Focal Segmental Glomerulosclerosis Lesions Research Articles

#417 Targeting parietal epithelial cell activation with mineralocorticoid receptor antagonism controls FSGS and crescentic glomerulonephritis

Abstract Background and Aims We have recently demonstrated that targeting specific pathways in parietal epithelial cells (PEC) can markedly alleviate experimental extracapillary glomerular injury [1]. Accumulating evidence has indicated the potential contributions of the mineralocorticoid receptor (MR) to the pathophysiology of chronic kidney disease. MR is expressed in endothelial cells, glomerular mesangial cells, podocytes, and distal tubular cells. Previous studies have shown that administering mineralocorticoid receptor antagonists has beneficial effects in various renal injury animal models, the role of the MR in extracapillary glomerulopathies is still elusive and mechanistically unclear. Methods To investigate the cell-specific role of the MR in PEC in the course of focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (GN), we generated chimeric mice specifically lacking MR (Pec Cre Nr3c2lox/lox) in PECs using an inducible Cre recombinase system. Maladaptive FSGS was induced by combining a high-salt diet and deoxycorticosterone acetate (DOCA) with unilateral nephrectomy (DOCA-UniN). Crescentic glomerulonephritis (GN) was induced using the anti-glomerular basement membrane nephrotoxic serum (NTS) model. Results At baseline, Pec Cre Nr3c2wt/wt and Pec Cre Nr3c2lox/lox mice displayed no kidney morphology and function differences. When challenged by DOCA-UniN, PEC-selective Nr3c2 targeting significantly inhibited the expression of PEC activation markers Ki67, CD44, and FSGS lesions. Importantly, Pec Cre Nr3c2lox/lox mice showed less albuminuria and preserved renal function compared to Pec Cre Nr3c2 wt/wt counterparts. Likewise, Pec Cre Nr3c2lox/lox mice showed less albuminuria and preserved renal function in the NTS-induced CGN model. Crescents were also more numerous and organised in Pec Cre Nr3c2wt/wt mice than in Pec Cre Nr3c2lox/lox animals. Next, we examined whether pharmacological MR inhibition could alleviate the severity of crescentic GN. When Pec Cre Nr3c2wt/wt mice were orally given eplerenone for 14 days after the onset of the crescentic GN, they were significantly protected from renal injury and failure (decreased proteinuria, normal BUN and reduced number of crescent). Such global action was associated with less expression of the CD44 activation marker on PECs. Thus, genetic disruption of MR in PEC and pharmacological inhibition using eplerenone reduced glomerular expression of CD44 and crescent formation. Furthermore, kidney biopsies of individuals diagnosed with crescentic glomerulonephritis displayed increased expression of MR in PEC within FSGS and crescents. We next evaluated PEC migration under various conditions (DMSO, HB-EGF, Eplerenone, or HB-EGF+Eplerenone) for 24 hours. Eplerenone fully abrogated HB-EGF-induced PEC migration and Pcna, Snai1, and Vim mRNA expressions. Conclusion Altogether, these results indicate the critical role of MR in PEC activation during crescentic glomerulonephritis, along with the recently discovered CD9/EGFR/PDGFR [1] and CLDN1 pathways. This further supports the idea that the PEC phenotype switch is not a bystander event but plays a targetable critical active pathogenic role in FGSS and, more surprisingly, in crescentic GN. MR modulation using eplerenone may be a new therapeutic option for the management of such severe disease.

#187 Vasorin (VASN) commands podocyte quiescence and glomerular homeostasis. A novel FSGS mechanism?

