The Renal Pathology Of Obesity: Structure-Function Correlations
Mar 22, 2022
In 1974, Weisinger et al1 reported four cases showing heavy proteinuria as a complication of massive obesity. Since then, similar cases of massively obese patients with proteinuric glomerulopathy have been described.2−8 In 2001, Kambham et al9 reported 71 obese patients with proteinuria based on systematic screening of a large-scale kidney biopsy archive and reported that the incidence of obese patients with similar clinicopathologic characteristics had increased during the past decades, and an independent disease concept of obesity-related glomerulopathy (ORG) was established. Subsequently, ORG cases categorized by different obesity criteria, according to each race, were reported from China in 200810 and from Japan, in 2013.11 It has been established that similar clinicopathologic presentations secondary to obesity can occur regardless of area or race.12,13 Given that obesity has become more prevalent in recent years, the increased incidence of chronic kidney disease (CKD) may be attributed significantly to the epidemic of obesity in the general population worldwide.14 In fact, among the various background factors that may be associated with the development of new-onset CKD in the general population, obesity has been identified consistently as a risk factor independent of other covariables, including hypertension or diabetes, which often occur as complications of obesity.15,16 This scenario is reflected by the annual changes in the distribution of the diagnoses of patients who undergo kidney biopsy. A report by Kambham et al9 showed an increased incidence of ORG among kidney biopsy cases evaluated at Columbia University in the United States, and the rate at which ORG was diagnosed in biopsy specimens increased from 0.2% in 1986 to 1990 to 2.0% in 1996 to 2000. A recent report by Hu et al,17 which analyzed a series of 34,630 native kidney biopsy cases at Zhengzhou University in China, showed that the annual incidence of ORG increased from 0.86% in 2009 to 1.65% in 2018. This review summarizes the current understanding of the renal pathology of obesity, with a particular focus on the structural and functional correlations of obesity-related kidney complications.
Keywords: Obesity, proteinuria, kidney biopsy, single-nephron GFR, glomerular hyperfiltration; kidney; renal
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CLINICAL FEATURES AND KIDNEY OUTCOMES
Obesity and Proteinuria In an analysis of nondiabetic adults in 34 international cohorts (n = 4,441,084), both increased body mass index (BMI) and the presence of albuminuria were independent risk predictors for glomerular filtration rate (GFR) decrease (estimated GFR, <60 mL/min per 1.73 m2 ).18 Another meta-analysis of 39 cohorts (n = 630,677) showed that obesity was an independent predictor of new-onset albuminuria without a GFR decrease in the general population.16 In obese adult participants (n = 12,000; median BMI, 35 kg/m2 ) enrolled in a randomized controlled trial of selective serotonin 2Creceptor agonist treatment for weight loss, the prevalence of low GFR and albuminuria was 20% and 19%, respectively.19 These rates were much higher than the rates of 3.8% and 2.9% that were identified in the general adult population.20 In severely obese cohorts subjected to bariatric surgery (mean BMI, >50 kg/m2 ), the rates of microalbuminuria and macroalbuminuria were 14% and 4% in adolescents (n = 230)21 and 41% and 4% in adults (n = 95),22 respectively. A series of previous epidemiologic and clinicopathologic studies have indicated that microalbuminuria or low-level isolated proteinuria is the important initial clinical phenotype in obese patients with kidney injury.
Clinical Features of ORG ORG often occur in young to middle-aged adults, with a male predominance; however, it can occur in all age groups, including children and elderly individuals.17,23,24 The frequent background comorbidities of ORG patients include hypertension and dyslipidemia.6−11 In general, the initial obesity-associated kidney phenotype is characterized as isolated proteinuria (without hematuria) with or without a GFR decrease.6−11 The clinicopathologic features in ORG patients that were reported in previous studies are listed in Table 1. ORG typically shows an insidious onset with varying degrees of proteinuria, which rarely accompanies an apparent decrease in the serum albumin concentration.6−11 Thus, the presence of full nephrotic syndrome is unusual and patients with ORG rarely show obvious symptoms, such as systemic edema. This clinical characteristic is useful for distinguishing these patients from those with other forms of glomerulopathy, especially idiopathic focal segmental glomerulosclerosis (FSGS), in which complete nephritic syndrome with an apparent albumin decrease often accompanies the presence of acute-onset, nephritic-range proteinuria, and systemic edema.9,12 Although the absence of a decrease in serum protein, even in the presence of relatively high urinary protein excretion, is a characteristic of ORG, the mechanism behind this remains largely unclear.
