Obesity-related Glomerulopathy Research Articles

Wen-Shen-Jian-Pi-Hua-Tan decoction protects against early obesity-related glomerulopathy by improving renal bile acid composition and suppressing lipogenesis, inflammation, and fibrosis

BackgroundObesity is an independent predictor of chronic kidney disease (CKD) development and may directly lead to kidney lesions such as obesity-related glomerulopathy (ORG) which might play a vital pathogenic role in obese patients with CKD. Wen-Shen-Jian-Pi-Hua-Tan decoction (WSHT) has been clinically used for the treatment of obesity and obesity-related metabolic diseases for years. However, the renoprotective effects and potential mechanism of action of WSHT against ORG remain unknown. PurposeThis study aimed to explore the potential effect of WSHT on ORG and reveal its mechanisms in high-fat diet (HFD)-induced obese rats. MethodsAn animal model of early stage ORG was established using HFD-induced obese rats. After treatment with WSHT for 6 weeks, an integrated metabolomics and molecular biology strategy was utilized to illustrate the effects and mechanism of WSHT on ORG. First, UPLC-ESI-MS/MS-based targeted metabolomics was used to analyze renal bile acid (BA) levels. Biochemical, histological, and immunofluorescence assays; electron microscopy; and western blotting were performed to evaluate the efficacy of WSHT against ORG and its underlying mechanisms in vivo. ResultsOur results showed that an HFD led to hyperlipidemia, proteinuria, renal lipid deposition, effacement of podocyte foot processes, and increased expression of proinflammatory factors and profibrotic growth factors in ORG rats. In addition, an HFD decreased the levels of renal BAs such as cholic acid, chenodeoxycholic acid, and lithocholic acid. After 6 weeks of treatment, WSHT markedly attenuated dyslipidemia and reduced body, kidney and epididymal fat weights in ORG rats. WSHT also significantly increased BA levels, suggesting that it altered BA composition; the effects of BAs are closely associated with farnesoid X receptor (FXR) activation. WSHT alleviated fat accumulation, podocyte loss and proteinuria, and reduced the expression of proinflammatory cytokines and profibrotic growth factors in the kidneys of ORG rats. Finally, WSHT remarkably upregulated the renal expression of FXR and salt-induced kinase 1 and blocked the renal expression of sterol regulatory element–binding protein-1c and its target genes. ConclusionWSHT attenuated early renal lesions in ORG rats by improving renal BA composition and suppressing lipogenesis, inflammation and fibrosis. This study develops a new way to alleviate obesity-induced renal damages.

Functional and morphological renal changes in a Göttingen Minipig model of obesity-related and diabetic nephropathy

Obesity-related glomerulopathy and diabetic nephropathy (DN) are serious complications to metabolic syndrome and diabetes. The purpose was to study effects of a fat, fructose and cholesterol-rich (FFC) diet with and without salt in order to induce hypertension on kidney function and morphology in Göttingen Minipigs with and without diabetes. Male Göttingen Minipigs were divided into 4 groups: SD (standard diet, n = 8), FFC (FFC diet, n = 16), FFC-DIA (FFC diet + diabetes, n = 14), FFC-DIA + S (FFC diet with extra salt + diabetes, n = 14). Blood and urine biomarkers, glomerular filtration rate (GFR), blood pressure (BP) and resistive index (RI) were evaluated after 6–7 months (T1) and 12–13 months (T2). Histology, electron microscopy and gene expression (excluding FFC-DIA + S) were evaluated at T2. All groups fed FFC-diet displayed obesity, increased GFR and RI, glomerulomegaly, mesangial expansion (ME) and glomerular basement membrane (GBM) thickening. Diabetes on top of FFC diet led to increased plasma glucose and urea and proteinuria and tended to exacerbate the glomerulomegaly, ME and GBM thickening. Four genes (CDKN1A, NPHS2, ACE, SLC2A1) were significantly deregulated in FFC and/or FFC-DIA compared to SD. No effects on BP were observed. Göttingen Minipigs fed FFC diet displayed some of the renal early changes seen in human obesity. Presence of diabetes on top of FFC diet exacerbated the findings and lead to changes resembling the early phases of human DN.

Clinicopathological Characteristics and Risk Factors for Rapid eGFR Decline in Chinese Patients with Biopsy-Proven Obesity-Related Glomerulopathy.