Abstract Background and Aims Podocyte dysfunction and loss of quiescence contribute to focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN). Here, we characterized the role of Vasorin (VASN) in podocytes. Method We combined laser capture microdissection and deep RNA sequencing of human glomeruli, RNAscope-based in situ hybridization, immunostaining and mouse models with Vasn-driven fluorescent reporter, targeted Vasn gene deletion in podocytes and cultures of human podocytes. Results VASN mRNA is strongly expressed in healthy human and mouse glomeruli with a podocyte-specific pattern. Both global and podocyte-specific, constitutive or inducible gene deletion of Vasn in mice induced a nephrotic syndrome and kidney failure after day 14, with podocyte dedifferentiation and loss and severe FSGS lesions, indicating a fundamental and non-developmental role of VASN in podocyte homeostasis. Furthermore, we measured markedly decreased VASN expression in podocytes of patients with FSGS and ANCA-associated CGN but not with Minimal Change Disease (MCD) and Membranous Nephropathy (MN). We thus wondered whether VASN abundance could be a disease modifier for glomerulopathies. Mice with podocyte-specific partial heterozygous deletion of Vasn showed no evident baseline renal abnormalities. Still, they showed significantly more podocyte loss, albuminuria and kidney failure than wild-type mice when challenged by type 1 diabetes with glomerular hyperfiltration or CGN experimental models. Human podocytes transduced with lentiviral VASN-targeting shRNA (shVASN) displayed increased focal adhesion dynamics, resistance to oscillating mechanical stretches, enhanced migratory capacity and epithelial-mesenchymal transition (EMT) markers. Moreover, shVASN podocytes had a higher proliferative capacity, increased cell-cycle reentry and a relative S-phase slow-down. Likewise, transcriptomics analysis found the up-regulation of genes involved in cell metabolism, adhesion and EMT and the down-regulation of genes involved in the S to G2/M phase transition. In vivo, we confirmed that VASN deficiency increased podocyte proliferation in situ and urinary shedding. Conclusion These findings highlight the novel role of VASN as an essential master protein that maintains podocyte quiescence and homeostasis during health and kidney diseases while offering a potential new therapeutic target. VASN control mechanisms driving podocyte cell-cycle reentry and detachment and FSGS. Precise mechanisms of VASN functions in podocytes need further insights into VASN molecular partners.

Adhesion G Protein-Coupled Receptor Gpr126 (Adgrg6) Expression Profiling in Diseased Mouse, Rat, and Human Kidneys

Uncovering the function of understudied G protein-coupled receptors (GPCRs) provides a wealth of untapped therapeutic potential. The poorly understood adhesion GPCR Gpr126 (Adgrg6) is widely expressed in developing kidneys. In adulthood, Gpr126 expression is enriched in parietal epithelial cells (PECs) and epithelial cells of the collecting duct and urothelium. Whether Gpr126 plays a role in kidney disease remains unclear. Here, we characterized Gpr126 expression in diseased kidneys in mice, rats, and humans. RT-PCR data show that Gpr126 expression is altered in kidney disease. A quantitative RNAscope® analysis utilizing cell type-specific markers revealed that Gpr126 expression upon tubular damage is mainly increased in cell types expressing Gpr126 under healthy conditions as well as in cells of the distal and proximal tubules. Upon glomerular damage, an increase was mainly detected in PECs. Notably, Gpr126 expression was upregulated in an ischemia/reperfusion model within hours, while upregulation in a glomerular damage model was only detected after weeks. An analysis of kidney microarray data from patients with lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), hypertension, and diabetes as well as single-cell RNA-seq data from kidneys of patients with acute kidney injury and chronic kidney disease indicates that GPR126 expression is also altered in human kidney disease. In patients with FSGS, an RNAscope® analysis showed that GPR126 mRNA is upregulated in PECs belonging to FSGS lesions and proximal tubules. Collectively, we provide detailed insights into Gpr126 expression in kidney disease, indicating that GPR126 is a potential therapeutic target.

Evidence from the large VALIGA cohort validates the subclassification of focal segmental glomerulosclerosis in IgA nephropathy

Evidence from the Oxford IgA nephropathy (IgAN) cohort supports the clinical value of subclassifying focal segmental glomerulosclerosis lesions (S1). Using the larger Validation in IgA (VALIGA) study cohort, we investigated the association between podocytopathic changes and higher proteinuria, kidney outcome and response to immunosuppressive therapy. All biopsies were evaluated for glomeruli with segmental capillary occlusion by matrix ("not otherwise specified", NOS lesion), simple capsular adhesion without capillary occlusion (Adh), tip lesions, and podocyte hypertrophy (PH). S1 required a NOS lesion and/or Adh. A Chi-Squared Automatic Interaction Detection method was used to identify subgroups of FSGS lesions associated with distinctive proteinuria at biopsy. We assessed survival from a combined event (kidney failure or 50% decline in estimated glomerular filtration rate). Finally, we evaluated within each subgroup if immunosuppression was associated with a favorable outcome using propensity analysis. In 1147 patients, S1 was found in 70% of biopsies. Subclassification found NOS lesions in 44%, Adh in 59%, PH in 13%, and tip lesions in 3%, with much overlap. Four subgroups were identified with progressively higher proteinuria: from lowest, S1 without NOS, S1 with NOS but without Adh/PH, to highest, S1 with NOS and Adh but without PH, and S1 with NOS and PH. These four subgroups showed progressively worse kidney survival. Immunosuppression was associated with a better outcome only in the two highest proteinuria subgroups. Propensity analysis in these two groups, adjusted for clinical and pathological findings, found a significantly reduced time-dependent hazard of combined outcome with corticosteroids. Podocyte hypertrophy and glomeruli with simple adhesions appeared to reflect active lesions associated with a response to corticosteroids, while other S1 lesions defined chronicity. Thus, our findings support subclassifying S1 lesions in IgAN.

