Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone

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Obesity Research & Clinical Practice (2017) xxx, xxx—xxx

ORIGINAL ARTICLE

Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone Steven P. Salvatore a,∗, James M. Chevalier b, Sheng F. Kuo c, Pat F. Audia d, Surya V. Seshan a a

Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA b Nephrology, Weill Cornell Medical College, New York, NY, USA c Nephrology, NewYork-Presbyterian Queens Medical Center, New York, NY, USA d Nephrology, St. Joseph’s Regional Medical Center, Paterson, NJ, USA Received 31 May 2016 ; received in revised form 16 March 2017; accepted 1 April 2017

KEYWORDS Obesity; Proteinuria; Chronic kidney disease

∗

Summary Objective: Patients with obesity are at risk for chronic kidney disease. The aim is to characterize the spectrum of kidney disease in these patients, which may be related to obesity, termed obesity-related glomerulopathy (ORG), or may have other diseases secondary to associated or unassociated medical conditions. Methods: Native kidney biopsies from 2000 to 2012 were retrospectively reviewed from all patients with body mass index >30 kg/m2 . Glomerular diameter was measured using a standard micrometer and clinicopathologic characteristics were analyzed. Results: 4% (287) of all biopsies were obtained from patients with obesity (mean: weight 122 kg, BMI 40.4 ± 7.35 kg/m2 ) for proteinuria in 93% and renal insufficiency in 53%. Frequent associated factors were abnormal glucose metabolism (31%), hypertension (60%), and obstructive sleep apnea (9%). Typical lesions of ORG were seen in 41% of cases and additional diseases in the rest. Glomerulomegaly, glomerular diameter >180 ␮m, was present in 84% of cases (mean 224 ␮m) vs normal size in 11% (mean 157 ␮m), but was not increased with higher magnitude of obesity. Proteinuria was highest in patients with idiopathic FSGS (mean 8 g/24 h) and immune complex diseases (mean 7.4 g/24 h) and was mainly subnephrotic in obesity-related FSGS and tubulo-interstitial diseases. Creatinine levels were highest in tubulointerstitial diseases (mean 8.4 mg/dL) and progressive diabetic nephropathy (mean 2.5 mg/dL).

Corresponding author at: 1300 York Ave, F309-C (Box 69), New York, NY 10065, USA. E-mail address: [email protected] (S.P. Salvatore).

http://dx.doi.org/10.1016/j.orcp.2017.04.003 1871-403X/© 2017 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Salvatore SP, et al. Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone. Obes Res Clin Pract (2017), http://dx.doi.org/10.1016/j.orcp.2017.04.003

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S.P. Salvatore et al. Conclusions: Diverse kidney pathology superimposed on ORG is present in patients with obesity with varied clinical renal disease, some of which may be amenable for therapy. Kidney biopsy will assist in delineating these lesions for appropriate management and prognosis. © 2017 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Introduction Obesity is a worldwide health issue with a prevalence of greater than 1/3 of all US adults [1]. As demonstrated in large epidemiologic studies, obesity is a known risk factor for chronic kidney disease (CKD) [2,3]. A renal pathologic entity, obesity related glomerulopathy (ORG), has been reported in these individuals, which is thought to be a consequence of excessive body weight [4]. However, ORG has proven to be a relatively rare diagnosis in biopsy studies and may not fully explain the increased risk of CKD in these patients independently. In addition, patients with obesity frequently have comorbidities which may also predispose them to CKD. In this study, we sought to fully characterize all renal biopsies from patients with obesity, defined as body mass index (BMI) greater than or equal to 30 kg/m2 , in order to elucidate factors contributing to poor renal outcomes. ORG is a well-recognized pathologic process, a form of podocytopathy, in which glomerular hypertrophy or glomerulomegaly with or without perihilar focal segmental glomerulosclerosis (FSGS) and partial foot process effacement is seen. Typically, it presents with either subnephrotic, or less commonly nephrotic range proteinuria, but without hypoalbuminemia or nephrotic syndrome [4,5]. While studies uniquely characterized isolated obesity-related glomerular/renal changes, the majority of obese patients have one or more associated confounding clinical conditions such as diabetes or hypertension, for which patients were excluded in these reports. Metabolic syndrome includes several related medical conditions which can be observed in patients with obesity. Depending on which definition of metabolic syndrome one uses, these associated conditions may include central obesity or increased BMI, insulin resistance, hypertension, hyperlipidemia, and even rate of albuminuria [6]. While the Adult Treatment Panel III (ATPIII) does not include albuminuria as a criteria for metabolic syndrome, the World Health Organization (WHO) has included albuminuria, recognizing the renal end-organ damage related to this constellation of clinical findings. What is not known is how metabolic syndrome or obesity in general plays a role in chronic kidney disease. Diabetes is the leading cause of end stage renal disease (ESRD) in the United States, but its role is not entirely clear in the development of CKD and ESRD in patients with obesity [2]. Small studies have demonstrated that in the setting of IgA glomerulonephritis (IgAN), obesity may contribute to the rate of progression to CKD more