Definition of Obesity in ORG Although obesity usually is defined as a BMI value of 30 kg/m2 or greater, some studies from Asia used a threshold of BMI values of 28 kg/m2 or greater in Chinese patients10 or 25 kg/m2 or greater in Japanese patients25,26 for the diagnosis of ORG. In a Columbia University study, the mean BMI of patients with ORG was 41.7 kg/ m2 ; 46% with class 1 or 2 obesity (BMI, ≥30 to <40 kg/ m2 ) and 54% in patients with class 3 obesity (BMI, ≥40 kg/m2 ).9 The findings of systematic biopsies performed during bariatric surgery for long-lasting morbid obesity (mean BMI, 53.6 kg/m2 ) showed that subclinical renal structural changes already exist, but that the extent was much less than that in ORG patients with overt glomerulopathy.22,27 These findings suggest that the development of ORG is not restricted to patients with morbid obesity and that the severity of renal lesions and clinical symptoms does not simply depend on the severity of obesity.
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Kidney Outcomes and Prognostic Indicators in ORG Only a few studies have examined the long-term outcomes of patients with biopsy-proven ORG.8,9,11 The typical clinical course is stable or slowly progressive proteinuric kidney impairment; however, the long-term outcome includes progression to end-stage kidney disease (ESKD) in 10% to 33% of the patients. Older age, renal dysfunction, and greater proteinuria at presentation, as well as greater time-averaged proteinuria during follow-up evaluation, were identified as predictors of poor kidney outcomes in multivariable analyses.8,9,11 Of note, BMI was not a predictor of kidney outcomes among patients diagnosed with ORG.9,11
HISTOPATHOLOGY OF ORG Gross Features The kidney weights in autopsies of obese individuals, even in the absence of apparent kidney disease, has been found to be significantly greater in comparison with normal-weight control subjects in both adults and children, suggesting that obesity itself is associated with kidney enlargement.2,28−30 Although the mechanism underlying the increased kidney weight in obese individuals is unknown, it may be related to compensatory hypertrophy of individual nephrons, as a result of increased tubular and glomerular functions in association with obesity. The intracellular or extracellular accumulation of lipid components additionally may contribute to the increased kidney weight in obese individuals. A recent study showed that the degree of accumulation of triglycerides in the human kidney cortex was correlated with BMI.31 Although the deposition of triglycerides was observed in both glomerular and tubular cells, it was found predominantly in proximal tubular cells.31
A study of morphometric measurements using three-dimensional computed tomography images showed that the volume of the kidney parenchyma in Japanese ORG patients at the stage before they showed an apparent GFR decrease (CKD stages G1-G2) was significantly greater than that in nonobese and obese control subjects.26 The mean parenchymal volume in CKD stage G1 to G2 ORG, nonobese kidney transplant donors, and obese kidney transplant donors was 173 § 48, 119 § 23, and 138 § 22 cm3, respectively, while the mean cortical volume was 123 § 34, 85 § 17, and 98 § 17 cm3 . These findings imply that excessive kidney enlargement is
involved in the initial stages of ORG, which is not equivalent to the change in body size. In the same study, the kidney parenchymal volume and cortical volume in ORG patients were found to decrease in accordance with the advancement of the CKD stage.26 The mean parenchymal volumes in ORG patients with CKD stages G1, G2, G3a, G3b, and G4-G5 were 184 § 65, 168 § 40, 140 § 20, 135 § 31, and 122 § 39 cm3, respectively, while the mean cortical volumes were 131 § 46, 119 § 28, 100 § 14, 96 § 22, and 87 § 28 cm3 , likely reflecting the atrophic change of the kidneys resulting from the progressive loss of functioning nephrons and replacement with fibrotic scarring as the CKD stage advanced.