Quantitative assessment of glomerular basement membrane collagen IV α chains in paraffin sections from patients with focal segmental glomerulosclerosis and Alport gene variants

Focal segmental glomerulosclerosis (FSGS) lesions have been linked to variants in COL4A3/A4/A5 genes, which are also mutated in Alport syndrome. Although it could be useful for diagnosis, quantitative evaluation of glomerular basement membrane (GBM) type IV collagen (colIV) networks is not widely used to assess these patients. To do so, we developed immunofluorescence imaging for collagen α5(IV) and α1/2(IV) on kidney paraffin sections with Airyscan confocal microscopy that clearly distinguishes GBM collagen α 3 α 4 α5(IV) and α 1 α 1 α2(IV) as two distinct layers, allowing quantitative assessment of both colIV networks. The ratios of collagen α5(IV): α1/2(IV) mean fluorescence intensities ( α5: α1/2 intensity ratios) and thicknesses ( α5: α1/2 thickness ratios) were calculated to represent the levels of collagen α 3 α 4 α5(IV) relative to α 1 α 1 α2(IV). The α5: α1/2 intensity and thickness ratios were comparable across all 11 control samples, while both ratios were significantly and markedly decreased in all patients with pathogenic or likely pathogenic Alport COL4A variants, supporting validity of this approach. Thus, with further validation of this technique, quantitative measurement of GBM colIV subtype abundance by immunofluorescence, may potentially serve to identify the subgroup of patients with FSGS lesions likely to harbor pathogenic COL4A variants who could benefit from genetic testing.

Aggressive treatment may be needed for idiopathic membranous nephropathy with focal segmental glomerulosclerosis lesions.

The purpose of this study was to analyze the clinical, pathological, prognostic features and treatment response of the coexistence of focal segmental glomerulosclerosis lesions with idiopathic membranous nephropathy. This is a two-center retrospective cohort study. Patients of idiopathic membranous nephropathy were enrolled and divided into two groups with or without focal segmental glomerulosclerosis lesions according to the renal biopsy. Laboratory data and pathological manifestation were compared. Renal phospholipase A2 receptor was detected by immunofluorescence. During the follow-up, the effects of different therapies and renal function were estimated. A total of 236 patients were finally enrolled in this study, of which 60 and 176 idiopathic membranous nephropathy patients were enrolled in the FSGS+ and FSGS- groups, respectively. The FSGS+ group showed a higher percentage of hypertension history (38.3 vs. 20.0%, p=0.004), with a significantly higher level of systolic pressure [137 (120, 160) mmHg vs. 130 (120, 140) mmHg, p=0.009]. Main laboratory findings, including serial albumin (20.4±7.8 g/L vs. 24.5±6.7 g/L, p<0.001), 24-h proteinuria [5.61 (3.10, 7.87) g/day vs. 3.82 (2.31, 5.79) g/day, p=0.002], serial creatinine [80.8 (65.8, 97.9) μmol/L vs. 72.0 (58.7, 84.9) μmol/L, p=0.003], and estimated glomerular filtration rate [86 (66, 101) mL/min/1.73 m2 vs. 95 (81, 108) mL/min/1.73 m2, p=0.007] showed significant differences between the two groups. Pathologically, patients with focal segmental glomerulosclerosis lesions appeared with a higher percentage of crescents, a more severe degree of interstitial fibrosis, and a higher level of membranous nephropathy stage. Renal phospholipase A2 receptor showed a relatively lower positive rate of only 75.0% in the FSGS+ group in comparison with the positive rate of 90.3% in the FSGS- group (p=0.031). The prognosis was generally similar between the two groups. Among patients who were given non-immunosuppression treatment, those with focal segmental glomerulosclerosis lesions took a relatively longer period of time to achieve complete remission (29.3±7.0 m vs. 15.4±8.9 m, p=0.025) and experienced a higher rate of renal function deterioration (37.5 vs. 5.4%, p=0.033) compared with the other ones. While among those receiving immunosuppression treatment, both groups received similar remission rates. Compared with FSGS- group, idiopathic membranous nephropathy with focal segmental glomerulosclerosis lesions represented more severe nephrotic syndrome and worse renal function. In view of the renal function decline during the follow-up, more aggressive treatment with the use of immunosuppressants should be considered for idiopathic membranous nephropathy patients with focal segmental glomerulosclerosis lesions.