rapidly than in control patients who are not obese [7]. We hypothesize that obesity-related renal injury plays an associated role in the renal pathology of our patients with obesity.

Materials and methods Retrospective review of native kidney biopsies read at one institution by a single pathologist specialized in nephropathology (SVS) was performed over the years 2000—2012, comprising a total of 6702 biopsies. Weight and height measurements were used to calculate the BMI in all patients in which these parameters were provided. The levels of obesity were classified based on guidelines of the National Heart, Lung, and Blood institute [8] as obesity class I (BMI 30.0—34.9 kg/m2 ), class II (BMI 35—39.9 kg/m2 ), and class III (BMI >40 kg/m2 ). Clinical parameters were analyzed on all patients with BMI > 30 kg/m2 or who had been identified as ‘‘obese’’ by the submitting physician. All renal biopsies from obese patients were rereviewed and confirmed by a second pathologist with subspecialty interest in nephropathology (SPS). Thirtytwo (32) patients’ biopsies were excluded due to insufficient number of glomeruli present (<7) based on minimum number of glomeruli for adequacy using the Banff criteria for allograft interpretation [9]. The diagnoses were based on routine light, immunofluorescence and electron microscopic examination and categorized for comparison as obesity-related with or without FSGS, idiopathic FSGS, diabetic nephropathy (DN), immune complex glomerulonephritis, and tubulointerstitial/vascular disease. Idiopathic FSGS was defined using both clinical and pathologic parameters with the biopsy showing FSGS, complete or nearly complete foot process effacement and lack of immune complex deposits, in conjunction with nephrotic range proteinuria and decreased serum albumin. Immune complex diseases included IgA nephropathy, lupus nephritis, membranous glomerulonephritis, postinfectious glomerulonephritis, fibrillary glomerulonephritis, C1q nephropathy, and immune complex disease that could not be further classified. Glomerular diameter was measured in all full glomeruli present in the biopsies, on the microscopic section in which the glomerulus had been cut through the hilum. The number of such glomeruli available ranged from 1 to 7 per biopsy, mean 4. Glomerular size was

Please cite this article in press as: Salvatore SP, et al. Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone. Obes Res Clin Pract (2017), http://dx.doi.org/10.1016/j.orcp.2017.04.003

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Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone

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Figure 1 Glomerulomegaly alone (A) and in conjunction with perihilar focal segmental glomerulosclerosis (B). PAS stain, magnification 20× (A) and 40× (B). compared to the historical normal range as seen in the literature, with normal range being 168 ± 12 ␮m [4]. For the purposes of this study glomerulomegaly is defined as glomerular size greater than 180 ␮m. ORG is defined as the clinicopathologic entity of glomerulomegaly in the setting of obesity, proteinuria, and chronic kidney disease with or without secondary FSGS in the absence of other glomerular processes. Statistical calculations were made using a student ttest or chi squared test, where appropriate. The retrospective study was conducted with IRB approval from Weill Cornell Medical College, New York NY.

