Obesity-related glomerulopathy: pathogenesis, pathologic, clinical characteristics and treatment

Abstract

In light of the rapid increase in the number of obesity incidences worldwide, obesity has become an independent risk factor for chronic kidney disease. Obesity-related glomerulopathy (ORG) is characterized by glomerulomegaly in the presence or absence of focal and segmental glomerulosclerosis lesions. IgM and complement 3 (C3) nonspecifically deposit in lesions without immune-complex-type deposits during ORG immunofluorescence. ORG-associated glomerulomegaly and focal and segmental glomerulosclerosis can superimpose on other renal pathologies. The mechanisms under ORG are complex, especially hemodynamic changes, inflammation, oxidative stress, apoptosis, and reduced functioning nephrons. These mechanisms synergize with obesity to induce end-stage renal disease. A slow increase of subnephrotic proteinuria (<3.5 g/d) is the most common clinical manifestation of ORG. Several treatment methods for ORG have been developed. Of these methods, renin–angiotensin–aldosterone system blockade and weight loss are proven effective. Targeting mitochondria may offer a novel strategy for ORG therapy. Nevertheless, more research is needed to further understand ORG.

Keywords

obesity-related glomerulopathy / pathogenesis / pathologic / clinical characteristics

Introduction

The obesity epidemic has led to an increase in the number of incidences of obesity-related glomerulopathy (ORG), which is pathologically defined as the occurrence of glomerulomegaly and focal and segmental glomerulosclerosis (FSGS) in patients with BMI of≥30 kg/m². ORG has become a global issue, and its prevalence has increased substantially [1]. A clinicopathological study of native renal biopsies showed that a progressive increase in incidence of biopsy proved ORG from 0.2% in 1986–1990 to 2.0% in 1996–2000 (P = 0.0001) and further to 2.7% in 2001–2015 [2,3]. This worldwide obesity epidemic has brought immense medical concern. Obesity is an important and independent risk factor for chronic kidney disease (CKD). The mechanisms involved in ORG are complicated and integrated, especially hemodynamic changes, inflammation, oxidative stress, and apoptosis. Nephrotic proteinuria (>3.5 g/d) is occasionally present, but typical nephrotic syndrome is characteristically absent. Furthermore, about 30% of ORG patients develop progressive renal failure or end-stage renal disease (ESRD). Hypertension and dyslipidaemia are also commonly observed in ORG patients. In this article, we review the clinical and pathological characteristics, pathogenesis, and treatment of ORG.

Pathology characters of ORG

ORG is characterized by glomerulomegaly in the presence or absence of FSGS lesions (Fig. 1) [2,4,5]. Glomerulomegaly is identified through measuring the diameters of all glomerulus samples or those sectioned through the hilus, which is in the central part of the glomerular globe [3]. In other methods, the serial sections of an individual glomerulus are used to estimate glomerular volume [6]. In a Columbian study, the glomerular diameter in ORG (mean 226mm) significantly increased to a greater extent in comparison with those in age- and sex-matched normal controls (mean 168mm; P<0.001) [2]. Glomerulomegaly is accompanied by mesangial proliferation, matrix accumulation, and hypertrophied podocytes with milder foot process fusion [7].

FSGS is defined as a segmental consolidation of the glomerular tuft by extracellular matrix and/or hyaline, resulting in capillary obliteration [4]. FSGS lesions are predominantly perihilar and typically observed in hypertrophied glomeruli [8]. Perihilar lesions might also contain other glomerular globe parts. Exclusively perihilar lesions are observed in 19% of ORG biopsy samples, and a mixture of perihilar and peripheral lesions in 81% [2]. This observation indicates that the ultrafiltration pressure at the afferent end of the glomerular capillary bed is greater than that at the efferent end, and this difference in ultrafiltration pressure leads to afferent arteriole reflex dilation [9]. In contrast to primary FSGS, which shows diffuse effacement, ORG-related FSGS presents an irregular mild foot process effacement under an electron microscope. Furthermore, the experimental models of ORG showed that glomerular tuft volume increases exponentially in relation to body weight gain in wild-type Fischer intact rats kept on anad libitum diet [10]. The numerical density of podocyte decreases as the renal mass and glomerular diameter increase, thereby inducing the extension of podocytic processes and covering the expanded area. This expansion can cause podocyte detachment, which induces loss in protein selectivity and formation of denuded areas. The loss of protein selectivity and presence of denuded areas trigger matrix deposition and inflict podocyte injury, finally causing glomerulosclerosis [11,12].