An integrated bioinformatics approach to identify key biomarkers in the tubulointerstitium of patients with focal segmental glomerulosclerosis and construction of mRNA–miRNA-lncRNA/circRNA networks

Objective The purpose of this study was to identify potential biomarkers in the tubulointerstitium of focal segmental glomerulosclerosis (FSGS) and comprehensively analyze its mRNA–miRNA-lncRNA/circRNA network. Methods The expression data (GSE108112 and GSE200818) were downloaded from the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/). Identification and enrichment analysis of differentially expressed genes (DEGs) were performed. the PPI networks of the DEGs were constructed and classified using the Cytoscape molecular complex detection (MCODE) plugin. Weighted gene coexpression network analysis (WGCNA) was used to identify critical gene modules. Least absolute shrinkage and selection operator regression analysis were used to screen for key biomarkers of the tubulointerstitium in FSGS, and the receiver operating characteristic curve was used to determine their diagnostic accuracy. The screening results were verified by quantitative real-time-PCR (qRT–PCR) and Western blot. The transcription factors (TFs) affecting the hub genes were identified by Cytoscape iRegulon. The mRNA–miRNA-lncRNA/circRNA network for identifying potential biomarkers was based on the starBase database. Results A total of 535 DEGs were identified. MCODE obtained eight modules. The green module of WGCNA had the greatest association with the tubulointerstitium in FSGS. PPARG coactivator 1 alpha (PPARGC1A) was screened as a potential tubulointerstitial biomarker for FSGS and verified by qRT–PCR and Western blot. The TFs FOXO4 and FOXO1 had a regulatory effect on PPARGC1A. The ceRNA network yielded 17 miRNAs, 32 lncRNAs, and 50 circRNAs. Conclusions PPARGC1A may be a potential biomarker in the tubulointerstitium of FSGS. The ceRNA network contributes to the comprehensive elucidation of the mechanisms of tubulointerstitial lesions in FSGS.

Clinicopathological differences in focal segmental glomerulosclerosis depending on the accompanying pathophysiological conditions in renal allografts

Primary focal segmental glomerulosclerosis (FSGS) is thought to be caused by circulating factors leading to podocytopathy, whereas segmental sclerotic lesions (FSGS lesions) have several causes. We studied the clinicopathological differences of FSGS-lesions in 258 cases of FSGS in renal allografts, depending on the following accompanying pathophysiology: recurrence of primary FSGS, calcineurin inhibitor (CNI)-induced arteriolopathy, antibody-mediated rejection (ABMR), and other conditions. All cases were categorized with the Columbia classification. Recurrent FSGS developed the earliest after transplantation and showed the highest percentage of the collapsing (COL) variant in which collapse of the glomerular capillaries with epithelial hypertrophy was apparent. FSGS accompanying CNI-induced arteriolopathy predominantly developed the not otherwise specified (NOS) variant, showing severe ultrastructural endothelial injury. On the contrary, approximately 7% of the cases showed the COL variant, presenting glomerular endothelial damage such as double contours of glomerular basement membrane and endothelial cell swelling as well as epithelial cell proliferation. FSGS with ABMR had the highest creatinine levels and cellular variant percentage, with marked inflammation and ultrastructural endothelial injury. Approximately two-thirds of the cases without ABMR, CNI-induced arteriopathy, or recurrent FSGS had other coexisting conditions such as glomerulonephritis, T cell-mediated rejection, and reflux nephropathy with progressive tubulointerstitial fibrosis. Most of these cases were of the NOS variant. The clinicopathologic features of post-transplant FSGS differed depending on the associated conditions, and endothelial injury was apparent especially in cases of CNI-induced arteriolopathy and ABMR. Precise observation of FSGS lesions may facilitate the diagnosis and clinical management of FSGS during renal transplantation.

Focal Segmental Glomerulosclerosis: Assessing the Risk of Relapse

Kidney outcomes are improved in primary focal segmental glomerulosclerosis (FSGS) by maintaining a remission in proteinuria. However, characteristics associated with relapses are uncertain. We sought to identify these by analyzing each remission. We performed a retrospective study in patients with biopsy-proven lesions of FSGS, absent identifiable secondary cause, who had at least 1 remission from nephrotic-range proteinuria. In each patient, we identified every remission, every relapse, and their durations. Using a multilevel logistic regression to account for the clustering of multiple remissions within a patient, we tested which clinical characteristics were independently associated with relapses. In 203 individuals, 312 remissions occurred, 177 with and 135 without relapse. A minority of remissions were atypical, defined by either absent hypoalbuminemia and/or no immunosuppression (IS), in contrast to the classic nephrotic syndrome that remits with IS. Atypical remission variants were just as likely to relapse as the classical presentation. Only 24% of remission events were on maintenance therapy at relapse. Independent characteristics associated with relapses were higher maximal proteinuria while nephrotic; and in remission, higher nadir proteinuria, lower serum albumin, and higher blood pressure. Using these variables, we created a tool estimating the 1-year risk of relapse ranging from 9% to 80%, well-calibrated to the observed data. In FSGS, relapses are frequent but predictable using independent clinical characteristics. We also provide evidence that atypical presentations remit and relapse following the same pattern as classic FSGS presentations. Treatment strategies to prolong remission duration should be addressed in future trials.