Results Of 6702 total biopsies, 287 (4%) were reviewed from patients with known obesity. The patients weighed on average 122 kg (range 74—236 kg) with mean BMI 40.3 kg/m2 (range 30—66.3 kg/m2 ). The percentage of kidney biopsies from patients with obesity increased over the study period, 1.8% from 2000 to 2003, 5.4% from 2004 to 2007, and 5.8% from 2008 to 2012. Other associated conditions included hypertension in 60% (153 patients), diabetes in 31% (80 patients), and obstructive sleep apnea in 9% (22 patients). Diabetes is defined as a fasting glucose level greater than 126 mg/dL, hypertension as systolic blood pressure >140 mmHg or diastolic >90 mmHg, and sleep apnea as interruptions of breathing during sleep which is associated with frequent awakening and daytime sleepiness. The full metabolic syndrome, as defined by ATPIII (insulin resistance, BMI greater than 30, hypertension, and hyperlipidemia) was seen in 25% (64 patients). The most common indication for renal biopsy was proteinuria, 93% of patients (237), of which 43% presented with nephrotic range (range 3.5—22 g/24 h) and the remaining 57% had subnephrotic proteinuria (range 0.1—3.4 g/24 h). CKD was listed as biopsy indication in 122 patients and fifty-two (52) percent of patients had creatinine greater than 1.5 mg/dL (range 1.5—9.7 mg/dL). Eighteen patients had acute renal fail-

ure. Hematuria was less frequently the cause for biopsy, but was present in 18% of patients (46 total), both in combination with proteinuria and as an isolated finding.

Pathological findings Of 255 total biopsies, forty percent (40%) showed ORG alone or in conjunction with FSGS without other superimposed pathology (Figs. 1 and 2). Sixty percent (60%) of patients had a secondary disease process not directly attributable to obesity alone (Table 1). Features of DN were most frequent, observed in 36% of patients of those who had an additional diagnosis on biopsy (Fig. 3A). These findings represented all classes of DN using the diabetic nephropathy classification system [10]: 11 class I, 10 class II, 24 class III, and 11 class IV. Immune complex mediated glomerular disease was present in 15%. Membranous glomerulonephritis (14 patients) was the most frequent, followed by lupus glomerulonephritis (10 patients), IgAN [6] (Fig. 3C), post infectious glomerulonephritis [4] (Fig. 3B), fibrillary glomerulonephritis [2],

Figure 2 Kidney biopsy findings in patients with obesity. A graphical representation of Table 1. Abbreviations: ORG—–obesity related glomerulopathy, FSGS—–focal segmental glomerulosclerosis, DN—–diabetic nephropathy, ICGN—–immune complex glomerulonephritis.

Please cite this article in press as: Salvatore SP, et al. Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone. Obes Res Clin Pract (2017), http://dx.doi.org/10.1016/j.orcp.2017.04.003

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S.P. Salvatore et al. Table 1

Secondary diseases on kidney biopsy in patients with obesity.

Secondary diseases on kidney biopsy in patients with obesity 60% (n = 154) had secondary disease Diabetic nephropathy (22%) Immune complex mediated diseases (15%) Podocytopathy, non-obesity related (7%) Tubulointerstitial disease (4%) Thrombotic microangiopathy (2%) Thin glomerular basement membranes (5%) Miscellaneous/other Extent of vascular sclerosis

Class I (11), class II (10), class III (24), class IV (11) IgAN (6), lupus nephritis (10), membranous GN (14), PIGN (4), fibrillary GN (2), C1q nephropathy (1), IC disease NOS (1) Idiopathic FSGS, minimal change disease, collapsing glomerulopathy Acute interstitial nephritis (hypersensitivity type) (7), acute tubular injury (2) Malignant hypertension (2), Pre-eclampsia (1), unknown (1) 12 cases (5 were isolated, 7 with superimposed disease) Pauci-immune Crescentic GN Severe (26%), moderate (58%), mild (16%)

Abbreviations: IgAN, IgA nephropathy; GN, glomerulonephritis; PIGN, postinfectious glomerulonephritis; IC, immune complex; FSGS, focal segmental glomerulosclerosis.

