4 anni. Ad un anno dall’intervento si osservava un aumento del GFR; in media ogni perdita di 5 kg era associata ad un aumento di 0,5 ml/min/1,73 m2 di filtrato glomerulare. In un sottogruppo di 108 pazienti si otteneva anche una significativa riduzione della proteinuria [73].

Buoni risultati sono stati riportati anche dal S.O.S. Study (Swedish Obesity Subject Study), uno studio svedese condotto da Carlsson per valutare gli effetti a lungo tempo della chirurgia bariatrica rispetto alla terapia non chirurgica sull’incidenza dell’albuminuria e che ha evidenziato una effettiva riduzione nel gruppo operato del 50% rispetto al gruppo controllo (non operato) [74].

Nel 2017 Neff et al hanno condotto uno studio prospettico su 190 pazienti sottoposti a bypass gastrico e 271 pazienti sottoposti a bendaggio gastrico regolabile laparoscopico, valutando la funzione renale, la pressione arteriosa e la glicemia in condizioni basali, a 1 anno e a 5 anni dall’intervento. Il GFR risultava aumentato a 5 anni dall’intervento sia nei pazienti sottoposti a bypass gastrico (GFR da 94 ± 2 a 102 ± 22 ml/min/1,73 m2) sia in quelli sottoposti a bendaggio (GFR da 88 ± 1 a 93 ± 22 ml/min/1,73 m2). Nei pazienti già affetti da insufficienza renale si riscontrava comunque un miglioramento del filtrato glomerulare a 5 anni (da 52 ± 2 a 68 ± 7 ml/min/1,73 m2). Migliori livelli pressori venivano raggiunti con il bypass (23 vs 11 % a 5 anni) [75].

Sheetz et al. nel 2020 hanno pubblicato i risultati di uno studio retrospettico condotto su 1597 pazienti sottoposti tra il 2006 e il 2015 a chirurgia bariatrica e confrontati con 4750 pazienti obesi trattati con terapia medica e non chirurgica. Nei soggetti operati si osservava una riduzione dei tassi di mortalità complessiva rispetto alle controparti non operate. Il follow-up dei pazienti è stato seguito per oltre sette anni dove è stato posto come outcome primario la mortalità per qualsiasi causa a cinque anni dall’intervento chirurgico, mentre come outcome secondario la mortalità per cause specifiche stratificate per: cardiovascolari, infezioni, sopravvivenza lontano dalla dialisi, altre cause. La curva di Kaplan-Meyer, per la stima dell’incidenza cumulativa degli outcome primario e secondario, ha dimostrato che durante il follow-up il rischio di morte per tutte le cause e per cause cardiovascolari risultava sensibilmente maggiore rispetto ai pazienti non trattati con chirurgia bariatrica. Nei pazienti portatori di trapianto renale, l’impiego della chirurgia bariatrica si associa a una maggiore sopravvivenza del graft a 5 anni [76].

Anche Canney ha dimostrato su 105 pazienti diabetici sottoposti a bypass gastrico una significativa riduzione della proteinuria, con completa remissione (ACR < 30 mg/g) in ben 82 pazienti [77].

Tutti questi studi sono dunque concordi, insieme a molti altri, nel riconoscere gli effetti benefici della chirurgia bariatrica sia sulla funzionalità renale che sulla proteinuria, indipendentemente dalla possibile lesione istologica sottesa. L’effetto sulla proteinuria potrebbe essere dovuto al miglioramento di vari fattori di rischio (tra cui diabete, ipertensione, sindrome metabolica), alla diversa alimentazione (drastica riduzione dell’assunzione di cibo dopo la chirurgia bariatrica), ad effetti diretti sui podociti. Futuri studi potranno sicuramente approfondire gli effetti renoprotettivi della chirurgia bariatrica in pazienti con insufficienza renale e proteinuria per meglio definire il rapporto rischi/benefici per ogni paziente.

 

