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Aim: To evaluate the clinical and pathological features and prognosis of idiopathic membranous nephropathy (IMN) with focal segmental sclerosis (FSGS) in a group of Russian patients., Materials and Methods: 101 patients with morphologically verified IMN were enrolled in our single-center cohort retrospective study. The patients were divided into IMN group and IMN+FSGS group. The primary and secondary outcomes were analyzed in 59 patients, which had follow-up data for period more than 6 months., Results: At the time of renal biopsy the median age was 46.0 (33.0; 55.0) years and the median follow-up was 6.8 (4.0; 15.6) months. Secondary FSGS was revealed in 15 (14.9%) patients with IMN. The IMN and IMN+FSGS groups did not differ in gender, age of onset IMN and age of renal biopsy. In the IMN+FSGS group proteinuria was higher and estimated glomerular filtration rate was lower than that in the IMN group ( p <0.05). The systolic arterial pressure and creatinine levels in the IMN+FSGS group were slightly higher than in the IMN group, but the difference was not significant. Anti-PLA2R positivity was similar in both groups. Chronic kidney disease (CKD) progression was observed in 10/52 (19.2%) and 5/7 (71.4%) patients in IMN and IMN+FSGS groups, respectively. In a multivariate Cox regression model, age of renal biopsy (odds ratio - OR 1.12, 95% confidence interval - CI 1.03-1.22; р =0.07), FSGS (OR 0.05, 95% CI 0.01-0.34; р =0.002) и response to initial course of immunosuppression (OR 0.33, 95% CI 0.12-0.95; р =0.039) were associated with the CKD progression., Conclusion: In patients with IMN secondary FSGS is associated with a greater severity of proteinuria and a decrease in estimated glomerular filtration rate, and is also an independent factor of the CKD progression.

Background: An unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin-angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longer-term treatment with sparsentan for FSGS are unknown., Methods: In this phase 3 trial, we enrolled patients with FSGS (without known secondary causes) who were 8 to 75 years of age; patients were randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy end point assessed at the prespecified interim analysis at 36 weeks was the FSGS partial remission of proteinuria end point (defined as a urinary protein-to-creatinine ratio of ≤1.5 [with protein and creatinine both measured in grams] and a >40% reduction in the ratio from baseline). The primary efficacy end point was the estimated glomerular filtration rate (eGFR) slope at the time of the final analysis. The change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary end point. Safety was also evaluated., Results: A total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At 36 weeks, the percentage of patients with partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P = 0.009), a response that was sustained through 108 weeks. At the time of the final analysis at week 108, there were no significant between-group differences in the eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 m 2 of body-surface area per year (95% confidence interval [CI], -1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 m 2 per year (95% CI, -1.3 to 3.0). The mean change in eGFR from baseline to week 112 was -10.4 ml per minute per 1.73 m 2 with sparsentan and -12.1 ml per minute per 1.73 m 2 with irbesartan (difference, 1.8 ml per minute per 1.73 m 2 ; 95% CI, -1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, and the frequency of adverse events was similar in the two groups., Conclusions: Among patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan. (Funded by Travere Therapeutics; DUPLEX ClinicalTrials.gov number, NCT03493685.)., (Copyright © 2023 Massachusetts Medical Society.)