Figure 3 Superimposed glomerular and tubulointerstitial pathology in biopsies of obese patients including (A) diabetic nephropathy (PAS 40×), (B) post-infectious glomerulonephritis (EM), (C) IgAN (IF), and (D) active interstitial nephritis (H&E, 60×). C1q nephropathy [1] and non-specific immune complex disease [1]. Of the cases of non-lupus related membranous glomerulonephritis (14 total), eight [8] were M-type phospholipase A2 receptor (PLA2R) positive (57%), 2 were

PLA2R negative (14%), and 4 (28%) did not have available tissue for testing. A podocytopathy was present in 7% of patients, including idiopathic FSGS, minimal change nephrotic syndrome, and collapsing glomeru-

Please cite this article in press as: Salvatore SP, et al. Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone. Obes Res Clin Pract (2017), http://dx.doi.org/10.1016/j.orcp.2017.04.003

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Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone

BMI (kg/m2) 55

Cr (mg/dl)

5

Male/Female (% bx)

10

50 8 45 6

40 35

4

30 2

25 20

0

Male Proteinuria (g/24hr) 10 9 8 7

Type of Proteinuria (% of cases)

Female

Ethnicity (% bx)

6 5 4 3 2 1 0

nephroc

White

Black

subnephroc

Hispanic

Asian

Figure 4 Clinical characteristics listed by category of pathology seen at biopsy from patients with obesity. Values shown are mean. lopathy. Tubulointersititial nephritis was noted in 4%, including acute interstitial nephritis (7 patients) (Fig. 3D) and acute tubular injury alone [2]. Thrombotic microangiopathy (TMA) was seen in 2% of biopsies (4 patients). TMA could be attributed to malignant range hypertension in 2 cases and pre-eclampsia in 1 woman, while the remaining case was of unknown etiology. Occasionally, other glomerular abnormalities such as diffusely thin glomerular basement membranes (defined by ultrastructural measurements of basement membranes measuring less than 200 nm), was seen in 5% of biopsies. In addition to the glomerular and tubulointerstitial pathology, vascular sclerosis was also scored as mild (10—25% occlusion), moderate (25—50% occlusion), or severe (>50% occlusion), based on the degree of vascular occlusion by fibrointimal sclerosis or medial hypertrophy of the vessels. Twenty-six percent (26%) of the biopsies showed severe vascular sclerosis, while 58% were moderate and 16% were mild. 85% of the patients with hypertension had moderate to severe vascular sclerosis. The breakdown by category of chronic global glomerulosclerosis, interstitial fibrosis, and vascular disease is depicted in Table 2. DN resulted in the most severe chronic renal parenchymal changes. As compared to normal glomerular basement membrane (GBM) thickness of 300—350 nm [11], there is variable GBM thickening in all

groups, most pronounced in DN (Ranges: 400—1350 nm with DN, 140—1150 nm without DN). Retrospective review of the BMI and pre-biopsy clinical parameters, with categorization into classes of diagnosis is shown in Fig. 4(a—e). While the BMIs were higher in the primary FSGS cases, the small number (n = 6, BMI only available on 4) may have skewed the results. There was no significant difference between BMI values between ORG-FSGS vs glomerulomegaly alone (P = 0.54), vs DN (P = 0.36), vs Primary FSGS (P = 0.40), vs ICGN (P = 0.22), or vs TIN (P = 0.72). There were more female patients in the immune complex GN (P = 0.05) and idiopathic FSGS groups although the later group was not statistically significant (P = 0.33). The ethnic background was not significantly different. The presenting creatinine level was highest in cases with tubulointerstitial nephritis or acute TMA, which was statistically significant (P = 0.004). The creatinine was also higher in DN as compared to ORGFSGS (P = 0.004). The other categories did not have a statistically different creatinine at the time of biopsy; ORG-FSGS vs ORG alone (P = 0.14), ORG-FSGS vs Primary FSGS (0.95), and ORG-FSGS vs ICGN (P = 0.189). The magnitude of proteinuria was the highest in primary FSGS and immune complex glomerulonephritis. Statistically there was greater proteinuria in ORG-FSGS than in ORG alone (P = 0.001) as well as compared to TIN (P = 0.0017)

Please cite this article in press as: Salvatore SP, et al. Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone. Obes Res Clin Pract (2017), http://dx.doi.org/10.1016/j.orcp.2017.04.003

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S.P. Salvatore et al. Table 2

Pathologic findings in kidney biopsies from patients with obesity, by category.