Adult-Onset Genetic Focal Segmental Glomerulosclerosis: A Tale of Two Mutations

Focal segmental glomerulosclerosis (FSGS) is a kidney histologic lesion that may be caused by multiple aetiologies and pathophysiological mechanisms, with podocyte injury and depletion as the common denominator. FSGS may be subdivided into different subclasses: primary, secondary, genetic and unknown forms. Notwithstanding the overlapping clinical and histological characteristics across the different forms of FSGS, their management and response to treatment are strikingly different. Genetic FSGS may be suggested by the appearance of nephrotic syndrome during childhood, but it may also present in adulthood, where the diagnosis is rather challenging due to widely variable clinical and histological phenotypes. Herein we present the case of a 34-year-old female with a family history of chronic kidney disease of undetermined aetiology, referred for a Nephrology consultation due to haematoproteinuria and de novo arterial hypertension. Complementary evaluation revealed a urinary protein/creatinine ratio of 4.3 g/g and albumin/creatinine ratio of 3.9 g/g with hypoalbuminaemia. Kidney biopsy revealed lesions of FSGS, associated with extensive foot process effacement. The constellation of findings and family history of kidney disease raised the suspicion of a genetic cause, therefore genetic testing was performed. Two variants in the NPHS2 gene [c.686G&gt;A, p.(Arg229Gln) and c.855_856del, p(Arg286Thrfs*17)] were found in compound heterozygosity, compatible with the diagnosis of genetic FSGS. This case highlights the importance of a detailed evaluation of patients with FSGS lesions in order to identify the FSGS form, given its therapeutic and prognostic impact, including after kidney transplantation.

Identification of Novel Genetic Risk Factors for Focal Segmental Glomerulosclerosis in Children: Results From the Chronic Kidney Disease in Children (CKiD) Cohort

Focal segmental glomerulosclerosis (FSGS) is a major cause of pediatric nephrotic syndrome, and African Americans exhibit an increased risk for developing FSGS compared with other populations. Predisposing genetic factors have previously been described in adults. Here we performed genomic screening of primary FSGS in a pediatric African American population. Prospective cohort with case-control genetic association study design. 140 African American children with chronic kidney disease from the Chronic Kidney Disease in Children (CKiD) cohort, including 32 cases with FSGS. Over 680,000 common single-nucleotide polymorphisms (SNPs) were tested for association. We also ran a pathway enrichment analysis and a human leucocyte antigen (HLA)-focused association study. Primary biopsy-proven pediatric FSGS. Multivariate logistic regression models. The genome-wide association study revealed 169 SNPs from 14 independent loci significantly associated with FSGS (false discovery rate [FDR]<5%). We observed notable signals for genetic variants within the APOL1 (P=8.6×10-7; OR, 25.8 [95% CI, 7.1-94.0]), ALMS1 (P=1.3×10-7; 13.0% in FSGS cases vs 0% in controls), and FGFR4 (P=4.3×10-6; OR, 24.8 [95% CI, 6.3-97.7]) genes, all of which had previously been associated with adult FSGS, kidney function, or chronic kidney disease. We also highlighted novel, functionally relevant genes, including GRB2 (which encodes a slit diaphragm protein promoting podocyte structure through actin polymerization) and ITGB1 (which is linked to renal injuries). Our results suggest a major role for immune responses and antigen presentation in pediatric FSGS through (1) associations with SNPs in PTPRJ (or CD148, P=3.5×10-7), which plays a role in T-cell receptor signaling, (2) HLA-DRB1∗11:01 association (P=6.1×10-3; OR, 4.5 [95% CI, 1.5-13.0]), and (3) signaling pathway enrichment (P=1.3×10-6). Sample size and no independent replication cohort with genomic data readily available. Our genetic study has identified functionally relevant risk factors and the importance of immune regulation for pediatric primary FSGS, which contributes to a better description of its molecular pathophysiological mechanisms. We assessed the genetic risk factors for primary focal segmental glomerulosclerosis (FSGS) by simultaneously testing over 680,000 genetic markers spread across the genome in 140 children, including 32 with FSGS lesions. Fourteen independent genetic regions were significantly associated with pediatric FSGS, including APOL1 and ALMS1-NAT8, which were previously found to be associated with FSGS and chronic kidney diseases in adults. Novel genes with relevant biological functions were also highlighted, such as GRB2 and FGFR4, which play a role in the kidney filtration barrier and in kidney cell differentiation, respectively. Finally, we revealed the importance of immune regulation in pediatric FSGS through associations involving cell surface proteins presenting antigens to the immune system and interacting with T-cell receptors.