To investigate the clinicopathologic features and the related risk factors for rapid estimated glomerular filtration rate (eGFR) decline in Chinese obesity-related glomerulopathy (ORG) patients. A total of 63 ORG patients, who underwent a renal biopsy and received follow-up for at least 12 months, were recruited in our study. These patients were classified as rapid decliners and slow decliners based on the eGFR slope value (-5.0 mL/min/1.73 m2/year). Logistic regression analysis was used to determine the risk factors for rapid eGFR decline. Of the 63 ORG patients, 48 (76.2%) were male, the mean age was 38.7 ± 9.0 years, the median of urinary protein excretion was 1.62 g/24 h, 27.0% of them had nephrotic-range proteinuria, while hypoalbuminemia was observed in 7.9% of them. The incidence of obvious hypertriglyceridemia, hypertension, glucose dysmetabolism and hyperuricemia were 71.4%, 60.3%, 36.5% and 27.0%, respectively. 13 (20.6%) patients became rapid decliners during the median 45 months of follow-up. Their mean BMI was 31.8 ± 3.6 kg/m2, the median of baseline eGFR and urinary protein excretion were 71.8 (range of 30.5-118.2) mL/min/1.73 m2/year and 3.57 g/24 h, respectively. Multivariate logistic regression analysis showed that smoking (OR 9.205, 95% CI 1.704-49.740, P = 0.01), hyperuricemia (OR 5.541, 95% CI 1.079-28.460, P = 0.04) and nephrotic-range proteinuria (OR 6.128, 95% CI 1.311-28.637, P = 0.021) were the independent risk factors for rapid eGFR decline. Chinese ORG patients were more likely to have clinical characteristics with hypertriglyceridemia, hypertension and hyperuricemia, and mild to severe degrees of urinary protein excretion at diagnosis, while patients with nephrotic-range proteinuria lacked hypoalbuminemia and hypercholesterolemia. Smoking, hyperuricemia and nephrotic-range proteinuria were independent risk factors for rapid eGFR decline in ORG patients.

Obesity-related glomerulopathy in children: connecting pathophysiology to clinical care.

Obesity has continued to emerge as a worldwide pandemic and has been associated with a significant increase in associated comorbidities. These include well-known conditions such as hypertension and diabetes, as well as lesser-known conditions such as obesity-related glomerulopathy (ORG). The main etiology of ORG is podocyte damage, but contributing theories include dysfunctional renin-angiotensin-aldosterone system activation, hyperinsulinemia and lipid deposition. Recent advances have made strides in understanding the complex pathophysiology of ORG. The key to treating ORG is weight loss and proteinuria reduction. Lifestyle modification, pharmacological interventions and surgery are mainstays of management. A special focus on obese children is required, as childhood obesity tracks into adulthood and primary prevention is key. In this review we discuss the pathogenesis, clinical features and established and newer treatment modalities of ORG.

The Beneficial Effects of Bariatric-Surgery-Induced Weight Loss on Renal Function.

Obesity represents an independent risk factor for the development of chronic kidney disease (CKD), leading to specific histopathological alterations, known as obesity-related glomerulopathy. Bariatric surgery is the most effective means of inducing and maintaining sustained weight loss. Furthermore, in the context of bariatric-surgery-induced weight loss, a reduction in the proinflammatory state and an improvement in the adipokine profile occur, which may also contribute to the improvement of renal function following bariatric surgery. However, the assessment of renal function in the context of obesity and following marked weight loss is difficult, since the formulas adopted to estimate glomerular function use biomarkers whose production is dependent on muscle mass (creatinine) or adipose tissue mass and inflammation (cystatin-c). Thus, following bariatric surgery, the extent to which reductions in plasma concentrations reflect the actual improvement in renal function is not clear. Despite this limitation, the available literature suggests that in patients with hyperfiltration at baseline, GFR is reduced following bariatric surgery, whereas GFR is increased in patients with decreased GFR at baseline. These findings are also confirmed in the few studies that have used measured rather than estimated GFR. Albuminuria is also decreased following bariatric surgery. Moreover, bariatric surgery seems superior in achieving the remission of albuminuria and early CKD than the best medical treatment. In this article, we discuss the pathophysiology of renal complications in obesity, review the mechanisms through which weight loss induces improvements in renal function, and provide an overview of the renal outcomes following bariatric surgery.