Secreted protein acidic and rich in cysteine (SPARC), an extracellular matrix (ECM) protein, was recently shown to induce collagen deposition through the production of a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) in the aging heart. ADAMTS1 regulates ECM turnover by degrading ECM components, and its excessive activation contributes to various pathological states, including fibrosis. The present study investigated the pathophysiological regulation and role of SPARC and ADAMTS1 in renal fibrosis using uninephrectomized rats treated with deoxycorticosterone acetate (DOCA, 40 mg/kg/week, subcutaneously) and salt (1% in drinking water). The administration of DOCA and salt gradually and significantly elevated systolic blood pressure during the 3-week treatment period, induced proteinuria, decreased creatinine clearance, and increased NADPH oxidase-derived superoxide production, malondialdehyde concentrations, and monocyte chemoattractant protein-1 and osteopontin expression in the kidneys. Glomerulosclerosis, fibrillar collagen deposition, and transforming growth factor-β expression increased in a time-dependent manner, and SPARC and ADAMTS1 expression showed a similar pattern to these changes. The angiotensin II type-1 receptor blocker losartan suppressed the overexpression of SPARC and ADAMTS1, and an in vitro exposure to angiotensin II induced the production of both SPARC and ADAMTS1 in renal fibroblast NRK-49F cells. Knockdown of the SPARC gene with small interfering RNA reduced all forms (the 110-kDa latent and 87- and 65-kDa bioactive forms) of ADAMTS1 expression as well as collagen production. These results suggest that SPARC is induced by the renin-angiotensin system and may be a fibrogenic factor, at least in part, by producing ADAMTS1 in hypertensive renal disease., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Focal segmental glomerulosclerosis (FSGS) is not a specific disease entity but a lesion that primarily targets the podocyte. In a broad sense, the causes of the lesion can be divided into those triggered by a presumed circulating permeability factor, those that occur secondary to a process that might originate outside the kidneys, those caused by a genetic mutation in a podocyte or glomerular basement membrane protein, and those that arise through an as yet unidentifiable process, seemingly unrelated to a circulating permeability factor. A careful attempt to correctly stratify patients with FSGS based on their clinical presentation and pathological findings on kidney biopsy is essential for sound treatment decisions in individual patients. However, it is also essential for the rational design of therapeutic trials in FSGS. Greater recognition of the pathophysiology underlying podocyte stress and damage in FSGS will increase the likelihood that the cause of an FSGS lesion is properly identified and enable stratification of patients in future interventional trials. Such efforts will facilitate the identification of effective therapeutic agents., (© 2021. Springer Nature Limited.)

Background: Transplantation is the optimal modality for children with ESRD. High risk of disease recurrence and graft loss with FSGS, and its financial implications, may result in families refusing transplantation. Deceased donation is often preferred for FSGS, but access is limited in many low- and middle-income group countries (LMIC; per capita gross national income between $1026 and $3995). As FSGS secondary to an underlying genetic etiology has low recurrence risk, we hypothesized that in LMIC such as India, families with children in ESRD secondary to FSGS with proven pathogenic mutation are more likely to consent for transplantation than those with unknown etiology., Methods: Prospective cross-sectional study with retrospective chart review was undertaken (March 2011 and February 2019) to identify children with ESRD from FSGS. The objective was to ascertain NGS uptake and findings, parental decision for transplantation, and transplant outcome., Results: 28 children with FSGS started transplant workup, and 15 (54%) families agreed for NGS testing. Pathogenic mutation (NPHS1 x 2, WT1 x 2, COL4A3 x 2, CD2AP, CRB2, COL4A5, INF 2, ACTN4, NPHP4: 1 each) was identified in 12 (80%). 92% (11/12) agreed to proceed with transplantation in contrast to 13% (2/16) who either did not undergo NGS testing or had no pathogenic mutation identified (P = .001). No disease recurrences were noted in those with a known pathogenic mutation., Conclusion: In LMIC, NGS results are useful in transplant discussions with families for children with ESRD secondary to FSGS., (© 2020 Wiley Periodicals LLC.)

Hereditary diseases of the glomerular filtration barrier are characterized by a more vulnerable glomerular basement membrane and dysfunctional podocytes. Recent clinical trials have demonstrated the nephroprotective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in chronic kidney disease (CKD). SGLT2-mediated afferent arteriole vasoconstriction is hypothesized to correct the hemodynamic overload of the glomerular filtration barrier in hereditary podocytopathies. To test this hypothesis, we report data in a case series of patients with Alport syndrome and focal segmental glomerulosclerosis (FSGS) with respect of the early effect of SGLT2i on the kidney function. Mean duration of treatment was 4.5 (±2.9) months. Mean serum creatinine before and after SGLT-2i initiation was 1.46 (±0.42) and 1.58 (±0.55) mg/dL, respectively, with a median estimated glomerular filtration rate of 64 (±27) before and 64 (±32) mL/min/1.73 m 2 after initiation of SGLT2i. Mean urinary albumin-creatinine ratio in mg/g creatinine before SGLT-2i initiation was 1827 (±1560) and decreased by almost 40% to 1127 (±854) after SGLT2i initiation. To our knowledge, this is the first case series on the effect and safety of SGLT2i in patients with hereditary podocytopathies. Specific large-scale trials in podocytopathies are needed to confirm our findings in this population with a tremendous unmet medical need for more effective, early on, and safe nephroprotective therapies.