In addition, lipids are deposited in mesangial cells, podocytes, and proximal tubular epithelial cells [13]. The loaded lipids in the mesangial cells induce structural damage and function loss. Lipid deposition in podocytes leads to insulin resistance and apoptosis, while accumulation of nonesterified fatty acid (NEFA)-bound albumin causes atrophy and interstitial fibrosis in tubular cells [14]. “Diabetoid” changes (focal mesangial sclerosis, focal thickening of glomerular and tubular basement membranes) in glomeruli are frequently observed in obese patients without diabetes [2,4], indicating shared molecular pathways in diabetic glomerulosclerosis and ORG [15]. In ORG-related FSGS, tubular atrophy and interstitial fibrosis are typically mild (mean 1.26+) similar to interstitial inflammation (mean 0.8+). Arteriolosclerosis ranges from mild to moderate (mean 1.42+) [2] and is generally milder than primary FSGS.

In ORG biopsy samples, nonspecific deposition of IgM and C3 in the lesions of sclerosis and hyalinosis can be detected through immunofluorescence. No other immune-complex-type deposit is present. ORG can also superimpose on other renal diseases, such as IgA nephropathy [16].

Clinically significant obesity is the leading cause of ORG. However, many studies confirmed that mild renal pathological alterations are observed in a large number of patients with morbid obesity but without clinical evidence of renal disease [17]. Thus, future research must focus on determining whether renal biopsies must be considered in patients with mild obesity for the detection of any presence of subclinical renal injury similar to that observed in extremely obese patients.

Mechanisms of ORG

The mechanisms involved in ORG are complex. Adipose tissue is unbalanced in terms of lipid accumulation in renal cells, and the effects of obesity-associated diseases, such as hypertension, diabetes, dyslipidemia, insulin resistance, and obstructive sleep apnea (OSA), contribute to ORG occurrence. ORG primarily contributes to renal injury through multiple effectors, adipokines, lipids, renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), inflammation, oxidative stress, and apoptosis (Fig.2) [18].

Renal hemodynamic changes

The most important pathogenesis of ORG is glomerular hyperfiltration, hypertension, and hyperperfusion. The hemodynamics of kidneys is indirectly measured by glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF). In 1974, Weisingeret al. [19] proposed that the cause of reversible proteinuria in obese patients is renal venous hypertension. Since then, the role of hyperfiltration in glomerular injury has attracted increasing attention. Glomerular hypertension promotes capillary wall stress and leads to basement membrane expansion, glomerulomegaly, and hyperfiltration [20]. Chagnac et al. [9] found that the GFR and RPF in the obese group exceeded those of the control by 51% and 31%, respectively. A cross-sectional study of 301 nondiabetic participants also confirmed that obesity is associated with increased GFR, effective renal plasma flow (ERPF), and FF values by comparing lean, overweight, and obese patients with respect to GFR (99, 110, and 117 mL/min, respectively,P<0.001), ERPF (424, 462, and 477 mL/min, respectively, P<0.01), and FF (0.23, 0.24, and 0.25, respectively, P<0.001) [21]. Furthermore, overweight individuals have higher GFR, RPF, and FF values than lean individuals. Meanwhile, several studies showed that renal hemodynamic changes appear at an early stage of adiposity. FF was found to be associated with waist circumference and waist-to-hip ratio apart from BMI. Some studies showed that losing weight, dietary salt restriction, and RAAS blockade can recover increased FF [22]. Chagnac et al. [22] demonstrated that ORG hyperfiltration is reversible following weight loss. Notably, improvement in hyperfiltration may prevent the development of overt ORG.