Vascular Lesions There are some morphologically detectable changes in the small kidney arteries that are typical of ORG. These include dilation of the glomerular arterioles and peripheral capillaries around the vascular pole of glomeruli (Figs. 1A and 2B),9,12,13 likely reflecting the high intravascular fellow rate and/or increased local plasma perfusion and pressure in ORG patients. Although findings such as arterial intimal thickening and arteriolar hyalinosis have been observed in ORG patients, thus far there have been no reports of histopathologic lesions in the arteries, arterioles, peritubular capillaries, or veins of the kidneys that are specific to ORG patients.
Glomerulomegaly Under a light microscope, the most prominent feature in ORG is extremely enlarged glomeruli, called glomerulomegaly (Figs. 1A and 2A).2,7,9,25,26,32 It is well established that the glomerular sizes of obese subjects are larger in comparison with nonobese subjects, even in the absence of apparent kidney disease.33,34 Previous studies consistently have shown that the glomerular sizes in ORG patients were significantly larger in comparison with control subjects with or without kidney diseases, including patients with idiopathic FSGS or nonobese and obese kidney transplantation donors. In agreement with the kidney parenchymal and cortical volume, the glomerular size is much larger in comparison with healthy obese kidney transplantation donors, suggesting that predisposing factors other than obesity are related to the development of glomerulomegaly in ORG.26 It has been reported that the glomerular size is 1.35 to 2.15 times larger in diameter and 1.58 to 2.63 times larger in volume in comparison with control subjects (Table 1).8,9,25,26,32,78 To date, there is no consensus on the quantitative definition of glomerulomegaly that is related to the clinicopathologic severity or outcomes in ORG. The increases in glomerular size found in obese subjects may be owing in part to an increase in the number of glomerular capillaries. The increased expression of capillary growth-promoting factors, such as vascular endothelial growth factor, in glomerular tissues isolated from ORG patients, supports this hypothesis.35
Focal Segmental Glomerulosclerosis Another important histopathologic feature in the glomeruli of patients with ORG is FSGS.6−10,25,26,32 In general, the diagnosis of FSGS may be made when some, but not all, glomeruli show segmental lesions in their glomerular tufts, in association with the collapse of areas of the glomerular capillary lumen.36 It now generally is accepted that FSGS is one pattern of glomerular scarring at the site of extremely impaired or detached podocytes. Sclerotic lesions may occur as a result of limited enlargement or duplication capacity of glomerular podocytes and/or replacement of the glomerular parietal epithelial cells. Some variants of FSGS lesions may occur depending on clinicopathologic background factors or lesions (Fig. 2D and E). Among the FSGS variants, the perihilar variant, a known form of FSGS, typically is identified in patients with ORG. This may be linked closely to glomerulomegaly, a representative feature of glomerular hyperfiltration/hypertension in ORG. Enlarged or vacuolated podocytes and proliferating parietal epithelial cells covering sclerotic lesions are identified occasionally at the site of FSGS lesions in ORG. In a Columbia University study, 57 (80%) of 71 patients showed FSGS lesions, and the distribution of segmental lesions was identified as perihilar in 11 cases (19%) and as mixed perihilar and peripheral in the remaining 46 cases (81%).9 In a report that analyzed 48 Japanese ORG patients, 20 (42%) patients had FSGS lesions.26 Of the total FSGS lesions identified in these patients, 13 (42%) were perihilar and 18 (58%) were found at sites other than perihilar locations. Findings typically identified another etiologic basis of FSGS, including intracranially or endocapillary formed cells and hyalinosis, in FSGS lesions may be identified in ORG patients.