ACE2 deficiency exacerbates obesity-related glomerulopathy through its role in regulating lipid metabolism

Obesity-related glomerulopathy is a secondary glomerular disease and its incidence has been increased globally in parallel with the obesity epidemic. ORG emerged as a growing cause of end-stage renal disease in recent years. Unbalanced production of adipokines at the adipose tissue as well as low-grade inflammatory processes play central roles in ORG progression. ORG mouse model with ACE2-knockout was generated and kidney injury was evaluated by biochemistry and histological staining assays. Protein and mRNA expressions were quantified by ELISA, western blot or qRT-PCR methods. ACE2 deficiency aggravated ORG-related renal injuries and stimulated both lipid accumulation and inflammatory responses. Further, Nrf2 pathway was deactivated upon ACE2-knockout. By contrast, ACE2 overexpression reactivated Nrf2 pathway and ameliorated ORG symptoms by decreasing fat deposition and reducing inflammatory responses. Our data demonstrated that ACE2 exerted the beneficial effects by acting through Nrf2 signaling pathway, suggesting the protective role of ACE2 against lipid accumulation and inflammatory responses in ORG pathogenesis.

Novel Insights in the Physiopathology and Management of Obesity-Related Kidney Disease

Obesity is recognized as an independent risk factor for the development of kidney disease, which has led to the designation of obesity-related glomerulopathy (ORG). Common renal features observed in this condition include glomerular hypertrophy, glomerulosclerosis, haemodynamic changes and glomerular filtration barrier defects. Additionally, and although less studied, obesity-related kidney disease also involves alterations in renal tubules, including tubule hypertrophy, lipid deposition and tubulointerstitial fibrosis. Although not completely understood, the harmful effects of obesity on the kidney may be mediated by different mechanisms, with alterations in adipose tissue probably playing an important role. An increase in visceral adipose tissue has classically been associated with the development of kidney damage, however, recent studies point to adipose tissue surrounding the kidney, and specifically to the fat within the renal sinus, as potentially involved in the development of ORG. In addition, new strategies for the treatment of patients with obesity-related kidney disease are focusing on the management of obesity. In this regard, some non-invasive options, such as glucagon-like peptide-1 (GLP-1) receptor agonists or sodium–glucose cotransporter-2 (SGLT2) inhibitors, are being considered for application in the clinic, not only for patients with diabetic kidney disease but as a novel pharmacological strategy for patients with ORG. In addition, bariatric surgery stands as one of the most effective options, not only for weight loss but also for the improvement of kidney outcomes in obese patients with chronic kidney disease.

Obesity and chronic kidney disease: A current review.

Obesity poses significant challenges to healthcare globally, particularly through its bi-directional relationship with co-morbid metabolic conditions such as type 2 diabetes and hypertension. There is also emerging evidence of an association between obesity and chronic kidney disease (CKD) which is less well characterized. A literature search of electronic libraries was conducted to identify and present a narrative review of the interplay between obesity and CKD. Obesity may predispose to CKD directly as it is linked to the histopathological finding of obesity-related glomerulopathy and indirectly through its widely recognized complications such as atherosclerosis, hypertension, and type 2 diabetes. The biochemical and endocrine products of adipose tissue contribute to pathophysiological processes such as inflammation, oxidative stress, endothelial dysfunction, and proteinuria. The prevention and management of obesity may prove critical in counteracting both the development and advancement of CKD. Moreover, measures of abdominal adiposity such as waist circumference, are generally associated with worse morbidity and mortality in individuals receiving maintenance hemodialysis. Obesity is a risk factor for the onset and progression of CKD and should be recognized as a potential target for a preventative public health approach to reduce CKD rates within the general population. Future research should focus on the use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors in patients with CKD and obesity due to their multi-faceted actions on major outcomes.