Background. Few data with adequate evidence exists as regards the effect of Cyclosporine (CsA) and mycophenolate mofetil (MMF) on pathological prognostic parameters in patients with steroid resistant focal segmental glomerulosclerosis (FSGS). The purpose of the present study is to compare the effect of cyclosporin and mycophenolate mofetil in addition to steroids on functional and histopathologic renal parameters in patients with steroid resistant FSGS one year after treatment. Material and methods. Thirty-seven adults with primary FSGS patients resistant to steroid therapy consecutively randomized to treatment with either MMF or cyclosporine. Low dose prednisolone added to both groups. Glomerular filtration rate (GFR) and blood pressure (BP) were determined at all examinations and a second renal biopsy was taken 12 months after treatment with either of cyclosporin and mycophenolate mofetil. Results. GFR significantly increased in MMF group p < 0.01 after 6 months and unchanged after 12 months. On the other hand, GFR significantly decrease in CsA group p < 0.001 after 6 months and reduced more after 12 months p < 0.001 compared to base line levels. There was a significant difference of GFR between the 2 groups at 6 months p < 0.001. The extent of proteinuria decreased significantly in CsA group after 12 months p < 0.001. The extent of arteriolar hyalinosis increased significantly in CsA group (0.78 to 1.81 score, p < 0.001) but was unchanged in MMF group (0.93 to 0.96 score), whereas interstitial fibrosis increased to same level in both groups (grade 3). Conclusion. Conversion to MMF in those patients may be superior to CsA as regards GFR after 12 months after treatment in spite of the presence of greater level of protein excretion. The increased arteriolar hyalinosis during CsA treatment most likely results in higher BP compared to MMF treatment in patients with FSGS resistant to steroids., (© 2021 Amin R. Soliman et al., published by Sciendo.)

Lipotoxicity was recently reported in several forms of kidney disease, including focal segmental glomerulosclerosis (FSGS). Susceptibility to FSGS in African Americans is associated with the presence of genetic variants of the Apolipoprotein L1 gene (APOL1) named G1 and G2. If and how endogenous APOL1 may alter mitochondrial function by the modifying cellular lipid metabolism is unknown. Using transgenic mice expressing the APOL1 variants (G0, G1 or G2) under endogenous promoter, we show that APOL1 risk variant expression in transgenic mice does not impair kidney function at baseline. However, APOL1 G1 expression worsens proteinuria and kidney function in mice characterized by the podocyte inducible expression of nuclear factor of activated T-cells (NFAT), which we have found to cause FSGS. APOL1 G1 expression in this FSGS-model also results in increased triglyceride and cholesterol ester contents in kidney cortices, where lipid accumulation correlated with loss of renal function. In vitro, we show that the expression of endogenous APOL1 G1/G2 in human urinary podocytes is associated with increased cellular triglyceride content and is accompanied by mitochondrial dysfunction in the presence of compensatory oxidative phosphorylation (OXPHOS) complexes elevation. Our findings indicate that APOL1 risk variant expression increases the susceptibility to lipid-dependent podocyte injury, ultimately leading to mitochondrial dysfunction., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Chronic allograft injury (CAI) is a significant reason for which many grafts were lost. The study was conducted to assess the usefulness of diffusional kurtosis imaging (DKI) technology in the non-invasive assessment of CAI., Methods: Between February 2019 and October 2019, 110 renal allograft recipients were included to analyze relevant DKI parameters. According to estimated glomerular filtration rate (eGFR) (mL/min/ 1.73 m 2 ) level, they were divided to 3 groups: group 1, eGFR ≥ 60 (n = 10); group 2, eGFR 30-60 (n = 69); group 3, eGFR < 30 (n = 31). We performed DKI on a clinical 3T magnetic resonance imaging system. We measured the area of interest to determine the mean kurtosis (MK), mean diffusivity (MD), and apparent diffusion coefficient (ADC) of the renal cortex and medulla. We performed a Pearson correlation analysis to determine the relationship between eGFR and the DKI parameters. We used the receiver operating characteristic curve to estimate the predicted values of DKI parameters in the CAI evaluation. We randomly selected five patients from group 2 for biopsy to confirm CAI., Results: With the increase of creatinine, ADC, and MD of the cortex and medulla decrease, MK of the cortex and medulla gradually increase. Among the three different eGFR groups, significant differences were found in cortical and medullary MK (P = 0.039, P < 0.001, P < 0.001, respectively). Cortical and medullary ADC and MD are negatively correlated with eGFR (r = - 0.49, - 0.44, - 0.57, - 0.57, respectively; P < 0.001), while cortical and medullary MK are positively correlated with eGFR (r = 0.42, 0.38; P < 0.001). When 0.491 was set as the cutoff value, MK's CAI assessment showed 87% sensitivity and 100% specificity. All five patients randomly selected for biopsy from the second group confirmed glomerulosclerosis and tubular atrophy/interstitial fibrosis., Conclusion: The DKI technique is related to eGFR as allograft injury progresses and is expected to become a potential non-invasive method for evaluating CAI.

