Dataset Information

Single-Nephron GFR in Patients With Obesity-Related Glomerulopathy.

ABSTRACT: Introduction:Obesity-related glomerulopathy (ORG) is a slowly progressive kidney disease occurring in association with obesity. It is characterized histopathologically by glomerulomegaly, likely caused by single-nephron hyperfiltration that has not been demonstrated in humans because of technical difficulty in measuring single-nephron glomerular filtration rate (SNGFR) in the clinical setting. Methods:Total glomerular number per kidney, with or without global glomerulosclerosis, was estimated by the combination of cortical volume assessment via unenhanced computed tomography and biopsy-based stereology. Mean glomerular volume was calculated from the measured area of glomerular tufts. Both SNGFR and single-nephron urinary protein excretion (SNUPE) were estimated by dividing values for estimated glomerular filtration rate and urinary protein excretion by the number of nonsclerotic glomeruli. Living kidney donors were used as healthy controls. Results:A total of 48 ORG patients with average nonsclerotic glomerular numbers of 456,000 ± 235,000 per kidney were included. The values for SNGFR in ORG patients with chronic kidney disease (CKD) stages 1 and 2 were higher than for nonobese and obese controls (97 ± 43 vs. 59 ± 21 vs. 64 ± 21 nl/min, respectively, P = 0.001). Nonsclerotic glomerular number decreased with advancing stages of renal functional impairment. The presence of ORG with more advanced CKD stages was associated with lower SNGFR and marked elevation in SNUPE levels, with no difference in the mean glomerular volume between the stages. Conclusions:These results provide functional evidence for single-nephron hyperfiltration in patients with ORG, and identify compensatory failure to maintain effective SNGFR as a feature of advanced-stage ORG.

SUBMITTER: Okabayashi Y

PROVIDER: S-EPMC7403629 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Single-Nephron GFR in Patients With Obesity-Related Glomerulopathy.

Okabayashi Yusuke Y Tsuboi Nobuo N Sasaki Takaya T Haruhara Kotaro K Kanzaki Go G Koike Kentaro K Shimizu Akira A D'Agati Vivette D VD Yokoo Takashi T

Kidney international reports 20200523 8

<h4>Introduction</h4>Obesity-related glomerulopathy (ORG) is a slowly progressive kidney disease occurring in association with obesity. It is characterized histopathologically by glomerulomegaly, likely caused by single-nephron hyperfiltration that has not been demonstrated in humans because of technical difficulty in measuring single-nephron glomerular filtration rate (SNGFR) in the clinical setting.<h4>Methods</h4>Total glomerular number per kidney, with or without global glomerulosclerosis, w ...[more]

PMID: 32775821

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Project description:BackgroundAdiponectin is an adipocytokine that plays a key regulatory role in glucose and lipid metabolism in obesity. The prevalence of obesity has led to an increase in the incidence of obesity-related glomerulopathy (ORG). This study aimed to identify the protective role of adiponectin in ORG.MethodsSmall-interfering RNA (siRNA) against the gene encoding adiponectin was transfected into podocytes. The oxidative stress level was determined using a fluorometric assay. Apoptosis was analyzed by flow cytometry. The expressions of podocyte markers and pyrin domain containing protein 3 (NLRP3) inflammasome-related proteins were measured by qRT-PCR, immunohistochemistry, and Western blot.ResultsPodocytes treated with palmitic acid (PA) showed downregulated expressions of podocyte markers, increased apoptosis, upregulated levels of NLRP3 inflammasome-related proteins, increased production of inflammatory cytokines (IL-18 and IL-1β), and induced activation of NF-κB as compared to the vehicle-treated controls. Decreased adiponectin expression was observed in the serum samples from high fat diet (HFD)-fed mice. Decreased podocin expression and upregulated NLRP3 expression were observed in the kidney samples from high fat diet (HFD)-fed mice. Treatment with adiponectin or the NLRP3 inflammasome inhibitor, MCC950, protected cultured podocytes against podocyte apoptosis and inflammation. Treatment with adiponectin protected mouse kidney tissues against decreased podocin expression and upregulated NLRP3 expression. The knockout of adiponectin gene by siRNA increased ROS production, resulting in the activation of NLRP3 inflammasome and the phosphorylation of NF-κB in podocytes. Pyrrolidine dithiocarbamate, an NF-κB inhibitor, prevented adiponectin from ameliorating FFA-induced podocyte injury and NLRP3 activation.ConclusionsOur study showed that adiponectin ameliorated PA-induced podocyte injury in vitro and HFD-induced injury in vivo via inhibiting the ROS/NF-κB/NLRP3 pathway. These data suggest the potential use of adiponectin for the prevention and treatment of ORG.