MO228: Clinical Features and Obesity Impact on Chronic Kidney Disease Progression in Patients with Glomerular Diseases

Abstract BACKGROUND AND AIMS The kidney disease secondary to obesity is obesity-related glomerulopathy characterized by the following: glomerulomegalia, progressive glomerulosclerosis, proteinuria and progression of renal failure. The aims of the present study were to evaluate the clinical features and 2 years outcome in obese and non-obese patients with glomerular diseases. METHOD This study included 125 patients with renal biopsy-proven glomerular diseases: minimal change disease, FSGS, IgA nephropathy, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mean age 46.93 ± 15.10 years). There were 63 obese (BMI ≥ 27 kg/m2) and 62 non-obese (BMI <27 kg/m2) patients. The serum concentration of protein, albumin, cholesterol, trygliceride, creatinine and daily proteinuria were measured at the time of kidney biopsy, 6, 12 and 24 months after the biopsy. The estimated glomerular filtration rate (eGFR) was calculated according to the equations: Cockcroft–Gault#(Cockcroft–Gault–BMI < 27 kg/m2 Cockcroft–GaultLBW-BMI ≥27kg/m2) and Chronic Kidney Disease Epidemiology Collaboration Equation (CKD–EPI). RESULTS At the time of kidney biopsy, the obese had significantly lower eGFR calculated by formulas: Cockcroft–Gault# (62.29 ± 27.53 versus 96.30 ± 38.80 mL/min) and CKD–EPI (71.52 ± 31.15 versus 86.36 ± 27.63 mL/min/1.73 m2), significantly higher daily proteinuria (6.11 ± 4.94 versus 4.47 ± 4.95 g/day), creatinine (122.14 ± 87.56 versus 93.66 ± 41.40 μmol/L), trygliceride (2.76 ± 1.39 versus 2.20 ± 1.30 mmol/L) in comparison with non-obese. There was statistically significant difference in eGFR calculated by Cockcroft-Gault# 6 months (t = 5.353, P < .01), 12 (t = 5.234, P < .01) and 24 months (t = 2.329, P < .05) after the kidney biopsy between obese and non-obese. The reduction in eGFR Cockcroft–Gault# after 24 months compared with baseline in obese was 14.7%, in non-obese 13.7% (P > 0.05). After 12 months follow-up significantly higher percentage of non-obese patients reached complete remission (59.4% versus 35.3%) compared with obese (χ2 = 4.548), but after 24 months there were no significant difference. CONCLUSION Obese patients at the time of kidney biopsy, 6, 12 and 24 months later had the significant lower eGFR compared to non-obese. After 24 months follow-up there was no significant difference in percentage of patients with complete remission between two groups, although after 12 months follow-up a significantly smaller number of obese were in complete remission.

High-calorie diet results in reversible obesity-related glomerulopathy in adult zebrafish regardless of dietary fat.

Obesity is a risk factor for the development of kidney disease. The role of diet in this association remains undetermined, in part due to practical limitations in studying nutrition in humans. In particular, the relative importance of calorie excess versus dietary macronutrient content is poorly understood. For example, it is unknown if calorie restriction modulates obesity-related kidney pathology. To study the effects of diet-induced obesity in a novel animal model, we treated zebrafish for 8 wk with diets varied in both calorie and fat content. Kidneys were evaluated by light and electron microscopy. We evaluated glomerular filtration barrier function using a dextran permeability assay. We assessed the effect of diet on podocyte sensitivity to injury using an inducible podocyte injury model. We then tested the effect of calorie restriction on the defects caused by diet-induced obesity. Fish fed a high-calorie diet developed glomerulomegaly (mean: 1,211 vs. 1,010 µm2 in controls, P = 0.007), lower podocyte density, foot process effacement, glomerular basement membrane thickening, tubular enlargement (mean: 1,038 vs. 717 µm2 in controls, P < 0.0001), and ectopic lipid deposition. Glomerular filtration barrier dysfunction and increased susceptibility to podocyte injury were observed with high-calorie feeding regardless of dietary fat content. These pathological changes resolved with 4 wk of calorie restriction. Our findings suggest that calorie excess rather than dietary fat drives obesity-related kidney dysfunction and that inadequate podocyte proliferation in response to glomerular enlargement may cause podocyte dysfunction. We also demonstrate the value of zebrafish as a novel model for studying diet in obesity-related kidney disease.NEW & NOTEWORTHY Obesity is a risk factor for kidney disease. The role of diet in this association is difficult to study in humans. In this study, zebrafish fed a high-calorie diet, regardless of fat macronutrient composition, developed glomerulomegaly, foot process effacement, and filtration barrier dysfunction, recapitulating the changes seen in humans with obesity. Calorie restriction reversed the changes. This work suggests that macronutrient composition may be less important than total calories in the development of obesity-related kidney disease.

