Integrated miRNA-mRNA Analysis Reveals Critical miRNAs and Targets in Diet-Induced Obesity-Related Glomerulopathy.

This study aimed to investigate obesity-related glomerulopathy (ORG) at cellular, structural, and transcriptomic levels. Thirty Wistar rats were randomized into two groups: 15 rats were fed with a standard diet (SD-rats), and 15 rats were fed with a high-fat diet (HFD-rats). After 10 weeks, the weight, kidney function, histological features, and transcriptomic changes were assessed. HFD-rats gained significantly more weight (55.8% vs. 29.2%; p < 0.001) and albuminuria (10,384.04 ng/mL vs. 5845.45 ng/mL; p < 0.001) compared to SD-rats. HFD-rats exhibited early stages of ORG, with predominant mesangial matrix increase and podocyte hypertrophy (PH). These lesions correlated with differentially expressed (DE) genes and miRNAs. Functional analysis showed that miR-205, which was DE in both the kidneys and urine of HFD-rats, negatively regulated the PTEN gene, promoting lipid endocytosis in podocytes. The downregulation of PTEN was proved through a higher PTEN/nephrin ratio in the SD-rats and the presence of lipid vacuoles in HFD-podocytes. This study has found a specific targetome of miRNAs and gene expression in early stages of ORG. Also, it emphasizes the potential value of miR-205 as a urinary biomarker for detecting podocyte injury in ORG, offering a tool for early diagnosis, and opening new avenues for future therapeutic research of obesity-related glomerulopathy.

The Impact of Obesity on Kidney Disease: Observational Cohort Study Analyzing 14,492 Kidney Biopsy Cases.

BACKGROUND: The obesity epidemic is associated with the emergence of new kidney diseases including obesity-related glomerulopathy (ORG) and metabolic syndrome-associated disorders. However, the effects of obesity on prevalence and outcome of biopsy-proven kidney disease are not well known. METHODS: We analyzed 14,492 kidney biopsies in 18 hospitals from 1979 to 2018 in Korea. Obesity was defined as a body mass index value of ≥ 30 kg/m². RESULTS: The most common disease was IgA nephropathy (IgAN) in both obese and non-obese participants (33.7% vs. 38.9%). Obesity was associated with a higher risk of focal segmental glomerulosclerosis (FSGS) and hypertensive nephropathy (HT-N) (odds ratio [OR], 1.72, 95% confidence interval [CI], 1.37-2.17; OR, 1.96, 95% CI, 1.21-3.19) and a lower risk of IgAN (OR, 0.74, 95% CI, 0.62-0.88). During the median follow up of 93.1 ± 88.7 months, obesity increased the risk of end-stage kidney disease (ESKD) in patients with IgAN (relative risk [RR], 1.49, 95% CI, 1.01-2.20) and lupus nephritis (LN) (RR, 3.43, 95% CI, 1.36-8.67). Of 947 obese individuals, ORG was detected in 298 (31.5%), and 230 participants had other kidney diseases, most commonly, IgAN (40.9%) followed by diabetic nephropathy (15.2%). Participants with ORG, when combined with other renal diseases, showed higher risks for developing ESKD compared to those with ORG alone (RR, 2.48, 95% CI, 1.09-5.64). CONCLUSION: Obesity is associated with an increased risk of FSGS and HT-N, and also increase the ESKD risk in IgAN and LN patients. ORG in obese participants may have favorable renal outcomes if it occurs alone without any other renal disease.

Renal Dysfunction Phenotypes in Patients Undergoing Obesity Surgery.