Diagnosis

N

Global GS

Segmental IF/TA sclerosis

Vascular disease (0—3)

Basement membrane thickness (nm)

Foot process effacement

Glomerular Size (nm) [normal range 156—180 nm]

ORG-FSGS

72 (28%)

30%

11%

30%

1.9

490 (140—1150)

28%

227 ± 15.5

ORG-no FSGS

22 perihilar 33 (13%)

16%

0%

16%

1.5

22.8%

223 ± 15.5

DN

56 (22%)

32%

5%

49.6%

2.3

34%

211 ± 17.5

1◦ FSGS

6 (2%)

23%

22%

32.5%

1.7

87.5%

208 ± 26

ICGN

39 (15%)

21%

9%

32%

1.4

58%

208 ± 15.5

TIN/TMA

10 (6%)

15%

3%

34%

1.9

386 (140—600) 765 (400—1350) 463 (325—700) 766 (165—1300) 597 (425—750)

22%

194 ± 16

Abbreviations: GS, glomerulosclerosis; IF/TA, interstitial fibrosis/tubular atrophy; ORG, obesity related glomerulopathy; FSGS, focal segmental glomerulosclerosis; DN, diabetic nephropathy; ICGN, immune complex glomerulonephritis; TIN, tubulointerstitial nephritis; TMA, thrombotic microangiopathy.

Figure 5 Mean glomerular size categorized by diagnosis on kidney biopsy. Red line at 168 ␮m ± 12 ␮m represents normal glomerular size. and less proteinuria than vs ICGN (P = 0.005). There was no difference as compared to DN (P = 0.23) or primary FSGS (P = 0.12) although the later may be due to a small number of cases. ORG with or without FSGS most frequently showed subnephrotic proteinuria (p = 0.001), as did the tubulointerstitial group (P = 0.04), whereas DN, primary FSGS, and ICGN were more likely to present with nephrotic range proteinuria (all statistically nonsignificant). Serum albumin levels were lower in the ICGN (2.7 g/dL) compared to ORG-FSGS or ORG alone (3.7 g/dL) Glomerular morphometric assessment was performed in all cases. The glomerular diameters are depicted in Fig. 5, categorized by disease. Glomerulomegaly (compared to normal range in literature 168 ± 12 ␮m) [4] was present in all subgroups, mean 224 ␮m ± 34 ␮m, in 215 of the 255 total biopsies (84%). The largest glomeruli were

seen in ORG with or without accompanying FSGS, mean 227 ± 15.5 ␮m and 223 ± 15.5 ␮m respectively. Glomerular diameter in DN measured mean 211 ± 17.5 ␮m, while they were on average 208 ± 26 ␮m for primary FSGS, 208 ± 15.5 ␮m in immune complex GN and 194 ± 16 ␮m in TIN/TMA cases. The remaining 40 cases in which glomerular diameter was within the normal range (<180 nm) were diagnosed as FSGS (11), DN (9), no specific changes (7), MCNS (2), IgAN (2), vascular sclerosis only (2), MGN (1), diffuse thin basement membranes (1), AIN (1), ATI (1), TIN (1), PIGN (1), and TMA (1). Of the 255 patients assessed, 18 of them had neither hypertension nor diabetes. These commonly showed ORG on biopsy (44%, 8/18) followed by ORG-FSGS in 22% and a variety of other diagnoses in the remaining 33%. In fact, 25% of all cases of glomerulomegaly alone without FSGS or other diagnoses were seen in the 18 patients without diabetes or hypertension. On the contrary, 61 patients had both hypertension and diabetes in addition to obesity. The majority of these patients were diagnosed with DN (72%, 44/61), followed by ORG-FSGS in 11%, other conditions 15% and glomerulomegaly alone in only 1/61 patients (2%). Interestingly, of patients who had clinical diabetes (80 patients), 70% were found to have DN. BMI data was available on 79 cases. The categories of obesity were separated into classes I (BMI 30—34.9 kg/m2 ), II (35—39.9 kg/m2 ), and III (>40 kg/m2 ) to assess for clinical and pathological differences, Table 3. Neither the clinical nor pathologic parameters varied significantly between the groups, aside from the BMI, with the exception of there being slightly more superimposed diseases present in class III, 57% vs 33% and 38% for classes I and II. The age of the patients was comparable. The proteinuria and presenting creatinine were highly variable within the individual groups, depending on the diagnosis, but the overall averages between the groups did not vary significantly. The glomerular size was