Prevalence of Obesity-Related Glomerulopathy in Morbidly Obese Patients at Cairo University Tertiary Hospital

BACKGROUND: Obesity has been reported to be a risk factor for chronic kidney disease and albuminuria. Obesity-related glomerulopathy (ORG) usually has a gradual onset, with microalbuminuria or clinically dominant proteinuria as the primary manifestation, with or without impaired renal function, and a small number of patients manifesting with microscopic hematuria or nephrotic syndrome. AIM: The present study aimed to evaluate the prevalence of ORG in morbidly obese patients and its impact on renal function. PATIENTS AND METHODS: This is a descriptive cross-sectional study that included patients with morbid obesity who visited the bariatric clinic in our institution during the period from October 2019 to February 2021. Patients who had no history of diabetes mellitus (DM) or hypertension underwent blood pressure measurement, assessment for 24-h urinary albumin to detect patients with laboratory-based ORG, kidney function tests, urine analysis and HbA1c, and examination by abdominal sonogram focused on both kidneys. Patients with asymptomatic micro or macroalbuminuria were recruited to the study. RESULTS: The total number of patients screened during the study period was 1,045, out of whom 100 patients were eligible for the study according to the inclusion and exclusion criteria, denoting an albuminuria prevalence of 9.5% and there is no statistically significant relationship between this albuminuria and age, gender, and BMI. CONCLUSION: ORG is a rising problem in the field of morbid obesity management, the current study shows that the prevalence of ORG is 9.5% in our screened cohort.

Effect of Normalizing eGFR to Standard Body Surface Area on Rates of Obesity-Related Hyperfiltration among Diverse Female Adolescents

Introduction: Obesity is more prevalent among African American individuals, increasing the risk for cardiorenal morbidity. We explored interactions between race, BMI, and the risk of hyperfiltration associated with obesity-related glomerulopathy (ORG). Methods: We created a cohort of female adolescents from electronic health records. Glomerular filtration rate (GFR) was estimated in two ways: (A) using standard age recommended formulae and (B) absolute eGFR – adjusted to individual body surface area (BSA). Multivariate logistic regression was used to analyze the contribution of risk factors for ORG-associated hyperfiltration defined as 135 mL/min/1.73 m² or 135 mL/min, according to BMI group. Pearson’s coefficient was used to assess correlation with creatinine clearance (CrCl). Results: The final cohort included 7,315 African American and 15,102 non-African American adolescent females, with CrCl available for internal validation in 207 non-African American and 107 African American individuals. Compared with non-African American ethnicity, African American ethnicity was independently associated with a lower risk of hyperfiltration with standard eGFR calculations (odds ratio [OR] = 0.57, 95% confidence intervals [CIs] 0.45–0.71), associations were enhanced for absolute eGFR (OR = 0.81, 95% CI 0.69–0.95). Absolute eGFR values agreed better with CrCl (r = 0.63), compared to standard indexed eGFR formulae. Proportions classified as hyperfiltration changed with standard versus absolute eGFR; they were similar across BMI groups with the first and reflected obesity with the later. Conclusion: Adjusting to individual BSA improves estimation of GFR and identification of obesity-related hyperfiltration. More accurate and earlier ascertainment of obesity-related hyperfiltration may have important consequences for preservation of kidney function.

Obesity-related glomerulopathy: Current approaches and future perspectives.

SummaryObesity‐related glomerulopathy (ORG) is a silent comorbidity which is increasing in incidence as the obesity epidemic escalates. ORG is associated with serious health consequences including chronic kidney disease, end‐stage renal disease (ESRD), and increased mortality. Although the pathogenic mechanisms involved in the development of ORG are not fully understood, glomerular hemodynamic changes, renin‐angiotensin‐aldosterone system (RAAS) overactivation, insulin‐resistance, inflammation and ectopic lipid accumulation seem to play a major role. Despite albuminuria being commonly used for the non‐invasive evaluation of ORG, promising biomarkers of early kidney injury that are emerging, as well as new approaches with proteomics and metabolomics, might permit an earlier diagnosis of this disease. In addition, the assessment of ectopic kidney fat by renal imaging could be a useful tool to detect and evaluate the progression of ORG. Weight loss interventions appear to be effective in ORG, although large‐scale trials are needed. RAAS blockade has a renoprotective effect in patients with ORG, but even so, a significant proportion of patients with ORG will eventually progress to ESRD despite therapeutic efforts. It is noteworthy that certain antidiabetic agents such as sodium‐glucose cotransporter 2 inhibitors (SGLT2i) or glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) could be useful in the treatment of ORG through different pleiotropic effects. In this article, we review current approaches and future perspectives in the care and treatment of ORG.