Obesity surgery candidates are at an increased risk of kidney injury, but pre-operative evaluation usually neglects kidney function assessment. This study aimed to identify renal dysfunction in candidates for bariatric surgery. To reduce the sources of bias, subjects with diabetes, prediabetes under metformin treatment, neoplastic or inflammatory diseases were excluded. Patients' (n = 192) average body mass index was 41.7 ± 5.4 kg/m2. Among these, 51% (n = 94) had creatinine clearance over 140 mL/min, 22.4% (n = 43) had proteinuria over 150 mg/day and 14.6% (n = 28) albuminuria over 30 mg/day. A creatinine clearance higher than 140 mL/min was associated with higher levels of proteinuria and albuminuria. Univariate analysis identified sex, glycated hemoglobin, uric acid, HDL and VLDL cholesterol as being associated with albuminuria, but not with proteinuria. On multivariate analysis, glycated hemoglobin and creatinine clearance as continuous variables were significantly associated with albuminuria. In summary, in our patient population prediabetes, lipid abnormalities and hyperuricemia were associated with albuminuria, but not with proteinuria, suggesting different disease mechanisms might be implicated. Data suggest that in obesity-associated kidney disease, tubulointerstitial injury precedes glomerulopathy. A significant proportion of obesity surgery candidates present clinically relevant albuminuria and proteinuria along with renal hyperfiltration, suggesting that routine pre-operative assessment of these parameters should be considered.

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.

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

Aim: 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. Methods: 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. Results: 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. Conclusion: 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.

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-Related Glomerulopathy: Clinical Management.

Obesity-related glomerulopathy (ORG) and other obesity-associated kidney diseases pose a major challenge to the treating nephrologist. We review the benefits of weight loss and optimal management of ORG and kidney disease in the setting of obesity. Therapeutic strategies in ORG were limited mainly in the past to weight loss through lifestyle interventions and bariatric surgery, antihypertensive treatment, and renin-angiotensin-aldosterone system blockade. Current approaches to obtain the desired weight loss include novel pharmacologic therapies that have been approved for the treatment of diabetes while offering kidney protection, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1-receptor agonists. This review focuses on the nephroprotective role of the renin-angiotensin-aldosterone system blockade and of these new pharmacologic agents, and on the renal effects of bariatric surgery in chronic kidney disease.

Overlapping obesity-related glomerulopathy and immunoglobulin A nephropathy: clinical and pathologic characteristics and prognosis.

BACKGROUND: In this study, we investigated the clinical and pathologic characteristics and prognosis of overlapping obesity-related glomerulopathy (ORG) and immunoglobulin A nephropathy (IgAN) (ORG + IgAN), which is rare in the clinic. METHODS: We included 62 cases of ORG + IgAN, 110 cases of ORG without other glomerulopathy (ORG alone) and 124 cases of IgAN without other glomerulopathy (IgAN alone). The clinical, pathologic and prognostic data were collected and compared. RESULTS: ORG + IgAN patients showed a higher incidence of body mass index (BMI), higher incidence of hyperuricemia, higher incidence of hypertriglyceridemia and higher blood glucose than the IgAN alone(all P < 0.05). ORG + IgAN patients presented with higher incidence of microscopic hematuria, greater mesangial cell proliferation and a higher proportion of crescents than the ORG alone (all P < 0.05). The ORG + IgAN patients who received corticosteroid or immunosuppressive therapy achieved a higher cumulative rate of partial or complete remission (PR or CR, P = 0.009). However, there was no significant difference in the cumulative renal survival rate between the ORG + IgAN patients in the glucocorticoids/immunosuppressors and non-glucocorticoids/immunosuppressors groups (P = 0.356). Obesity-related focal segmental glomerulosclerosis (O-FSGS) and body mass index (BMI) were significantly associated with poor prognosis (all P < 0.05). CONCLUSIONS: ORG + IgAN should be considered in obese patients who present with metabolic abnormalities and microscopic hematuria. Although corticosteroid or immunosuppressive therapy achieves higher cumulative incidence rates of PR or CR, there is no benefit to long-term prognosis but an increased risk of infection. Moreover, O-FSGS and BMI are significantly associated with poor prognosis.

Protective effects of liraglutide on glomerular podocytes in obese mice by inhibiting the inflammatory factor TNF-α-mediated NF-κB and MAPK pathway.