Immunofluorescence and Electron Microscopy Findings Immunoflfluorescence microscopy typically shows no specific findings in ORG, whereas nonspecific focal and segmental or global staining of the glomerular tuft with IgM and C3 can be seen occasionally, which correspond to the areas of glomerulosclerosis.9 The findings of electron microscopy in ORG include less-prominent foot process effacement in comparison with patients with idiopathic FSGS.9,12,13 Podocyte foot process effacement is segmental and usually covers less than 50% of the glomerular capillary surface area; however, it can be seen diffusely in the glomeruli of ORG. Mild podocyte hypertrophy, intracytoplasmic protein resorption droplets, and mild glomerular basement membrane thickening can be observed in some ORG patients. Focal intracytoplasmic lipid vacuoles can be identified occasionally in mesangial cells and tubular epithelial cells; however, these findings are not specific to ORG.12,13
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Tubulointerstitial Lesions Tubulointerstitial lesions specific to ORG have not been identified thus far. Consistent with the marked enlargement and hypertrophic changes in glomeruli, the kidney tubules likely are enlarged in size. A study of biopsy specimens from proteinuric obese patients showed that the cross-sectional area of proximal tubular epithelial cells was 33% larger, and the proximal tubular lumen was 54% larger, in comparison with proteinuric nonobese patients.37 Another important histopathologic characteristic of ORG that indirectly indicates tubular hypertrophy is low glomerular density.25,26,32 Because the kidney is composed largely of tubular structures, it is conceivable that tubular hypertrophy results in a relative decrease in glomerular density in biopsy specimens. Given that the kidney cortical volume is increased significantly in ORG patients with a preserved kidney function, it, therefore, is conceivable that tubular hypertrophy precedes the occurrence of advanced glomerulosclerosis and the compensatory hypertrophy of the remaining nephrons.
Differential Diagnosis ORG is defined as proteinuric kidney disease in obese patients and is diagnosed based on the absence of other known kidney diseases, both clinically and histopathologically.9,12,13 In kidney biopsy specimens, glomerulomegaly with or without FSGS lesions can be detected; however, these findings are not specific to ORG. Therefore, when diagnosing this entity, it is crucial to exclude diseases that are related closely to obesity, such as hypertensive nephrosclerosis or diabetic glomerulosclerosis. The presence of hypertension is not an exclusion criterion. The biopsy specimens of some obese hypertensive patients show moderate to severe vascular lesions, which are accompanied by the appearance of diffusely collapsed glomeruli. Patients with such histologic features are diagnosed with hypertensive nephrosclerosis rather than ORG. In obese patients with type 2 diabetes mellitus, it often is difficult to determine whether diabetes or obesity has a predominant role in the development of proteinuria. In typical ORG cases, glomerular nodular lesions or glomerular microaneurysm formation, which often are identified in advanced diabetic nephropathy, are not seen. Increased glomerular basement membrane thickness alone is not a criterion for exclusion because obese patients can show an increased glomerular basement membrane thickness in the absence of diabetes.38,39
PATHOPHYSIOLOGY INVOLVED IN OBESITY-ASSOCIATED KIDNEY IMPAIRMENT
Intrarenal Hemodynamic Changes and SingleNephron Glomerular Hyperfifiltration Previous intervention studies in obese individuals have shown that total blood volume, renal plasma fellow, and total GFR increase with obesity.40−43 In addition, the increase in the filtration fraction (GFR/renal plasma fellow) is a characteristic change in obesity.41,42 The total filtration function of the kidney is the sum of the filtration function in individual nephrons, termed the single nephron glomerular filtration rate (SNGFR). These SNGFR values have been suggested to be particularly valuable for understanding the pathophysiology of progressive kidney diseases.43−47 Based on the unique histopathologic features of glomerulomegaly and the perihilar location of FSGS lesions, it has been hypothesized that compensatory and/or decompensatory glomerular hyperfiltration is very likely to be involved in the development and progression of ORG.11,12 However, abnormalities in the SNGFR of ORG patients have not been shown owing to technical difficulties in measuring the SNGFR in the clinical setting. Recent studies have developed a method to estimate the total glomerular number per kidney in living kidney donors based on the combination of computed tomography (CT) angiography and biopsy-based stereology.48,49 By dividing the total nephron GFR by the total number of nonsclerotic (functioning) glomeruli in both kidneys, SNGFR was estimated and several factors were identified that possibly influence the SNGFR in healthy subjects, including obesity.50 Recently, Sasaki et al51,52 further modified this method and established a regression equation model to estimate the kidney cortical volume by measuring kidney parenchymal volume using unenhanced CT images in human beings. Evaluation of cortical volume by this method has allowed estimation of total glomerular number per kidney in patients with kidney disease who often are not suitable candidates for image analyses using contrast media.