Background: Blood pressure is an important and modifiable cardiovascular risk factor. Ambulatory blood pressure monitoring (ABPM) provides valuable prognostic information in patients with chronic kidney disease (CKD), yet little is known about the association of various types of BP measurements with target organ damage (TOD) in patients with primary glomerular disease. The goal of this study was to investigate whether ambulatory blood pressure is better associated with TOD than clinic blood pressure in patients with primary glomerular disease., Methods: 1178 patients with primary glomerular disease were recruited in this cross-sectional study. TOD were assessed by the following 4 parameters: left ventricular mass index (LVMI or LVH, left ventricular hypertrophy), estimated glomerular filtration rate (eGFR< 60 ml/min/1.73m 2 ), albumin-to-creatinine ratio (ACR ≥ 30 mg/g) and carotid intima-media thickness (cIMT) or plaque. Receiver operating characteristic (ROC) curve and multivariate logistic regression analyses were used to evaluate the relationship between ambulatory or clinic systolic blood pressure (SBP) indexes and TOD., Results: Among 1178 patients (mean age, 39 years,54% men), 116, 458, 1031 and 251 patients had LVH, eGFR < 60 ml/min/1.73m 2 , ACR ≥ 30 mg/g and cIMT≥0.9 mm or plaque respectively. Area under ROC curves for TOD in ambulatory SBP, especially nighttime SBP, was greater than that in clinic SBP (P < 0.05). Multivariate logistic regression analyses showed that 24 h SBP, daytime SBP and nighttime SBP were significantly associated with LVH, eGFR< 60 ml/min/1.73m 2 and ACR ≥ 30 mg/g after adjustment for clinic SBP, while the association of clinic SBP was attenuated after further adjustment for nighttime SBP., Conclusions: Ambulatory blood pressure, especially nighttime blood pressure, is probably superior to clinic blood pressure and has a significant association with TOD in primary glomerular disease patients.

Nephrotic syndrome (NS) is a renal disorder that is characterized by massive proteinuria, hypoalbuminemia and edema. One of the main causes of NS is focal segmental glomerulosclerosis (FSGS), which has extremely poor prognosis. Although steroids and immunosuppressants are the first line of treatment, some FSGS cases are refractory, prompting the need to find new therapeutic strategies. We have previously demonstrated that an optimized combination treatment of mild electrical stimulation (MES) and heat shock (HS) has several biological benefits including the amelioration of the pathologies of the genetic renal disorder Alport syndrome. Here, we investigated the effect of MES + HS on adriamycin (ADR)-induced NS mouse model. MES + HS suppressed proteinuria and glomerulosclerosis induced by ADR. The expressions of pro-inflammatory cytokines and pro-fibrotic genes were also significantly downregulated by MES + HS. MES + HS decreased the expression level of cleaved caspase-3 and the number of TUNEL-positive cells, indicating that MES + HS exerted anti-apoptotic effect. Moreover, MES + HS activated the Akt signaling and induced the phosphorylation and inhibition of the apoptotic molecule BAD. In in vitro experiment, the Akt inhibitor abolished the MES + HS-induced Akt-BAD signaling and anti-apoptotic effect in ADR-treated cells. Collectively, our study suggested that MES + HS modulates ADR-induced pathologies and has renoprotective effect against ADR-induced NS via regulation of Akt-BAD axis.

Autophagy is a conserved lysosomal pathway for the degradation of cytoplasmic components. Basal autophagy in kidney cells is essential for the maintenance of kidney homeostasis, structure and function. Under stress conditions, autophagy is altered as part of the adaptive response of kidney cells, in a process that is tightly regulated by signalling pathways that can modulate the cellular autophagic flux - mammalian target of rapamycin, AMP-activated protein kinase and sirtuins are key regulators of autophagy. Dysregulated autophagy contributes to the pathogenesis of acute kidney injury, to incomplete kidney repair after acute kidney injury and to chronic kidney disease of varied aetiologies, including diabetic kidney disease, focal segmental glomerulosclerosis and polycystic kidney disease. Autophagy also has a role in kidney ageing. However, questions remain about whether autophagy has a protective or a pathological role in kidney fibrosis, and about the precise mechanisms and signalling pathways underlying the autophagy response in different types of kidney cells and across the spectrum of kidney diseases. Further research is needed to gain insights into the regulation of autophagy in the kidneys and to enable the discovery of pathway-specific and kidney-selective therapies for kidney diseases and anti-ageing strategies.