PS-C26-3: THE ASSOCIATION BETWEEN GLOMERULAR DIAMETER AND SECONDARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS IN CHRONIC KIDNEY DISEASE

Introduction: When nephron loss occurs, glomerular filtration rate (GFR) is suggested to be maintained by glomerular hypertrophy, but excessive hypertrophy can rather lead to the formation of focal segmental glomerulosclerosis (FSGS), thereby cause progressive kidney damage. However, it is not clear how much glomerular hypertrophy leads to the formation of FSGS. We examined the association between glomerular diameter and FSGS lesions in chronic kidney disease (CKD) patients. Methods: We recruited 77 patients who underwent renal biopsy during 2016–2017; however, those identified with primary FSGS and glomerulonephritis with active glomerular lesion were excluded. We evaluated the maximal glomerular diameter (Max GD), an indicator of glomerular size, in each renal biopsy specimen and examined its association with FSGS lesion. Results: The median age, blood pressure, and estimated GFR of the patients were 53 years, 122/70 mmHg, and 65 ml/min/1.73 m2, respectively. The optimal cutoff threshold of Max GD for predicting the presence of FSGS lesions, assessed by receiver operating characteristic curve analysis, was determined to be at 224 μm (area under the curve, 0.81; sensitivity, 81%; specificity, 72%). Multivariate logistic regression analyses demonstrated that Max GD ≧ 224 μm was significantly associated with the presence of FSGS lesions, independent of other confounding factors (odds ratio, 11.70; 95% confidence interval, 1.93–70.84). Discussion/Conclusion: Glomerular hypertrophy (Max GD ≧ 224 μm) has been associated with FSGS lesions in CKD patients and may reflect the limits of the compensatory process

The Location and Character of Focal Segmental Glomerulosclerosis Lesions: The Prevalence, Overlap, and Clinical Relevance

The Location and Character of Focal Segmental Glomerulosclerosis Lesions: The Prevalence, Overlap, and Clinical Relevance

Non-glomerular Tip Lesion Focal Segmental Glomerulosclerosis as a Negative Predictor in Idiopathic Membranous Nephropathy

ObjectiveTo assess the significance of focal segmental glomerulosclerosis (FSGS) variants on clinicopathological characteristics and short-term outcomes in idiopathic membranous nephropathy (IMN) patients.MethodsThe clinicopathological data of 146 IMN patients diagnosed between December 2016 and March 2019 in our center were collected and analyzed. These patients were divided into the pure IMN group, IMN with glomerular tip lesion (GTL) group, and IMN with non-GTL FSGS group.ResultsThe IMN with non-GTL FSGS and IMN with GTL groups both had higher proportions of patients with hypertension, lower serum albumin, and severe proteinuria, while the IMN with non-GTL FSGS group additionally showed higher blood pressure and serum cholesterol, and lower serum IgG than the IMN group (all P<0.05). As for pathology, the IMN with non-GTL FSGS group had higher proportions of patients with acute tubular injury and moderate to severe chronic injuries than the IMN group (all P<0.05). In the IMN, IMN with GTL, and IMN with non-GTL FSGS groups, the overall one-year remission rates were 81.6%, 76%, and 58.8%, respectively. Furthermore, the IMN with non-GTL FSGS group showed the lowest cumulative incidence to reach remission within one year. Multivariate Cox logistic analysis demonstrated that higher level of serum anti-M-type phospholipase A2 receptor antibody and the existence of non-GTL FSGS lesion were independent predictors for no remission in IMN patients.ConclusionThe non-GTL FSGS lesion was a novel negative predictor in IMN and should be taken into account in the management of IMN.

Focal Segmental Glomerulosclerosis caused by Hepatitis B Infection Comorbid with HIV Infection

Glomerulonephritis is an inflammatory condition on renal glomerulus. These entities can manifest as nephrotic syndrome. One of causes of secondary glomerulonephritis is hepatitis B infection. Glomerulonephritis due to hepatitis B only happens in 0.1 – 25% cases, with the focal segmental glomerulosclerosis (FSGS) is rarely reported. We reported 20 years old male with nephrotic syndrome. He was homosexual with history of unprotected sex and multiple partners. From kidney biopsy, we found focal segmental glomerulosclerosis lesion. Blood examination showed he had both hepatitis B (HBV-DNA 1.7x108 IU/mL) and HIV infection (HIV-RNA 820 copies/mL, CD4 839 cell/uL). We treated this patient with combination of anti-viral drugs which consist of tenofovir, lamivudine and efavirenz. After three weeks of treatment, he showed improvement in the clinical symptoms and urinalysis.