OBJECTIVE: To evaluate the protective effects of Glucagon-like peptide-1(GLP-1) receptor agonist (liraglutide) on glomerular podocytes of obese mice, and explore the possible underlying mechanism. METHODS: Twelve of the thirty-four healthy and clean male mice were randomly selected as the normal control group. The remaining twenty-two mice were included in the high-fat diet (HFD) feeding group. After twelve weeks of high-fat diet and normal diet, two mice each from the HFD feeding group and the normal control group were randomly selected and sacrificed to suggested that the modeling was successful in the HFD feeding group. Then, twenty mice were randomly divided into HFD + liraglutide group (liraglutide group, n = 10) and HFD group (n = 10). The morphology and the structure of glomerular podocytes were observed using electron microscopy. Podocyte foot process diameter, glomerular basement membrane thickness were measured. ELISA was performed to determine the serum tumor necrosis factor α (TNF-α) level. The expression levels of TNF-α protein and nuclear factor-kappa B (NF-κB) in kidney tissues, extracellularsignal regulating kinase(ERK), c-Jun N-terminal kinase (JNK) and p38MAPK in the mitogenactivated protein kinases(MAPK) pathway were detected by western blotting. RESULTS: HFD-feeding caused significant renal injury, podocyte pathological changes, podocyte foot process diameter and glomerular basement membrane thickness were significantly increased compared with the control group. Liraglutide injection significantly alleviated HFD-induced effects on renal functions and podocyte morphology, as 24 h urine protein, urinary albumin and podocyte histomorphology. Moreover, HFD-induced Inflammatory reaction were obviously attenuated by Liraglutide administration, so did the HFD-induced activation of TNF-α-mediated NF-κB and MAPK pathways. CONCLUSION: Liraglutide reduced urinary albumin excretion in obesity-related glomerulopathy model mice, and improved podocyte morphology and structural damage. The mechanism may be partly related to the inhibition of TNF-α-mediated NF-κB and MAPK pathways.

Childhood Obesity and the Metabolic Syndrome.

Obesity is a leading cause of chronic kidney disease. Children with severe obesity have an increased prevalence of early kidney abnormalities and are at high risk to develop kidney failure in adulthood. The pathophysiology of obesity-related kidney disease is incompletely understood, although the postulated mechanisms of kidney injury include hyperfiltration, adipokine dysregulation, and lipotoxic injury. An improved understanding of the long-term effects of obesity on kidney health is essential treat the growing epidemic of obesity-related kidney disease. The purpose of this article is to review the epidemiology, pathophysiology, clinical features, and management of obesity-related kidney disease in children and adolescents.

Proteomic Analysis Reveals the Renoprotective Effect of Tribulus terrestris against Obesity-Related Glomerulopathy in Rats.

Tribulus terrestris L. (Zygophyllaceae) (TT) is usually used as a cardiotonic, diuretic, and aphrodisiac, as well as for herbal post-stroke rehabilitation in traditional Chinese medicine. However, little is known about the renoprotective effects of TT on obesity-related glomerulopathy (ORG). In this study, 340 monomeric compounds were identified from TT extracts obtained with ethyl acetate combined with 50% methanol. In vitro, IC50 of TT was 912.01 mg/L, and the appropriate concentration of TT against oxidized-low density lipoprotein (ox-LDL) induced human renal glomerular endothelial cells (HRGECs) was 4 mg/L. TT significantly increased the viability (63.2%) and migration (2.33-fold increase) of HRGECs. ORG model rats were induced by a chronic high-fat diet (45%) for 20 weeks and were then treated with TT extract (2.8 g/kg/d) for 8 weeks. Subsequently, the kidneys were removed and their differentially expressed protein profile was identified using two-dimensional electrophoresis coupled with matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)-TOF MS. Molecular categorization and functional analysis of bioinformatic annotation suggested that excessive energy metabolism, decreased response to stress and low immunity were the potential etiologies of ORG. After TT administration for 8 weeks, body weight, blood pressure, serum cystatin C and cholesterol were decreased. Additionally, TT significantly enhanced the resistance of rats to ORG, decreased energy consumption and the hemorrhagic tendency, and improved the response to acute phase reactants and immunity. In conclusion, TT may play a protective role against ORG in rats.