Please cite this article in press as: Salvatore SP, et al. Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone. Obes Res Clin Pract (2017), http://dx.doi.org/10.1016/j.orcp.2017.04.003

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Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone Table 3

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Clinical and pathologic variables by class of obesity.

N Age (mean) Gender BMI (kg/m2 ) Proteinuria (g/24 h) Creatinine (mg/dL) Albumin (mg/dL) Superimposed disease Global glomerulosclerosis Glomerular size (␮m)

Class I (BMI 30—34.9)

Class II (35—39.9)

Class III (40+)

18 39.5 10 M:8 F 31.7 (30—34.5) 4.95 (0.7—21) 2.5 (0.8—3.3) 3.45 (2.3—4.2) 6/18 32% 224.7 (185—310)

24 39.1 9 M:15 F 37.8 (35—39.7) 3.95 (0.2—10.8) 2.1 (0.8—3.5) 3.5 (2.5—4.7) 9/24 28% 228.8 (155—302)

37 42.9 18 M:19 F 46 (10—66.3) 5.0 (0—20) 2.4 (0.7—10.6) 3.5 (1—4.6) 21/37 26% 219.6 (160—275)

Abbreviations: BMI, body mass index.

enlarged in all 3 groups but did not increase with increasing BMI.

Discussion Herein, we present the full spectrum of kidney biopsy results from patients with obesity. This is the first report on such a cohort of cases, demonstrating the diverse renal pathologic diagnoses, with a range of glomerular, tubulointerstitial, and vascular lesions present in this patient population. Although, ORG with or without FSGS was observed in approximately 40% of patients, an alternative diagnosis was more commonly seen particularly associated with the co-morbid conditions of the metabolic syndrome, such as impaired glucose metabolism, diabetes, hypertension, etc. Moreover, while increased BMI is a known risk factor for CKD, systematic biopsy studies have not been performed to suggest a reason for the development of the chronic disease process. Significant glomerulomegaly appears universal in our cohort, found in 84% of the renal biopsies, and may be playing some role in the development of CKD over the multiple diseases present. Glomerulomegaly is known to be present in patients with morbid obesity. Two studies with similar design were performed using protocol biopsies taken during bariatric surgery in patients without overt renal disease. In a Spanish cohort of 95 patients with morbid obesity, 38% had glomerulomegaly compared to 2.5% of controls [12]. In Greek patients with BMI >50 kg/m2 , glomerular surface area was higher than controls, particularly in males [13]. Additionally, the authors noted that the glomerular surface area had a direct correlation with the body weight. However, none of the patients in either study manifested elevated creatinine or proteinuria of greater than 0.5 g per 24 h. Although in our study the biopsies were for-cause, typically proteinuria, an 84% rate of glomerulomegaly likely reflects both metabolic and hemodynamic changes. While the rate of glomerulomegaly was high in all of the patients, when categorized by obesity group, no significant difference in glomerular size between the mild and significant class of obesity was observed. This could indicate that the enlargement of glomeruli as a result of sustained hyperfiltration injury is not directly proportional to the increasing BMI and reaches a maximal size at lower levels of obesity, regardless of ethnic variabil-