Background: Glomerulosclerosis represents the final stage of glomerular injury during the course of kidney disease and can result from a primary disturbance in disorders like focal segmental glomerulosclerosis or a secondary response to tubulointerstitial disease. Overall, primary focal glomerulosclerosis (FSGS), the focus of this review, accounts for 10-20% of patients of all ages who progress to end stage kidney disease. There are no FDA approved therapeutic options that effectively prevent or delay the onset of kidney failure., Areas Covered: Current immunosuppressive therapy and conservative management including inhibitors of the renin-angiotensin-aldosterone axis and sodium-glucose cotransporter are reviewed. FSGS is now recognized to represent a heterogeneous entity with multiple underlying disease mechanisms. Therefore, novel approaches targeting the podocyte cytoskeleton, immunological, inflammatory, hemodynamic and metabolic pathways are highlighted., Expert Opinion: A number of factors are driving the development of drugs to treat focal segmental glomerulosclerosis in particular and glomerulosclerosis in general including growing awareness of the burden of chronic kidney disease, improved scientific understanding of the mechanism of injury, and the development of noninvasive profiles to identify subgroups of patients with discrete mechanisms of glomerular injury.

Rituximab is currently used after the conventional agents have failed in the management of steroid-dependent (SD)/ steroid-resistant (SR) podocytopathies and have a safer toxicity profile. We report 53 adults with podocytopathies who were managed effectively with CD19-targeted rituximab therapy., Methods: This was a prospective study carried out at a tertiary care centre in India between January 2014 and June 2019. Adults between 16 and 60 years with SD, frequently relapsing (FR), and SR nephrotic syndrome (NS) due to podocytopathy received rituximab in a CD19-targeted approach., Primary Outcome: Percentage of patients who were in remission at 6 and 12 months. Secondary outcome: Percentage of patients in remission at the last follow-up, rituximab dose and adverse events of rituximab therapy., Results: Fifty-three adults with SD/FR/SR NS received CD19-targeted rituximab. The median age at the time of first rituximab injection was 30.09 ± 13.21 (16.53) years. At the time of first rituximab infusion, all patients were in remission with steroids and/or calcineurin inhibitors (CNIs). Fifty (94.33%) patients were in remission at the end of 6 and 12 months and the last follow-up (median: 36 months). The mean total dose of rituximab at 1 year was 788.7 ± 128.1 (6 001 100) mg. At last follow-up (median 36 months), 42 (79%) patients did not require any additional CNI or steroids therapy. No serious adverse events to rituximab were noted., Conclusion: CD19-targeted rituximab therapy is safe and efficacious in the management of SD/SR adult podocytopathy. Also, rituximab is effective in maintaining remission in treatment naïve adult SD or FR podocytopathy., (© 2020 Asian Pacific Society of Nephrology.)

Background: Preeclampsia (PE) refers to the development of hypertension and new-onset proteinuria or progressive organ damage (especially kidney) in a previously normotensive pregnant women after 20 weeks of gestation. Thus, new-onset nephrotic syndrome due to PE before 20 weeks of gestation seems to be rare, making its diagnosis difficult in this time period., Case Presentation: A 28-year-old woman presented with a new-onset nephrotic syndrome at 16 weeks of gestation. A high dose of oral glucocorticoids (prednisolone, 40 mg) was initiated for presumed glomerulonephritis since she presented with severe nephrotic syndrome before 20 weeks of gestation, however, the treatment was not effective. At 21 weeks of gestation, we confirmed that the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio was very high (sFlt-1, 13,400 pg/mL; PlGF, 21.9 pg/mL; serum sFlt-1/PlGF ratio 611.9). Therefore, we diagnosed nephrotic syndrome due to PE, and oral glucocorticoids were discontinued. After she underwent a cesarean section at 24 weeks & 3 days, we performed a kidney biopsy. Focal segmental sclerotic lesions with epithelial cell hyperplasia and foam cells in the tubular poles were seen on light microscopy. On immunofluorescence tests, C4d staining showed linear peripheral patterns in the glomeruli. Electron microscopy revealed diffuse subendothelial edema with focal foot process effacement. The histological diagnosis was severe glomerular endotheliosis with focal segmental glomerulosclerosis. Furthermore, the histology of placenta was consistent with PE. Eight months after delivery, her proteinuria disappeared completely., Conclusions: We not only confirmed an abnormal serum sFlt-1/PlGF ratio but also presented the histology compatible with pure PE in the kidney and placenta in a case of nephrotic syndrome before 20 weeks of gestation. The serum sFlt-1/PlGF ratio may be useful in determining the treatment strategy for atypical cases of pregnant women with nephrotic syndrome, particularly before 20 weeks of gestation.