Complicanze metaboliche e renali della chirurgia bariatrica

I benefici che si ottengono dalla chirurgia bariatrica sono notevoli, ma ovviamente essa non esclude alcune possibili complicanze metaboliche. In un RCT di Cohen [78] et al. si è indagato sugli effetti della chirurgia bariatrica e delle complicanze post-operatorie a trenta giorni, selezionando una coorte affetta da CKD e ESRD e si è evidenziato che i pazienti in ESRD hanno un alto rischio post-operatorio (sia di re-operazione che di ri-ospedalizzazione) a trenta giorni rispetto alla popolazione in CKD. Non è da trascurare i deficit nutrizionali determinati dalla sindrome da malassorbimento secondaria alla chirurgia: deficit di vitamine del gruppo B (tiamina, acido folico, cobalamina), vitamina D, vitamina A, calcio, rame, zinco e ferro favorendo soprattutto l’insorgenza di anemia sia ipo- che ipercromica, fratture ossee, ipoprotidemia. La nefrolitiasi associata a chirurgia bariatrica è stata approfondita nel trial di Lieske [79] et al. dove sono stati selezionati 759 pazienti sottoposti a chirurgia bariatrica (RYGB, very-very long RYGB, altre procedure chirurgiche restrittive come bendaggio gastrico o sleeve gastrectomy) confrontati con gruppo controllo di 759 pazienti con caratteristiche di base similari (ipertensione, obesità, diabete, osteoartrite, apnea del sonno) e con incindenza di CKD e di nefrolitiasi similare nei due gruppi, all’inizio dello studio (10,4 % vs 8,7%). Al follow-up (in media a sei anni) si è osservato un’incidenza di nuovi casi di nefrolitiasi nei pazienti sottoposti a chirurgia bariatrica rispetto al controllo (11,1% rispetto al 4,3%): precisamente l’incidenza risulta significativa nei primi due anni dopo l’intervento chirurgico. L’analisi dei calcoli espulsi ha dimostrato che erano prevalenti i calcoli di ossalato di calcio, in minima parte quelli di idrossiapatite, rari quelli di struvite e acido urico. Inoltre il rischio di nefrolitiasi era correlato anche alla tipologia di chirurgia bariatrica a cui i pazienti si erano sottoposti: il rischio risultava più alto nelle procedure malassorbitive e RYGB rispetto alle procedure restrittive (sleeve gastrectomy).

L’iperossaluria enterica associata a procedure chirurgiche malassorbitive si presenta a causa del malassorbimento degli acidi grassi. Questa condizione è frequente nei disordini gastrointestinali che colpiscono la mucosa del tratto ileale (resezione o bypass o sindrome dell’intestino corto) oppure in associazione ad insufficienza pancreatica. Il meccanismo con cui la RYGB e VLLRYGB (very-long-limb RYGB) lo scatenano non è ancora ben chiarito ma il malassorbimento degli acidi grassi e la steatorrea, conseguente alle suddette procedure di chirurgia bariatrica possono determinare la comparsa di calcoli renali da ossalato di calcio, causando o peggiorando una condizione di malattia renale cronica [80]. Non tutti i pazienti con malassorbimento degli acidi grassi, come osservato nei precedenti trial, sviluppano calcolosi renale. Uno studio osservazionale retrospettivo [81] su 51 pazienti ha osservato come la formazione di calcoli di ossalato di calcio risulta significativamente maggiore quando sussistono le seguenti condizioni rispetto al gruppo controllo: aumentata escrezione urinaria di ossalato (0,66 vs 0,38 mmol/die) con riduzione delle concentrazioni di citrato urinario (309 vs 607 mg/die) e sovrasaturazione dell’ossalato di calcio urinario per ridotto volume urinario. La meta-analisi condotta da Thongprayoon C. ha preso in considerazione quattro studi (un RCT, tre studi di coorte) [82] per un totale di 11 348 pazienti, incentrandosi sul rischio di calcolosi renale dopo RYGB, dopo procedure restrittive (bendaggio gastrico e sleeve gastrectomy) e dopo procedure malassorbitive includendo VLLRYGB e diversione bilio-pancreatica con switch duodenale. I risultati hanno dimostrato che le procedure malassorbitive favoriscono più facilmente l’incidenza di calcolosi per l’iperossaluria determinata (soprattutto con VLLRYGB e meno frequente con RYGB); mentre le procedure restrittive, che favoriscono comunque una significativa perdita di peso, spesso non si associano a comparsa di iperossalaturia (ma talvolta il ridotto introito idrico può favorire una ridotta diuresi, favorendo la cristalizzazione elettrolitica).

 

Conclusioni

La principale manifestazione clinica del danno renale nei pazienti obesi è rappresentata dalla proteinuria, nel 30% dei casi in range nefrosico [83].

La terapia dell’ORG si basa fondamentalmente sulla perdita di peso e sull’utilizzo di farmaci come GLP1-RA, fentermina, fentermina/topiramato, bupropione-naltrexone, orlistat. Quando però non si ottengono risultati con la terapia medica, ci si può avvalere della chirurgia bariatrica. Questa, senza dubbi non è priva di complicanze anche a lungo termine come l’anemia, i deficit vitaminici, la calcolosi. È però in grado di garantire un buon mantenimento del calo ponderale ottenuto con scomparsa o riduzione dell’incidenza e della gravità delle comorbilità legate all’obesità. La prevenzione del danno renale nel paziente obeso risulta importante ai fini della sua sopravvivenza: l’aumento del BMI si associa oltre al peggioramento della funzione renale e alla comparsa di nefropatie secondarie, ad un aumentato rischio cardiovascolare con aumento del tasso di mortalità rispetto alla popolazione generale.

 

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