In obese patients, renal vasodilation and RPF increase in the afferent arteriole. Elevation in their GFRs is mainly attributed to increased transcapillary hydraulic pressure difference [9]. Meanwhile, systemic hypertension is extremely common in adiposis, and some studies confirmed its important role in the pathogenesis of renal hyperfiltration.

Hemodynamic changes lead to increases in filtered sodium load accompanied with hyperfiltration in adiposis. Tubular sodium resorption also increases to prevent volume depletion, which may contribute to renal damage and accelerate GFR decline. Reabsorbing glucose and sodium via tubular SGLT2 and SGLT1 results in decreased sodium load to macula densa and distal tubule. This decrease stimulates tubuloglomerular feedback, which induces preglomerular vasodilation and increases GFR, resulting in tubular origin hyperfiltration [23]. Recent studies showed that SLGT2 inhibitors lower the GFR of diabetic patients and have an important protective role in renal hyperfiltration [23,24]. Zingerman et al. [25] found that the carboanhydrase inhibitor, acetazolamide, can decrease GFR by 21% in nondiabetic and severely obese patients.

Renin-angiotensin-aldosterone system

Both kidney and adipose tissue contains the major components of RAAS. Adipose tissue products, such as angiotensinogen, increase RAAS activation. Increased levels of angiotensin II and aldosterone more specifically constrict efferent arterioles than afferent arterioles and further raise transcapillary hydraulic pressure difference and GFR. Angiotensin II promotes the production of transforming growth factor-b (TGF-b) and leads to renal fibrosis and podocyte apoptosis [18]. However, some research showed that aldosterone can increase human GFR and promote endothelial dysfunction, inflammation, and fibrosis [26,27]. In obesity cases, RAAS is overactivated and thus may act as an effect factor for renal hyperfiltration.

RAAS overactivation can cause excessive sodium reabsorption, resulting in renal hypertension and hyperfiltration. Angiotensin II stimulates luminal Na⁺-H⁺ exchanger and basolateral Na⁺-K⁺-ATPase, thereby increasing sodium reabsorption by the proximal tubule. Angiotensin II also activates epithelial Na⁺ channels (ENaCs), thereby enabling the distal tubule to increase its sodium reabsorption. It can also directly activate mineralocorticoid receptors and thus promotes sodium reabsorption and results in positive sodium balance [28].

Insulin resistance

Insulin resistance results in renal hemodynamic changes, especially glomerular hyperfiltration, hypertension, and excessive sodium reabsorption. Hyperinsulinaemia, which is secondary to insulin resistance, increases salt retention. Its mechanism might be excessive sodium reabsorption in the distal tubule through ENaC activation. Insulin resistance causes renal damage, including endothelial dysfunction, increased vascular permeability, protein traffic, mesangial hyperplasia, renal hypertrophy, and enhanced endothelial cell proliferation [29,30]. Some studies showed that insulin activities in podocytes play an essential part in glomerular function and morphology, cytoskeleton remodelling, and survival [29]. Insulin resistance also causes metabolic syndrome, hyperinsulinaemia, adipocytokine dysregulation, and low-grade inflammation [31,32].