Background: Focal segmental glomerulosclerosis (FSGS) causes renal fibrosis and may lead to kidney failure. FSGS and its common complication, proteinuria, are challenging to treat. Corticosteroids are ineffective in many patients with FSGS, and alternative treatments often yield suboptimal responses. Repository corticotropin injection (RCI; Acthar® Gel), a naturally sourced complex mixture of purified adrenocorticotropic hormone analogs and other pituitary peptides, may have beneficial effects on idiopathic FSGS via melanocortin receptor activation., Methods: Two studies in a preclinical (female Sprague-Dawley rats) puromycin aminonucleoside FSGS model assessed the effect of RCI on renal function and morphology: an 8-week comparison of a single RCI dose with methylprednisolone (N = 27), and a 12-week chronic RCI dose range study (N = 34). Primary outcomes were proteinuria and renal pathology improvements for measures of renal fibrosis, tubular damage, glomerular injury, and total kidney injury score. Impact of RCI treatment was also determined by assessing urinary biomarkers for renal injury, podocyte expression of podoplanin (a biomarker for injury), podocyte effacement by electron microscopy, and histological staining for fibrosis biomarkers., Results: Compared with saline treatment, RCI 30 IU/kg significantly reduced proteinuria, with a 38% reduction in peak mean urine protein levels on day 28 in the 8-week model, and RCI 10 IU/kg, 30 IU/kg, and 60 IU/kg reduced peak mean urine protein in the 12-week model by 18, 47, and 44%, respectively. RCI also showed significant dose-dependent improvements in fibrosis, interstitial inflammation, tubular injury, and glomerular changes. Total kidney injury score (calculated from histopathological evaluations) demonstrated statistically significant improvements with RCI 30 IU/kg in the 8-week study and RCI 60 IU/kg in the 12-week study. RCI treatment improved levels of urinary biomarkers of kidney injury (KIM-1 and OPN), expression of podoplanin, and podocyte morphology. RCI also reduced levels of desmin and fibrosis-associated collagen deposition staining. Methylprednisolone did not improve renal function or pathology in this model., Conclusions: These results provide evidence supporting the improvement of FSGS with RCI, which was superior to corticosteroid treatment in this experimental model. To the authors' knowledge, this is the first evidence that a drug for the treatment of FSGS supports podocyte recovery after repeated injury.

Purpose of Review: The recent years have been marked by the publication of several articles highlighting the pathophysiological role of glomerular parietal epithelial cells (PEC) and refining their phenotypic heterogeneity., Recent Findings: The present review synthetizes recent findings on (i) the potential regenerative role of PEC in glomerular diseases, and (ii) the mechanisms and signaling of leading to PEC pathogenic involvement in crescentic glomerulonephritis (CGN) and focal segmental glomerulosclerosis (FSGS)., Summary: The debate is still open regarding the podocyte regenerative properties of PEC in glomerular disease, whereas the pathogenic involvement of PEC activation in glomerular disease is increasingly admitted. Recent highlights on the podocyte regenerative role of PEC, on one hand, and on their pathological function, on the other hand, for sure will feed the debate in the kidney community for the next years. Nevertheless, from a therapeutic perspective, the two options, boosting cellular regeneration and blocking PECs pathogenicity, should not be seen as antagonistic but, rather, complementary.