Retraction for Su et al., SHP-1 aggravates obesity-related glomerulopathy and palmitic acid-induced podocyte injury via regulating the PI3K/Nrf2/SIRT1 axis.

Obesity-related glomerulopathy (ORG) is described as obesity-driven glomerular hypertrophy. SHP-1 is associated with glomerular pathology. This study is designed to investigate the molecular mechanism of Src homology region 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) in ORG and palmitic acid (PA)-induced podocyte injury. After analysis of clinical samples, an ORG mouse model was established via high-fat diet feeding, followed by detection of physiological and biochemical indexes, glomerular area, and inflammatory factor levels. In vitro cell model was established using (PA). Cell viability, apoptosis, and lipid deposition were determined. SHP-1, nuclear factor-erythroid 2-related factor 2 (Nrf2), phosphatidylinositol 3-kinase (PI3K), and sirtuin 1 (SIRT1) expressions were measured, and their binding relationships were testified. SHP-1 was highly expressed in ORG patients and was associated with renal function indexes. Silencing SHP-1 alleviated symptoms of ORG mice and PA-induced podocyte injury in vitro. SHP-1 bound to PI3K to inhibit PI3K phosphorylation and Nrf2 expression. Nrf2 bound to the SIRT1 promoter to promote SIRT1 transcription. Inhibition of Nrf2 or SIRT1 reversed the role of silencing SHP-1 in podocyte injury. Overall, SHP-1 was highly expressed in ORG and inhibited PI3K phosphorylation to block activation of Nrf2/SIRT1, thereby aggravating ORG-induced renal injury in vivo and PA-induced podocyte injury in vitro.

Chronic kidney disease predictors in obese adolescents

BackgroundGlomerular hyperfiltration, initiating development of obesity-related glomerulopathy, results in an enlargement of the glomeruli and unsealing of the filtration barrier. It can be followed by adaptive focal segmental glomerulosclerosis and chronic kidney disease (CKD). The aim of the study was to determine the expression pattern of lipid metabolism and selected kidney damage markers in obese adolescents and to identify potential factors which can predict CKD.MethodsThe study group consisted of 142 adolescents with a BMI z-score > 2. Sixty-two healthy and normal-weight individuals served as controls. The factors associated with the rate of glomerular filtration in obese adolescents were assessed by linear regression methods using univariate and multivariate analyses. The risk of developing CKD was estimated using the Fisher’s exact test.ResultsThe study group was divided into “elevated,” “normal,” and “decreased” glomerular filtration rate (GFR) patients. Increased urine galectin-3 (Gal-3) concentration was diagnosed in all patients. “Decreased GFR” subjects expressed increased urine concentration of neutrophil gelatinase-associated lipocalin (NGAL) and daily megalin excretion. Thirty-nine study participants developed CKD. Increased uric acid (UA) concentration was associated with CKD development both in “normal” and “decreased GFR” patients. Additionally, in “normal” GFR patients, increased concentrations of cholesterol (Ch), triglycerides (TG), and NGAL were associated with CKD.ConclusionsIncreased serum concentrations of Ch, TG, and UA and increased urine concentration of NGAL might predict CKD development in obese adolescents with normal and decreased GFR.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Obesity Related Glomerulopathy in Adolescent Women: The Effect of Body Surface Area.