Mitochondrial dysfunction

Szeto et al. [33] demonstrated mitochondrial dysfunction is the main cause of renal pathology induced by high-fat diet (HFD). Given that the kidney is an organ that demands continuous high-energy provision, mostly from mitochondrial fatty acidb-oxidation (FAO), lipid overload and impaired FAO lead to a disturbance in fatty acid uptake and utilization, further aggravating lipid accumulation in kidney cells and tissue [34]. Renal lipid deposition and downregulated FAO are often present in both obese mice and humans [35]. In previous research, reduction of AMP-activated protein kinase (AMPK) activity was demonstrated to be a downstream consequence of mitochondrial dysfunction [34]. Adiponectin-AMPK pathway downregulates both inflammation and profibrotic pathways in both ORG and diabetic kidney disease [36,37]. AMPK regulates not noly NFkB activation but also NADPH oxidases [36]. AMPK activation can decrease mesangial matrix expansion and lower the levels of profibrotic and proinflammatory markers, such as TGF-b1, tumor necrosis factor-a (TNF-a), and monocyte chemoattracting protein (MCP) -1 [37,38]. Mitochondrial dysfunction generates reactive oxygen species (ROS), which limit mitochondrialb-oxidation and cause cellular lipid accumulation, which results in further increase in mitochondrial ROS levels. Lipids can damage mitochondria and decrease AMPK activity and thus can promote podocyte apoptosis and damage.

Inflammation

Adipose cells release a series of adipokines, such as TNF-a, leptin, adiponectin, interleukins (IL)-6, IL-10, MCP-1, plasminogen activator inhibitor (PAI) -1, resistin, and CRP, and promote chronic low-grade inflammation in obese patients. These lipid-mediated inflammations lead to renal structural and functional changes in obesity cases [39]. Chronic adipose inflammation, which forms from the imbalance between proinflammatory and anti-inflammatory factors, is a major factor for ORG [40].

Obese individuals have high levels of leptin, which binds to specific receptors in mesangial cells. Leptin upregulates TGF-b and TGF-b receptor II, thus inducing an increment of type I and type IV collagen fibers in the mesangium and promoting the formation of fibrosis. Leptin binds to obRb receptors in the hypothalamus and overactivates SNS, which induces renal hemodynamic changes and renal damage [41,42].

Obese individuals have low concentrations of adiponectin. As an anti-inflammatory and insulin-sensitizing factor, adiponectin activates AMPKs to protect podocyte functions and structures by reducing podocyte permeability [43]. Resistin, a proinflammatory factor produced by the monocytemacrophage cells, enhances insulin resistance. The level of resistin reflects the levels of inflammatory factors participating in ORG. Resistin concentration also rises in patients with low GFR. Furthermore, fetuin-A level is elevated in obesity, especially in obesity-related disorders, such as metabolic syndrome, diabetes, and nonalcoholic fatty liver disease. Fetuin-A is associated with increased insulin resistance, inflammation, and fibrosis in the liver and kidney. Fetuin-A also suppresses adiponectin transcription in adipocytes and participates in ORG.

Abnormal lipid metabolism

Abnormal lipid metabolism majorly includes perivascular fat deposits, intracellular lipid load, and fat deposition in the mitochondria. Perivascular fat can regulate blood flow in arteries, and its accumulation is related to exercise-induced albuminuria. Excessive lipid loads cause structural damage and result in capillary loop dysfunction in mesangial cells. Lipid loading produces metabolic abnormalities in insulin and apoptosis in podocytes. Lipids can damage mitochondria and decrease AMPK activity, thereby resulting in podocyte apoptosis. Furthermore, lipid accumulation increases mitochondrial ROS, which causes further amassing of lipids in return.

Others

OSA activates renal SNS and induces sodium retention and hypertension [44]. Renal hemodynamic changes further aggravate ORG. Some studies suggested that a certain extent of protein intake is importantly involved in glomerular hyperfiltration [45].

Innate or acquired glomerular density reduction may be an ORG risk factor. Epidemiological studies showed that CKD risk is significantly high in subjects with low birth weight owing to inadequate intrauterine development. Obese individuals usually have reduced glomerular densities and then are associated with hyperfiltration. Tsuboi demonstrated that patients with biopsy-proven ORG have significantly lower glomerular density than control patients [46].