ity and co-morbid conditions. This observation of limited ability of the glomerulus to adapt to progressive weight gain has not been reported in prior studies pertaining to ORG. There are several possible causes of glomerulomegaly postulated in obesity. The driving force is increased intraglomerular intracapillary pressure due to an increase in excretory load (reviewed in Ref. [14]). Afferent arteriolar vasodilatation and efferent arteriolar vasoconstriction results in hyperfiltration podocyte injury that leads to proteinuria. Glomerular hypertrophy exerts a conformational change in podocytes, which may become mechanically stressed or denuded from the glomerular basement membranes leading to adhesion to the Bowman capsule and segmental sclerosis [15,16]. Similar glomerular changes may also develop in the hypertrophic/hyperfiltration response seen in type 2 diabetes mellitus, a condition which may be present or imminent in many patients with obesity [17]. Glomerular hypertrophy has been associated with increased, subnephrotic proteinuria. In ORG or ORG with FSGS, proteinuria may appear early, and is sometimes the only manifestation of disease [4]. However, when other disease states are present in the setting of obesity, a higher magnitude of proteinuria has been observed. In a Japanese cohort, patients with IgA glomerulonephritis (IgAN) and obesity had larger glomeruli and more proteinuria than patients of normal weight [18]. The GBM were also thicker. Patients with IgAN and obesity not only have more proteinuria but also a more rapid progression to CKD than those who were not obese [7]. Proteinuria is known to be a clinical risk factor for progressive kidney disease in IgAN according to the Oxford classification data and prior studies [19]. Just as obesity may complicate IgAN, the majority of patients at our centre who underwent biopsy had numerous comorbidities. These comorbidities were sometimes related to obesity, such as diabetes, hypertension, hyperlipidemia, obstructive sleep apnea, whereas others were seemingly unrelated or superimposed (approximately 28% of cases): immune complex glomerulonephritides, ANCA vasculitis, and tubulointerstitial nephritis (Table 4). As patients with obesity are a challenging group due to multiple comorbidities, it is not unexpected that the pathology is also diverse. Prior case reports and studies generally have reported cases of isolated ORG in the absence of other conditions, imparting a selection bias with specific histologic association to obesity. However,

Please cite this article in press as: Salvatore SP, et al. Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone. Obes Res Clin Pract (2017), http://dx.doi.org/10.1016/j.orcp.2017.04.003

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S.P. Salvatore et al. Table 4 Renal pathology in kidney biopsies from patients with obesity, divided into caused by obesity, associated with obesity, or not related to obesity. Renal pathology in kidney biopsies from patients with obesity [•]Obesity caused — — Glomerulomegaly alone (obesity-related glomerulopathy) — Secondary FSGS (perihilar variant) [•]Obesity associated [—]Diabetic nephropathy — HTN-related vascular sclerosis (with or without OSA) — Co-morbidity associated conditions (examples: gout, medication or infection related diseases) [•]Not obesity related [—]Immune complex-related glomerular diseases (PIGN, MPGN, IgAN, MGN, LN, fibrillary GN, C1q nephropathy) — Podocytopathy (Primary FSGS, minimal change disease, collapsing glomerulopathy) — Tubulointerstitial nephritis — Acute tubular injury — Thrombotic microangiopathy Abbreviations: FSGS, focal segmental glomerulosclerosis; HTN, hypertension; OSA, obstructive sleep apnea; PIGN, postinfectious glomerulonephritis; MPGN, membranoproliferative glomerulonephritis; IgAN, IgA nephropathy; MGN, membranous glomerulonephritis; LN, lupus nephritis; GN, glomerulonephritis.

most patients have additional hypertension or diabetes or both. A small study in 1986 comprising a small subset of 17 patients with marked obesity found similar heterogeneous results with 9 cases of FSGS, 2 minimal change nephrotic syndrome, 5 DN, 1 membranoproliferative glomerulonephritis, and 1 mesangial immune complex disease not further classified [20]. Serum albumin levels in their patients were higher than in non-obese controls. However, in this small study, they excluded patients with diabetes treated with insulin, and glomerular size was not evaluated or at least not reported. In our cohort, serum albumin levels were important to help differentiate a superimposed immune complex glomerulonephritis from hyperfiltration-related disease alone (Albumin 2.7 g/dL in IC disease vs 3.7 in ORG or ORG-FSGS). A potential follow-up study to this one could evaluate the change in glomerular filtration rate on subsets of patients with additional diagnoses in addition to glomerulomegaly, either prospectively or retrospectively, to specifically evaluate the impact of obesity on renal function in patients with a secondary renal disease. Obtaining a renal biopsy in patients with obesity may be more challenging than in non-obese patients. The kidney biopsy specimens may be inadequate or nondiagnostic with routine ultrasound guided techniques and patients may need to undergo interventional radiology CT guided procedures. There is also a theoretically increased concern of bleeding, possibly undetected and/or harder to control, as well as post-biopsy infection in these patients. While this is not the primary focus of this study, increased biopsy related complications compared to nonobese patients were not seen. However, risks should be assessed on an individual basis.