Background: Low birth weight (LBW) is associated with end-stage kidney disease and hypertension and is considered to be a surrogate marker of low nephron number. Low nephron number is hypothesized to contribute to glomerular hyperfiltration that may cause kidney injury; however, this is not yet proven. Until now, the hyperfiltration in LBW patients has not been shown directly yet., Case Presentation: A 23-years-old female was referred with the persistent proteinuria and decreased renal function (estimated glomerular filtration rate by cystatin C (eGFR cys ); 41.86 ml/min). She was a premature baby with low birth weight (704 g, 24 gestational weeks). Renal biopsy demonstrated focal segmental glomerulosclerosis (FSGS) of the perihilar variant with expanded glomerular diameter. We calculated the single-nephron estimated glomerular filtration rate (SN-eGFR) that was higher than that of the same age group in the healthy living kidney donors and speculated that glomerular hyperfiltration is a pathophysiological cause of FSGS., Conclusion: This is the first case of SN-eGFR measurement in a patient with LBW. The increased SN-eGFR in this case provides an important insight into the pathophysiological mechanisms of LBW for its progression to kidney disease.

Background and Objectives: FSGS recurrence after kidney transplantation is a major risk factor for graft loss. However, the natural history, clinical predictors, and response to treatment remain unclear because of small sample sizes and poor generalizability of single-center studies, and disease misclassification in registry-based studies. We therefore aimed to determine the incidence, predictors, and treatment response of recurrent FSGS in a large cohort of kidney transplant recipients., Design, Setting, Participants, & Measurements: The Post-Transplant Glomerular Disease (TANGO) project is an observational, multicenter, international cohort study that aims to investigate glomerular disease recurrence post-transplantation. Transplant recipients were screened for the diagnosis of idiopathic FSGS between 2005 and 2015 and details were recorded about the transplant, clinical outcomes, treatments, and other risk factors., Results: Among 11,742 kidney transplant recipients screened for FSGS, 176 had a diagnosis of idiopathic FSGS and were included. FSGS recurred in 57 patients (32%; 95% confidence interval [95% CI], 25% to 39%) and 39% of them lost their graft over a median of 5 (interquartile range, 3.0-8.1) years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset (hazard ratio [HR], 1.37 per decade; 95% CI, 1.09 to 1.56). Other predictors were white race (HR, 2.14; 95% CI, 1.08 to 4.22), body mass index at transplant (HR, 0.89 per kg/m 2 ; 95% CI, 0.83 to 0.95), and native kidney nephrectomies (HR, 2.76; 95% CI, 1.16 to 6.57). Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival., Conclusions: Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases., (Copyright © 2020 by the American Society of Nephrology.)

Background: Obesity has become a major public health problem, and the prevalence of kidney diseases has increased in parallel. Among kidney diseases caused by metabolic disorders, obesity-related glomerulopathy (ORG) is secondary to obesity., Summary: ORG is mainly caused by glomerular hyperfiltration, dysregulation of hormone and cytokine secretion in adipose tissues, and ectopic lipid accumulation in renal cells. ORG is pathologically characterized by glomerular hypertrophy, with or without focal and segmental glomerulosclerosis. Patients with ORG usually present with proteinuria concomitant with metabolic disorders such as dyslipidemia and hypertension. Weight loss, RAAS inhibitors, and improved insulin resistance can reduce the progression of ORG., Conclusion: ORG is a growing renal pathological change in obese individuals, and a comprehensive understanding of the disease is pivotal to avoid its occurrence and improve quality of life for those with obesity. Key Messages:This review comprehensively describes the characteristics of ORG in pathological changes, clinical manifestations, pathogeneses and treatments., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Background: A current, albeit unproven, hypothesis is that an acceleration of cellular senescence is involved in impaired renal repair and progression of glomerular diseases. Focal segmental glomerulosclerosis (FSGS) is a glomerular disease with a substantial risk for progression to ESRD. However, if and to what extent cell senescence predicts a negative outcome in FSGS is still unknown., Methods: The hypothesis that cell senescence represents a proximate mechanism by which the kidney is damaged in FSGS (NOS phenotype) was investigated in 26 consecutive kidney biopsies from adult FSGS cases (eGFR 72 ± 4 mL/min, proteinuria 2.3 ± 0.6 g/day) who were incident for 2 years in a Northern Italian nephrology center and had a 6-year clinical follow-up., Results: Cell senescence (p16INK4A, SA-β-galactosidase [SA-β-Gal]) was upregulated by ∼3- to 4-fold in both glomerular and tubular cells in kidney biopsies of FSGS as compared to age-matched controls (p < 0.05-0.01). Tubular SA-β-Gal correlated with proteinuria and glomerulosclerosis, while only as a trend, tubular p16INK4A was directly associated with interstitial fibrosis. At univariate analysis, basal eGFR, proteinuria, and tubular expression of SA-β-Gal and p16INK4A were significantly directly related to the annual loss of eGFR. No correlation was observed between glomerular p16INK4A and eGFR loss. However, at multivariate analysis, eGFR, proteinuria, and tubular p16INK4A, but not SA-β-Gal, contributed significantly to the prediction of eGFR loss., Conclusions: The results indicate that an elevated cell senescence rate, expressed by an upregulation of p16INK4A in tubules at the time of initial biopsy, represents an independent predictor of progression to ESRD in adult patients with FSGS., (© 2021 S. Karger AG, Basel.)