Clinical manifestation of ORG

The most characteristic and common clinical presentation of ORG is proteinuria with normal urinary sediment, which may or may not be accompanied by renal dysfunction [2,47,48]. In most cases, subnephrotic proteinuria (<3.5 g/d) is prevalent [48,49]. Some studies reported that about 30% of ORG patients can reach nephrotic range proteinuria but with the characteristic absence of edema, hypoalbuminemia, and typical disproportionate hyperlipidemia of nephrotic syndrome [2,46]. Even in massive proteinuria cases (>20 g/d), the presence of full nephrotic syndrome is exceptional. The reasons that ORG patients do not develop typical nephrotic syndrome are currently unclear, although may be accounted by the following reasons. First, the slow progression of proteinuria might allow the development of compensation for hepatic metabolism. Second, mechanisms of tubular degradation and reabsorption of filtered proteins in nephropathies caused by ORG may be different from those in other glomerular diseases that cause full nephrotic syndrome [2,8,50‒52].

Progressive increase in proteinuria without full nephrotic syndrome can be undetectable for years until late clinical presentation. This characteristic of ORG greatly facilitates the discrimination of ORG from primary FSGS in a full nephrotic syndrome [2,47,51,53]. Table 1 summarizes the main distinctive clinical and histological characteristics of obesity-associated FSGS and primary FSGS.

Several cohort studies showed that obesity is associated with high CKD incidence and increased ESRD risk. The clinical process is indolently evolving, stable, or slowly progressive proteinuria, and 10%–33% of the patients possibly develop progressive renal dysfunction and ESRD. The percentage increases at prolonged follow-ups [2,47,49]. Comparative studies showed that primary FSGS has a more sudden and aggressive disease process than ORG and more easily develops to ESRD [2,47]. Other common clinical manifestations of ORG include hypertension (50%–75% of patients) and dyslipidaemia (70%–80% of patients) [2,47‒49].

Treatment strategy of ORG

Various kidney pathology superimposed on ORG is present in patients with obesity. Kidney biopsy assists in performing appropriate management and prognosis [54]. Weight loss and RAAS blockade are the two efficient treatments of ORG. The final aim is to slow down eGFR decline in order to delay ESRD progression.

Weight loss

Weight loss, either by diet or bariatric surgery, reduces the incidence of UAE or proteinuria [2, 47, 55]. That is, weight loss are in a positive correlation with the reduction of incidence of UAE or proteinuria.

Many studies, including nonrandomized prospective studies, randomized controlled trials (RCTs), systematic reviews, and meta-analyses, confirmed the relationship between low-calorie diets and proteinuria reduction [56‒58]. Hypertension, metabolic syndrome, diabetes, dyslipidaemia, and salt intake should be controlled at the same time with low-calorie diet.

Weight loss by bariatric surgery is generally much more effective than low-calorie diets [59]. Some clinical reports showed dramatic proteinuria reduction in ORG patients after bariatric surgery. Patients, who underwent bariatric surgeries, including Roux-en-Y gastric bypass, adjustable gastric banding, sleeve gastrectomy, had more severe obesity than dietary intervention patients. In a study, 92 morbidly obese (MO) patients showed that patients with normal renal functions and mild ORG lesions in presurgery period exhibit short- and long-term maintenance of normal renal functions and improvement in both renal arterial hypertension and albuminuria after drastic weight loss after bariatric surgery [60]. Recently, some uncontrolled research indicated that bariatric surgery is beneficial to ORG [61‒65]. However, these studies included patients with normal renal functions and minimal albuminuria. For MO patients with CKD, some studies considered that the rate of perisurgical complications is significantly high [66]. Thus, prospective controlled studies in ORG patients with CKD or nephrotic proteinuria are necessary to the evaluation of the efficacy and safety of bariatric surgery [8].

Although some studies showed that weight loss is beneficial to GFR progress [58], these studies often had a short follow-up periods and used a small sample size. The antiproteinuric effect of protection on renal function should be confirmed through large prospective RCTs.