The new technology of unenhanced CT and biopsy-based stereology was applied recently to estimate the total glomerular number and SNGFR in patients with ORG. Okabayashi et al26 estimated the total nephron number and the SNGFR in patients with biopsy-diagnosed ORG using a combination of unenhanced CT and biopsy-based stereology (Fig. 3). The SNGFR values in ORG patients with CKD stage G1 and G2 were 64% and 52% higher than in nonobese and obese controls (ORG, 97 § 43; nonobese control, 59 § 21; obese control, 64 § 21 nL/min, respectively), whereas the SNGFR
values of obese and nonobese controls did not differ to a statistically significant extent. These results present clinical evidence of single-nephron hyperfiltration in an early stage of kidney impairment in ORG. In addition, the same study showed that SNGFR peaked at the early CKD stage and showed a gradual decrease with advancing CKD stage, in contrast to the marked increase in single-nephron urinary protein excretion (total urinary protein excretion per total nonsclerotic glomerular number in both kidneys) (Fig. 4). This may illustrate the process of decompensated glomerular hyperfiltration in subjects with ORG with advancing CKD stages.
Increased Tubular Salt and Water Reabsorption in Obesity There are two major mechanisms through which the glomerular and tubular functions are communicated within a nephron: glomerulotubular balance (GTB) and tubuloglomerular feedback (TGF). The tubules respond to glomeruli with GTB, whereas glomeruli respond to tubules through TGF.53 GTB refers to the phenomenon whereby a constant fraction of the filtered load of the nephron is resorbed across a range of GFRs. The proximal tubule is the principal segment in which the GTB operates, and approximately 70% of the filtered load of sodium and water is reabsorbed in the proximal tubule, regardless of the GFR value.54 Tubular overload caused by glomerular hyperfiltration therefore may stimulate sodium and water reabsorption in the proximal tubules via GTB. In response to an increased sodium fellow rate, TGF, the principal mechanism that is responsible for maintaining glomerular blood fellow and thereby the GFR, acts to increase preglomerular vascular resistance.55 Previous studies in ORG patients and obese subjects have implied that the increased tubular reabsorption and glomerular hyperfiltration, which may constitute a vicious cycle of hyperfunction of the whole kidney, is fundamentally important in the renal pathology of obesity (Fig. 5).12,13,56,57
Role of the Renin-Angiotensin-Aldosterone System The changes in kidney hemodynamics found in obesity are linked closely to increased salt sensitivity.57 In fact, in comparison with lean subjects, obese subjects are more likely to develop salt-sensitive hypertension and proteinuria as a result of excessive salt intake.58,59 Mechanisms by which salt sensitivity and absolute reabsorption are increased with obesity include activation of the intrarenal renin-angiotensin-aldosterone system (RAAS)60,61 and kidney sympathetic nerves.62,63 Adipose tissue is known to constitute an independent RAAS system, and it is known that activation of the RAAS system occurs in obese individuals.64,65 The increased production of angiotensinogen, aldosterone, and aldosterone-stimulating factor are shown in adipocytes from obese individuals.66−68 The plasma aldosterone concentrations in obese subjects are correlated with the visceral fat volume, which is decreased by weight loss.69,70
Potential Contribution of Altered Kidney Glucose Metabolism Kidney glucose reabsorption is a major contributor to systemic glucose homeostasis. The reabsorption of glucose in the proximal tubules is mediated by sodium-glucose co-transporters (SGLTs); among these, 90% of all glucose reabsorption occurs via SGLT-2.71 Hyperglycemia and angiotensin II are known to increase the expression of SGLT-2.72,73 Thus, in obese individuals, in whom both hyperglycemia and RAAS activation may occur, the kidney tubular reabsorption of glucose may be increased via up-regulation of SGLT-2. A recent largescale study showed that SGLT-2 inhibitor therapy slowed the progressive loss of kidney function in proteinuric CKD patients without diabetes, suggesting a potential beneficial role of SGLT-2 inhibitors in ORG patients.74
Total Nephron Number and Pathogenesis of Kidney Disease in Obese Individuals The reason why most patients tolerate obesity without showing any signs of kidney impairment, whereas others show progression to kidney failure, is unknown. Praga et al75 examined the clinical characteristics of patients at risk of developing proteinuria after unilateral nephrectomy and found that BMI was significantly higher in patients who developed proteinuria and kidney insuffifi- ciency, in comparison with that observed in patients who did not show these abnormalities. A study by the same group showed that obesity is an independent predictor of proteinuria or kidney impairment among patients with congenital kidney agenesis and remnant kidney.76 In addition, a recent large-scale, long-term, observational study in living kidney transplantation donors identified obesity as an independent risk factor for the progression of ESKD.77 These results suggest the possibility that obesity participates in the development of kidney injury in the setting of kidney mass reduction.