Blocking ribosomal protein S6 phosphorylation inhibits podocyte hypertrophy and focal segmental glomerulosclerosis

Ribosomal protein S6 (rpS6) phosphorylation mediates the hypertrophic growth of kidney proximal tubule cells. However, the role of rpS6 phosphorylation in podocyte hypertrophy and podocyte loss during the pathogenesis of focal segmental glomerulosclerosis (FSGS) remains undefined. Here, we examined rpS6 phosphorylation levels in kidney biopsy specimens from patients with FSGS and in podocytes from mouse kidneys with Adriamycin-induced FSGS. Using genetic and pharmacologic approaches in the mouse model of FSGS, we investigated the role of rpS6 phosphorylation in podocyte hypertrophy and loss during development and progression of FSGS. Phosphorylated rpS6 was found to be markedly increased in the podocytes of patients with FSGS and Adriamycin-induced FSGS mice. Genetic deletion of the Tuberous sclerosis 1 gene in kidney glomerular podocytes activated mammalian target of rapamycin complex 1 signaling to rpS6 phosphorylation, resulting in podocyte hypertrophy and pathologic features similar to those of patients with FSGS including podocyte loss, leading to segmental glomerulosclerosis. Since protein phosphatase 1 is known to negatively regulate rpS6 phosphorylation, treatment with an inhibitor increased phospho-rpS6 levels, promoted podocyte hypertrophy and exacerbated formation of FSGS lesions. Importantly, blocking rpS6 phosphorylation (either by generating congenic rpS6 knock-in mice expressing non-phosphorylatable rpS6 or by inhibiting ribosomal protein S6 kinase 1-mediated rpS6 phosphorylation with an inhibitor) significantly blunted podocyte hypertrophy, inhibited podocyte loss, and attenuated formation of FSGS lesions. Thus, our study provides genetic and pharmacologic evidence indicating that specifically targeting rpS6 phosphorylation can attenuate the development of FSGS lesions by inhibiting podocyte hypertrophy and associated podocyte depletion.

First Report in the Literature of Biopsy-Proven Noncollapsing Focal Segmental Glomerulosclerosis Relapse in a Second Renal Transplant Presenting With Thrombotic Microangiopathy: A Case Report

Primary focal segmental glomerulosclerosis (FSGS) is a podocytopathy with an irregular response to immunosuppressive therapies. FSGS relapse occurs in 30% to 80% of kidney grafts, and poor survival outcomes include large proteinuria and the nephrotic syndrome's cardinal clinical features. Thrombotic microangiopathy (TMA) is caused by endothelial injury due to complement dysregulation including acute kidney injury, proteinuria, and severe hypertension common renal presentations. Both pathologies have well-described genetic forms, but their relationship remains uncertain. FSGS lesions can be found in kidney biopsy specimens in patients with TMA, and TMA has been reported in patients with collapsing glomerulopathy. However, this combination has not been clearly described in renal transplant recipients. We present the case of a 22-year-old man who received his second kidney allograft and developed an early graft disfunction with nephrotic syndrome and clinical TMA. His background was remarkable for primary, biopsy-confirmed FSGS in childhood, and he started hemodialysis in 2006 and received a living donor kidney graft the same year. He presented with a FSGS relapse with malignant hypertension and seizures in the first posttransplant month and had an irregular response to plasma exchange and rituximab, and dialysis was reinitiated 10 years later. A total of 3 biopsies were performed after his second kidney transplant showing the evolution of a FSGS relapse with histologic and clinical TMA in the absence of identified genetic mutations. Partial responses to treatments with plasma exchange, eculizumab, and rituximab were obtained, but the allograft was lost after 26 months. This case is the first report of concomitant FSGS and TMA in a renal transplant recipient.

Proteomic Study of Low-Birth-Weight Nephropathy in Rats.