Since 60% of our patients had secondary disease processes, many of which require a different therapy based on the biopsy results, we believe that kidney biopsy in patients with obesity should have similar indications to those in non-obese patients, with the possible exception of proteinuria of less than 1 g per 24 h in the absence of other features of nephrotic syndrome. Therefore, proposed criteria for when to obtain biopsy in patients with obesity include 1) proteinuria of greater than 1 g/24 h, 2) acute renal failure, 3) hematuria, and 4) in the setting of clinical renal disease with abnormal serologies. In several clinical and pathologic instances, ORG and DN may both be considered in the differential diagnosis for individual patients. The clinical symptoms may be similar with insulin resistance and other characteristics of the metabolic syndrome. They could both have proteinuria which could either be subnephrotic or nephrotic range, preserved albumin, as well as chronic renal insufficiency. Pathologically, both conditions can show glomerulomegaly due to hyperfiltration, secondary FSGS, and podocyte injury, usually manifesting as partial foot process effacement. Pathologically, diabetic nephropathy will usually show more mesangial matrix expansion as well as glomerular and tubular basement membrane thickening on biopsy. Being retrospective in nature, there are a few limitations. Patients’ weights, heights and BMIs were dependent on the clinical information received from the nephrologist around the time of the biopsy. BMI values were not available for all 6702 patients biopsied. In practice, as additional clinical information was solicited from nephrologists based on the biopsy findings, it is possible that the solicited rate of obesity may have been skewed for cases with larger glomeruli as compared to

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Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone biopsies with normal sized glomeruli where the weight may not have been specifically inquired. Varying degrees of glomerulomegaly may be seen secondary to numerous diseases, including immune complex glomerulonephritis, the hyperfiltration stage of DN, primary FSGS, or associated with decreased nephron numbers from premature birth or loss of renal mass. It is not possible to determine to what extent obesity is contributing to the glomerular diameter in concomitant immune complex mediated or diabetic glomerular change. Since prematurity and low birth weights are known to cause secondary glomerular hypertrophy, low number of total glomeruli or nephrons could contribute to the enlarged glomeruli for some patients in the study. Birth weight information could not be obtained. Additionally, the renal biopsies were done ‘for cause’ and therefore it is not clear what role glomerular size has in kidneys that do not require a kidney biopsy. Obesity is a global health risk and a known risk factor for CKD. ORG can present with proteinuria due to hyperfiltration, secondary glomerulomegaly and perihilar FSGS. Apart from the tendency to develop obesity related renal lesions and the complications of long standing obesity, increased susceptibility to infections and medication associated renal disease, this patient group may contract any renal disease as seen in the general population. The majority of the cases included in this cohort had other renal diseases with or without significant glomerulomegaly (40%), and obesity may be a factor for potentiating the course of other superimposed diseases.

Funding

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No funding was used for this research.

Disclosure

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The authors or authors’ families do not have any conflicts of interest. [11]

Acknowledgments The authors would like to thank Drs. Nathaniel Berman, Chandra B. Chandran, Chiam Charytan, Marilyn Galler, Vincent Graziano, C. Nathan Okechukwu, and Raymond Sherman for providing clinical information for the study. This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors.

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Please cite this article in press as: Salvatore SP, et al. Kidney disease in patients with obesity: It is not always obesity-related glomerulopathy alone. Obes Res Clin Pract (2017), http://dx.doi.org/10.1016/j.orcp.2017.04.003