Adolescent obesity, a risk factor for cardiorenal morbidity in adulthood, has reached epidemic proportions. Obesity-related glomerulopathy (ORG) has an early reversible stage of hyperfiltration. Age-appropriate formulae for eGFR, which are standardized to ideal body surface area (BSA) and provide assessment of kidney function in ml/min/1.73 m2, may underestimate prevalence of early ORG. We investigated whether adjusting eGFR to actual BSA more readily identifies early ORG. We studied a cohort of 22,417 young individuals, aged 12-21 years, from a New York metropolitan multi-institutional electronic health records clinical database. eGFR was calculated in two ways: BSA-standardized eGFR, and absolute eGFR. Hyperfiltration was defined above a threshold of 135 ml/min per 1.73 m2 or 135 ml/min, respectively. The prevalence of hyperfiltration according to each formula was assessed in parallel to creatinine clearance. Serum creatinine values and hyperfiltration prevalence according to BSA-standardized eGFR were similar, 13%-15%, across body mass index (BMI) groups. The prevalence of hyperfiltration determined by absolute eGFR differed across BMI groups: underweight, 2%; normal weight, 6%; overweight, 17%; and obese, 31%. This trend paralleled the rise in creatinine clearance across BMI groups. Absolute eGFR more readily identifies early ORG than the currently used formulae, which are adjusted to a standardized BSA and are not representative of current population BMI measures. Using absolute eGFR in clinical practice and research may improve the ability to identify, intervene, and reverse early ORG, which has great importance with increasing obesity rates.

Period circadian clock 3 inhibits palmitic acid-induced oxidative stress and inflammatory factor secretion in podocytes.

High fat-induced podocyte injury is one of the important factors leading to obesity related nephropathy (ORG), but the mechanism is not clear. This study aims to explore the mechanism of period circadian clock 3 (PER3) in the oxidative stress and inflammation induced by palmitic acid (PA) in podocytes. The C57BL/6J mice were fed with chow and high-fat diet for 16 weeks. The PER3 expression in kidney tissues were detected in the normal body weight group and the obesity group. The PER3 mRNA and protein expression were detected after the podocytes were induced with different concentrations (0, 50, 150 and 300 μmol/L) of PA for 48 h. The PER3 mRNA and protein expression were detected after the podocytes were induced with 150 μmol/L PA for 0, 24, 36, and 48 h. Triglyceride (TG) levels were examined in the PA group, the adenovirus (ad)-PER3+PA group, and the siRNA-PER+PA group after the podocytes were transfected by Ad-PER3 or small interfering RNA (siRNA)-PER3 for 48 h and subsequently were induced with 150 μmol/L PA for 48 h. The differential gene expression was detected using RNA sequencing (RNA-seq) after podocytes were transfected by siRNA-PER3 (siRNA-PER3 group) and siRNA-control (siRNA-control group), respectively. The mRNA levels of nephrin, podocin, podocalyxin, podoplanin, superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPX1), catalase (CAT), and the levels of malondialdehyde (MDA), glutathione (GSH), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and interleukin-2 (IL-2) were detected after podocytes were transfected with Ad-PER3 or Ad-control for 48 h and then they were induced by 150 μmol/L PA for 48 h. The PER3 was down-regulated in the obesity group compared with the normal body weight group (P<0.05), and the PER3 was significantly down-regulated after the podocytes were treated with 150 μmol/L for 48 h compared with 0, 24, and 36 h (all P<0.01). The TG contents were significantly decreased in the Ad-PER3+PA group compared with the PA group (P<0.05). On the contrary, TG contents were increased in the siRNA-PER3+PA group compared with the PA group (P<0.05). The RNA-seq results showed that: compared with the siRNA-control group, the differential genes in the siRNA-PER3 group were enriched in different pathways including oxidative phosphorylation, TNF signaling pathway, extracellular matrix receptor interaction, fatty acid metabolism, and fatty acid degradation (all P<0.05). The podocyte marker genes (nephrin, podocin, podocalyxin and podoplanin), oxidative stress (SOD1, GPX1, CAT and GSH), and inflammation factors (TNF-α, IL-6, IL-1β and IL-2) were significantly down-regulated in the Ad-PER3+PA group compared with the PA group (all P<0.05). PER3 can decrease the PA-induced oxidative stress and inflammatory factor secretion via inhibiting the lipogenesis in podocytes.