Mast Cell and M1 Macrophage Infiltration and Local Pro-Inflammatory Factors Were Attenuated with Incretin-Based Therapies in Obesity-Related Glomerulopathy.

BACKGROUND: The global increase of obesity parallels the obesity-related glomerulopathy (ORG) epidemic. Dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 receptor agonists were well recognized to attenuate renal injury independent of glucose control in diabetic nephropathy. There are limited studies focusing on their effects on ORG. We explored the effects of incretin-based therapies on early ORG and the inflammatory responses involved mainly concentrated on mast cell (MC) and macrophage (M) infiltration and local pro-inflammatory factors. METHODS: ORG rat models were induced by high-fat diet and then divided into ORG vehicle, vildagliptin (3 mg/kg/day, qd) and liraglutide (200 µg/kg, bid) treated groups. After 8 weeks of treatments, albuminuria, glomerular histology, renal inflammatory cell infiltration, and pro-inflammatory factors were analyzed. RESULTS: Early ORG model was demonstrated by albuminuria, glomerulomegaly, foot process fusion, and mesangial and endothelial mild proliferation. Incretin-based therapies limited body weight gain and improved insulin sensitivity. ORG was alleviated, manifested by decreased average glomerular area, attenuated mesangial and endothelial cell proliferation, and revived cell-to-cell propagation of podocytes, which contributed to reduced albuminuria. Compared with ORG vehicle, MC and M1 macrophage (pro-inflammatory) infiltration and M1/M2 ratio were significantly decreased; M2 macrophage (anti-inflammatory) was not significantly increased after incretin-based treatments. Tumor necrosis factor-α (TNF-α) and IL-6 in renal cortex were significantly downregulated, while transforming growth factor-ß1 (TGF-ß1) remained unchanged. CONCLUSIONS: Incretin-based treatments could alleviate high-fat diet-induced ORG partly through the systemic insulin sensitivity improvement and the attenuated local inflammation, mainly by the decrease of MC and M1 macrophage infiltration and reduction of TNF-α and IL-6.

Proteinuria rebound in IgA nephropathy associated with obesity-related glomerulopathy.

IgA nephropathy (IgAN), the most prevalent primary chronic glomerulonephritis worldwide, has three major risk factors: hypertension, proteinuria >1 g/day, and severe renal lesions. Obesity also portends a poor prognosis. A Japanese boy with IgAN showed nephrotic syndrome at presentation. Pathological features resembled those of membranoproliferative glomerulonephritis (MPGN), although IgA deposition differed from MPGN and IgAN. Combination therapy improved renal lesions, but rebound deterioration of proteinuria occurred in this patient, who had marked obesity and hypertension. Serial kidney biopsy specimens were compatible with obesity-related glomerulopathy (ORG). Rebound proteinuria was apparently attributable to ORG rather than relapse and flaring up of IgAN.

Two children with obesity-related glomerulopathy identified in a school urinary screening program.

The incidence of obesity-related glomerulopathy (ORG) has increased over the last decade, but there have been few reports on ORG in Japanese children. Reported herein are two children with ORG identified on school urinary screening (SUS). Patient 1 was a 12-year-old boy in whom proteinuria was first detected on SUS. His body mass index (BMI) was 33.8 kg/m(2) and he had hypertension and hyperuricemia. Patient 2, a 10-year-old boy, also had proteinuria identified on SUS. His BMI was 34.8 kg/m(2) , and he had fatty liver, hyperuricemia, and hypercholesterolemia. Both were diagnosed with ORG based on obesity, proteinuria, and renal pathological findings. After treatment, including candesartan, food restriction and physical exercise, urinary protein excretion was decreased in both cases. We believe that such school urinary screening programs may be effective for the early identification and treatment of children with ORG.