RAAS blockade

The role of RAAS makes it an important target for ORG treatment. RAAS blockade, including angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), has a significant antiproteinuric effect on ORG patients. Antialdosteronic agents can also decrease proteinuria in obese patients. In retrospective studies, using ACEI or ARB for the treatment obese patients with proteinuria or biopsy-proven ORG obviously decreases proteinuria to 30%–80% of the baseline [2,47,49]. Mallamaci et al.[67] confirmed that the antiproteinuric effect of ramipril in obese and overweight patients is more increasingly prominent than those in patients with normal BMI, and that ramipril reduces ESRD incidents. Obese patients are more sensible to antiproteinuric and renoprotective effects of ramipril than nonobese patients.

A prospective RCT compared the effects of weight loss (low-calorie diet or orlistat treatment) with RAAS blockade in obese patients with proteinuria. The antiproteinuric effects of the two groups are similar [68]. Some studies with long follow-up periods suggested that the reduction of proteinuria through RAAS blockers can be exhausted over time, particularly during further weight gain or absence of weight loss [47,49].

Others

Insulin resistance plays an important role in ORG pathogenesis. Some studies reported that insulin-sensitizing agents, such as thiazolidinedione, alleviate kidney dysfunction and prevent the further worsening of kidney functions. Miyazakiet al. [69] showed that type 2 diabetes mellitus patients treated with rosiglitazone for three months had better insulin sensitivity than the placebo group, who had higher serum adiponectin concentration and reduced UAE. An animal experiment showed that metformin improves metabolic disorders, upregulates renal AMPK activity, diminishes the expression of renal TNF-a, decreases renal lipid accumulation, and prevents renal injury [70].

Several animal trials were conducted to discover potential drugs for ORG treatment. Antioxidants, such as SS-31, lycopene, and melatonin, were studied recently. Szetoet al. demonstrated that mitochondrial dysfunction is the cause of HFD-induced renal pathology. Herman-Edelstein et al. [35] suggested that renal lipid metabolism might be a target for specific therapies aimed at slowing the progression of glomerulosclerosis. Furthermore, SS-31 prevents the loss of glomerular endothelial cells and podocytes, mesangial expansion, glomerulosclerosis, macrophage infiltration, and upregulation of proinflammatory (TNF-a, MCP-1, nuclear factor k B (NF-kB)) and profibrotic (TGF-b) cytokines. SS-31 is a tetrapeptide that targets cardiolipin, protects mitochondrial cristae structure, and effectively prevents HFD-related renal pathology [33,71]. Meanwhile, targeting the mitochondria may provide a novel strategy for ORG therapy [33]. Pierine et al. demonstrated that lycopene might be beneficial in preventing and treating oxidative stress and inflammation in ORG by inhibiting NF-kB and TNF-a [72]. Melatonin has a critical role in the prevention of oxidative mitochondrial damage and exerts beneficial effects on mitochondrial morphology and dynamics [73]. Wang et al. [74] confirmed that a low dose of acetaminophen decreases renal lipid deposition, ER-stress related signaling, apoptosis, and albuminuria. These experimental interventions are still in the animal experiment stage and far from human applications. More related research is needed to evaluate the safety and effectiveness of these interventions in human treatment.

Conclusions

We reviewed the clinical and pathological characteristics and pathogenesis of ORG and treatment strategies for this condition. ORG is characterized by glomerulomegaly in the presence or absence of FSGS lesions. Renal hemodynamic changes, renin-angiotensin-aldosterone system, insulin resistance, mitochondrial dysfunction, inflammation, and abnormal lipid metabolism can all contribute to ORG progression. Although subnephrotic proteinuria is the most common ORG manifestation, less than half of ORG patients have nephrotic-range proteinuria. Furthermore, up to one-third of these patients develop progressive renal failure and ESRD, although the clinical course is characterized by stable or slow and progressive proteinuria. Control of obesity and other methods, such as RAAS blockage, can relieve ORG. However, owing to the increase in ORG cases, more studies are necessary to understand the disease.

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