Although the low glomerular density observed in the kidney biopsy specimens of ORG patients may be caused by several factors, the possibility that ORG patients show low nephron numbers remains to be investigated. To examine this possibility, we recently estimated the total glomerular number in patients with ORG.26 Overall, the total numbers of functioning glomeruli (without globally sclerotic glomeruli) were significantly lower in the ORG group in comparison with obese or nonobese healthy kidney donors. In the ORG group, the number of functioning glomeruli decreased significantly as the CKD stage advanced. These results support the possibility that a low number of functioning nephrons, either inherent or acquired, is one of the risk factors that sensitizes obese individuals to the progression of already established ORG. However, the total nonglobally sclerotic glomerular number in ORG patients with preserved kidney function (CKD stage G1 and G2; n = 25), nonobese healthy kidney donors (n = 20), and obese healthy kidney donors (n = 13) was 0.542 § 0.227 £ 106 , 0.652 § 0.211 £ 106, and 0.673 § 0.217 £ 106 per kidney, respectively, and did not differ to a statistically significant extent. In addition, the comparison of the total glomerular number, including globally sclerotic glomeruli, also failed to show a significant difference. The similar numbers of nephrons in ORG patients with preserved kidney function and in healthy nonobese and obese donor controls suggest that it is unlikely that a low nephron number is a sole factor that predisposes obese individuals to the development of ORG.
Role of the Relative and Absolute Decrease in Podocyte Number Given the crucial roles of glomerular podocytes in the maintenance of the structure and filtration capacity of glomeruli, metrics such as the total number or density of glomerular podocytes may provide useful insight into the mechanisms underlying the progressive loss of the filtration function in ORG. In fact, one study reported that podocyte density in patients with ORG was 55% lower and that the mean glomerular volume was 58% higher than in nonobese kidney donors, suggesting the adaptive failure of podocytes in covering glomerular tufts is involved in the pathogenesis of protein leakage.78 The compensatory failure observed in advanced ORG patients with FSGS lesions therefore may be explained by a functional adaptation failure in glomerular podocytes. Similar to the variability in nephron number, recent studies have shown broad variability in the podocyte number per glomerulus among normal individuals.79 Mismatch between abnormally enlarged glomeruli and individual podocyte endowment could constitute another factor that predisposes ORG patients to glomerular injury.
Obesity-Proteinuria Syndrome An increased incidence of obese patients with CKD in the general population suggests that patients with biopsy-diagnosed ORG represent only the tip of the iceberg and that a vast number of obese subjects show insidious proteinuria may have the potential to progress to overt nephropathy and ESKD. This is quite analogous to the situation of diabetic nephropathy as a kidney complication of diabetes, in which the initial symptom is microalbuminuria, which then progresses to overt proteinuria and ESKD.80 Likewise, ORG patients and obese patients with subclinical proteinuria likely represent different stages or grades of the same disease entity of obesity-proteinuria syndrome (Fig. 5). Similar to kidney diseases of other etiologies, impaired kidney function and heavy proteinuria at presentation are predictors of worse kidney outcomes, suggesting the need for an early diagnosis and early intervention in this growing patient group. The elucidation of the background characteristics and biomarkers associated with the new development of proteinuria in obese subjects may help to better understand the factors involved in kidney complications in obesity.
CONCLUSIONS
Clinical and histopathologic observations in ORG patients have shown pathophysiological pathways that may link obesity and chronic kidney injury. Structural and functional changes resulting from abnormalities in glomerulotubular and tubuloglomerular interactions may lead to compensatory glomerular filtration failure, podocyte loss, and tubulointerstitial scarring owing to proteinuria overload, and constitute a vicious cycle leading to overt nephropathy and ESKD. Factors that determine sensitivity to, or tolerance of, obesity-related kidney injury remain poorly understood and further studies are needed.