The hyperfiltration theory has been used to explain the mechanism of low birth weight (LBW)-related nephropathy. However, the molecular changes in the kidney proteome have not been defined in this disease, and early biomarkers are lacking. We investigated the molecular pathogenesis of LBW rats obtained by intraperitoneal injection of dexamethasone into pregnant animals. Normal-birth-weight (NBW) rats were used as controls. When the rats were four weeks old, the left kidneys were removed and used for comprehensive label-free proteomic studies. Following uninephrectomy, all rats were fed a high-salt diet until 9 weeks of age. Differences in the molecular composition of the kidney cortex were observed at the early step of LBW nephropathy pathogenesis. Untargeted quantitative proteomics showed that proteins involved in energy metabolism, such as oxidative phosphorylation (OXPHOS), the TCA cycle, and glycolysis, were specifically downregulated in the kidneys of LBW rats at four weeks. No pathological changes were detected at this early stage. Pathway analysis identified NEFL2 (NRF2) and RICTOR as potential upstream regulators. The search for biomarkers identified components of the mitochondrial respiratory chain, namely, ubiquinol-cytochrome c reductase complex subunits (UQCR7/11) and ATP5I/L, two components of mitochondrial F1FO-ATP synthase. These findings were further validated by immunohistology. At later stages of the disease process, the right kidneys revealed an increased frequency of focal segmental glomerulosclerosis lesions, interstitial fibrosis and tubular atrophy. Our findings revealed proteome changes in LBW rat kidneys and revealed a strong downregulation of specific mitochondrial respiratory chain proteins, such as UQCR7.

Renal diseases secondary to interferon-β treatment: a multicentre clinico-pathological study and systematic literature review.

ABSTRACTBackground The spectrum of interferon-β (IFN-β)-associated nephropathy remains poorly described and the potential features of this uncommon association remain to be determined.MethodsIn this study we retrospectively analysed the clinical, laboratory, histological and therapeutic data of patients with biopsy-proven renal disease in a context of IFN-β treatment administered for at least 6 months.ResultsEighteen patients (13 women, median age 48 years) with biopsy-proven renal disease occurring during IFN-β therapy were included. The median exposure to IFN-β (14 patients were treated with IFN-β1a and 4 patients with IFN-β1b) was 67 months (range 23–165 months). The clinical presentation consists in hypertension (HT; 83%), malignant HT (44%), proteinuria (protU) >1 g/g (94%), reduced renal function (78%), biological hallmark suggesting thrombotic microangiopathy (TMA; 61%), oedematous syndrome (17%) or nephritic syndrome (11%). The pathological findings included typical features of isolated TMAs in 11 cases, isolated focal segmental glomerulosclerosis (FSGS) lesions in 2 cases and 5 cases with concomitant TMA and FSGS lesions. An exploration of the alternative complement pathway performed in 10 cases (63%) did not identify mutations in genes that regulate the complement system. The statistical analysis highlighted that the occurrence of IFN-β-associated TMA was significantly associated with Rebif, with a weekly dose >50 µg and with multiple weekly injections. In all cases, IFN-β therapy was discontinued. Patients with TMA lesions received other therapies, including corticosteroids (44%), eculizumab (13%) and plasma exchanges (25%). At the end of a 36-month median follow-up, persistent HT and persistent protU were observed in 61% and 22% of patients, respectively. Estimated glomerular filtration rate <60 mL/min/1.73 m2 was present in 61% of patients.ConclusionsIFN-β-associated nephropathy must be sought in the case of HT and/or protU onset during treatment. When TMA and/or FSGS are observed on renal biopsy, early discontinuation of IFN-β is essential.

Identification of Genetic Causes of Focal Segmental Glomerulosclerosis Increases With Proper Patient Selection

ObjectiveTo increase the likelihood of finding a causative genetic variant in patients with a focal segmental glomerulosclerosis (FSGS) lesion, clinical and histologic characteristics were analyzed. Patients and MethodsIndividuals 18 years and older with an FSGS lesion on kidney biopsy evaluated at Mayo Clinic from November 1, 1999, through October 31, 2019, were divided into 4 groups based on clinical and histologic characteristics: primary FSGS, secondary FSGS with known cause, secondary FSGS without known cause, and undetermined FSGS. A targeted gene panel and a customized gene panel retrieved from exome sequencing were performed. ResultsThe overall rate of detection of a monogenic cause was 42.9% (21/49). Individuals with undetermined FSGS had the highest rate of positivity (87.5%; 7/8) followed by secondary FSGS without an identifiable cause (61.5%; 8/13) and secondary FSGS with known cause (33.3%; 5/15). Four of 5 (80%) individuals in the latter group who had positive genetic testing results also had a family history of kidney disease. Univariate analysis showed that family history of kidney disease (odds ratio [OR], 13.8; 95% CI, 3.7 to 62.4; P<.001), absence of nephrotic syndrome (OR, 8.2; 95% CI, 1.9 to 58.1; P=.004), and female sex (OR, 5.1; 95% CI, 1.5 to 19.9; P=.01) were strong predictors of finding a causative genetic variant in the entire cohort. The most common variants were in the collagen genes (52.4%; 11/21), followed by the podocyte genes (38.1%; 8/21). ConclusionIn adults with FSGS lesions, proper selection of patients increases the rate of positive genetic testing significantly. The majority of individuals with undetermined FSGS in whom the clinical presentation and histologic parameters are discordant had a genetic diagnosis.