Project description:Background:The objective of this study was to investigate obesity-related glomerulopathy (ORG) at a cellular, structural and transcriptomic level. Methods:Thirty Wistar rats were randomized into two groups: control rats(n=15), which were fed a standard diet(SD) and study rats(n=15), which were fed a high-fat diet (HFD). After 10 weeks, weight, parameters of kidney function, renal histological features, transcriptomic changes, miRNA and mRNA isolation were compared. Results:HFD gained more weight(55.8%) than SD(29.2%), p<0.001. Albuminuria was also significantly higher in HFD(10,384.04 ng/ml) compared with SD(5,845.45 ng/ml), p<0.001. HFD showed typical lesions of early stages of ORG, with a predominance of mesangial matrix increase (MMI) and podocyte hypertrophy (PH). All histologic lesions correlated with genes differentially expressed (DE) in kidneys of HFD group and PH, also correlated with specific miRNAs DE in the urine of HFD. The functional analysis showed 4 miRNAs DE in the kidneys of HFD group that negatively regulates PTEN gene, which promotes podocyte endocytosis of lipids in ORG. The electronic microscope confirmed the spaces of lipid vacuoles in the podocytes of HFD. Between those 4 miRNAs DE, miR-205 was also found to be upregulated in the urine of HFD group. Conclusions: Wistar rats fed a HFD developed early-stages of ORG, with a specific targetome of miRNAs and gene expression. The upregulation of miR-205 in kidney and its isolation in urine is associated with lipid endocytosis of podocytes, which could become a plausible biomarker of early-stages of ORG and open new avenues for future therapeutics research. Translational Statement: The findings of the basic research in this study can be replicated in human models of obesity. The results of the study on miRNA in humans may contribute to improving the understanding of the pathophysiology of obesity-related glomerulopathy, aiding in the search for early biomarkers, and exploring new therapeutic targets. Keywords: MicroRNA, Biomarker, targetome, obesity-related glomerulopathy, mesangial matrix increase, podocyte hypertrophy, Wistar rats

Project description:BACKGROUND:Obesity is increasing globally. Chronic kidney disease (CKD) is strongly associated with obesity. Kidney function is commonly estimated with equations using creatinine (such as CKD-EPI equation) which is a product of muscle metabolism. Decisions about categorizing CKD, planning modality of renal replacement therapies, and adjusting dosages of medications excreted by the kidneys are done using these equations. However, it is not well appreciated that creatinine-based equations may not accurately estimate kidney function in obese individuals. We plan a systematic review of diagnostic studies which will compare estimating equations to actual measured kidney function. METHODS:We will systematically search electronic bibliographic databases including MEDLINE, EMBASE, and the Cochrane Library with no restrictions on language or specific dates. The search terms will be adapted for the different databases using a combination of Medical Subject Heading and relevant keywords contained in titles and abstracts. Our preliminary search strategy using Cochrane, MEDLINE, and EMBASE databases have identified 190, 1246, and 1660 citations, respectively. For all studies selected, we will extract information on general study characteristics, study participant (age, sex, ethnicity, weight, height, BMI, BSA), type and protocol of reference standard utilized, the index test studied, the methodology of measurement of index test, categories of GFR, the proportion of eGFR within 10, 20, 30, 40, and 50% of measured GFR, and bias between eGFR and measured GFR. If the quality of methods and risk of bias are adequate, we will perform a meta-analysis. We will assess the heterogeneity using the χ2 and the I2 statistics to examine whether the estimates from studies included could be pooled. Sensitivity and multivariate meta-regression analyses will be performed to assess the effects of clinical factors and socio-demographic characteristics reported in included studies on the meta-analytic estimates. All analysis will be performed using the Comprehensive Meta-analysis software. DISCUSSION:This systematic review might help to inform clinicians on the best equation to use in patients with obesity and CKD for staging of CKD and for medication dosing. If no equation is deemed suitable, this review will form a basis for future studies of GFR in obese individuals. SYSTEMATIC REVIEW REGISTRATION:PROSPERO CRD42018104345.

Dataset Information

Single-Nephron GFR in Patients With Obesity-Related Glomerulopathy.

Publications

Single-Nephron GFR in Patients With Obesity-Related Glomerulopathy.

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