Abstract 10245: Egfr Calculation Without the Race Coefficient Obscures Obesity Related Glomerulopathy in Female Adolescents

Introduction: Obesity is more prevalent among minorities, increasing the risk for cardio-renal morbidity. Hypothesis: We explored interactions between race, body mass index (BMI), and the risk of hyperfiltration associated with Obesity Related Glomerulopathy (ORG). Methods: We created a cohort of women and girls ages 12-21 from the New York Metropolitan area using their longitudinal electronic health records (EHR). Glomerular filtration rate (GFR) was estimated in two ways: I) using the standard age recommended formulae, and II) eGFRr -without a race-specific coefficient. Multivariate logistic regression was used to analyze the relative contribution of risk factors for ORG associated hyperfiltration, defined by a threshold of ≥135ml/min/1.73m 2 . Results: 7315 Black and 15,102 non-Black women and girls were evaluated for kidney function in parallel to body measures. Hyperfiltration was more frequent in Black compared to non-Black individuals when using standard eGFR but was lower after eliminating the race-specific coefficient. Black race was independently associated with hyperfiltration with standard eGFR calculation (OR=3.43, 95% CI 2.95-3.99) but the association was reversed when estimated by eGFRr (OR=0.56, 95% CI 0.45-0.70). Risk of hyperfiltration was higher for Black individuals across all BMI strata with standard eGFR estimates, but when estimated as eGFRr hyperfiltration risk was reduced for overweight (OR =0.70 95% CI 0.54-0.89) and obese (OR=0.47, 95% CI 0.37-0.60) black participants. Simultaneous removal of the race coefficient and adjustment to individual BSA provided the most accurate estimation of GFR compared to creatinine clearance. Conclusions: Estimated CKD prevalence among Black adolescents and young adults increases following removal of the race coefficient while fewer have evidence of ORG. Removing the race coefficient should be accompanied by adjustment to individual BSA in order to estimate more realistically GFR.

Obesity-Related Glomerulopathy: From Mechanism to Therapeutic Target.

Obesity-related glomerulopathy (ORG) is a secondary glomerular disease caused by obesity, with clinical manifestations such as proteinuria and glomerulomegaly. Currently, the high incidence of obesity brings a change in the spectrum of kidney diseases across the globe, including China. ORG has become another important secondary nephropathy leading to end-stage renal disease (ESRD), and its incidence has increased significantly. This trend is bound to bring about a serious socioeconomic burden. Therefore, it is urgent to study its pathogenesis and intervention measures. Currently, the occurrence and development mechanisms in ORG are complicated by many factors, which are still unclear. In the past 20 years, with the continuous intensive research on mechanisms such as hypoxia in the metabolic process, immune inflammation, and pyroptosis, there have been new advances in the mechanism of ORG, especially the important role of inflammation in podocyte injury and its impact on the progress of ORG. Here, we briefly review the possible pathogenic role of the inflammasome in the podocyte damage in ORG and summarize the possible therapeutical strategies targeting inflammasome.

Alpha-1 Acid Glycoprotein and Podocin mRNA as Novel Biomarkers for Early Glomerular Injury in Obese Children.

Introduction: Obesity, which is a serious problem in children, has a negative impact on many organs, including kidneys, and obesity-related glomerulopathy (ORG) is an increasingly common cause of ESKD (end-stage kidney disease) in adults. Early-detected and -treated glomerular lesions are reversible, so it is important to find a useful marker of early damage. The study aimed to evaluate the albumin-to-creatinine ratio (ACR), urinary alpha-1-acid glycoprotein (α1-AGP), and mRNA of podocyte-specific proteins as indicators of glomerular injury and their relationship with the degree of obesity and metabolic disorders. Materials and Methods: A total of 125 obese children and 33 healthy peers were enrolled. Patients were divided into two groups, depending on SDS BMI values. ACR, α1-AGP, mRNA expression of nephrin, synaptopodin, podocin, and C2AP protein in urine sediment were measured. Results: ACR values did not differ between groups and were within the normal range. α1-AGP and mRNA expression were significantly higher in obese children compared with controls. mRNA expression of the remaining podocyte proteins was similar in both groups. No significant differences concerning all examined parameters were found depending on the degree of obesity. There was a positive significant correlation between α1-AGP and ACR. Conclusions: Increased α1-AGP before the onset of albuminuria suggests its usefulness as a biomarker of early glomerular damage in obese children. An increased podocin mRNA expression also indicates podocyte damage and may be linked to ORG development. The lack of increase in expression of other podocyte proteins suggests that podocin mRNA may be a more specific and sensitive biomarker. The degree of obesity has no impact on the tested parameters, but further studies are needed to confirm it.