Introduction: We qualitatively examined the symptoms and impact of recurrent primary focal segmental glomerulosclerosis (rpFSGS) in kidney transplant recipients, compared with two related FSGS populations, to characterize the experience of patients with rpFSGS., Methods: A literature review identified 58 articles concerning the experience of patients with pFSGS and/or rpFSGS in three groups: pre-transplant pFSGS, post-transplant rpFSGS, or post-transplant non-recurrent pFSGS. Literature findings were used to construct a preliminary conceptual model incorporating the symptoms and impact of rpFSGS, which was refined on the basis of qualitative interviews with clinicians. Twenty-five patients (rpFSGS: n = 15; pre-transplant pFSGS: n = 5; post-transplant non-recurrent pFSGS: n = 5) were interviewed to characterize the experience of patients with rpFSGS and compare it with other FSGS populations, and findings were used to finalize the conceptual model., Results: The impact of pFSGS/rpFSGS described in the literature was diverse. Treatment-related symptoms, along with anxiety and depression, were considered important features of rpFSGS in addition to the findings from the literature review, according to clinicians. Patient-reported tiredness and swelling were the most common/disturbing symptoms associated with rpFSGS, while physical activity restrictions and adverse effects on work/social life were considered the most profound impact concepts. The collective disease experience was different for patients with rpFSGS and non-recurrent pFSGS, although psychological impact, including treatment-related anxiety and depression, were common to both groups., Conclusions: Post-transplant recipients with rpFSGS display a greater symptom burden and experience a more diverse impact than those with non-recurrent pFSGS, highlighting the importance of effective patient monitoring and introducing effective treatments for the prevention and management of pFSGS recurrence., Funding: Astellas Pharma Global Development, Inc.

Background: Recently, living-donor kidney transplantation from marginal donors has been increasing. However, a simple prediction model for graft function including preoperative marginal factors is limited. Here, we developed and validated a new prediction model for graft function using preoperative marginal factors in living-donor kidney transplantation., Methods: We retrospectively investigated 343 patients who underwent living-donor kidney transplantation at Kyushu University Hospital (derivation cohort). Low graft function was defined as an estimated glomerular filtration rate of < 45 mL/min/1.73 m 2 at 1 year. A prediction model was developed using a multivariable logistic regression model, and verified using data from 232 patients who underwent living-donor kidney transplantation at Tokyo Women's Medical University Hospital (validation cohort)., Results: In the derivation cohort, 89 patients (25.9%) had low graft function at 1 year. Donor age, donor-estimated glomerular filtration rate, donor hypertension, and donor/recipient body weight ratio were selected as predictive factors. This model demonstrated modest discrimination (c-statistic = 0.77) and calibration (Hosmer-Lemeshow test, P = 0.83). Furthermore, this model demonstrated good discrimination (c-statistic = 0.76) and calibration (Hosmer-Lemeshow test, P = 0.54) in the validation cohort. Furthermore, donor age, donor-estimated glomerular filtration rate, and donor hypertension were strongly associated with glomerulosclerosis and atherosclerotic vascular changes in the "zero-time" biopsy., Conclusions: This model using four pre-operative variables will be a simple, but useful guide to estimate graft function at 1 year after kidney transplantation, especially in marginal donors, in the clinical setting.

Background: This study aimed to investigate the effect of the Phellinus linteus (Mesima) decoction on podocyte injury in a rat model of focal and segmental glomerulosclerosis (FSGS) and evaluate the potential mechanisms., Methods: FSGS resembling primary FSGS in humans was established in rats by uninephrectomy and the repeated injection of doxorubicin. The FSGS rats were randomly divided into the model group, low-dose group of P. linteus decoction (PLD-LD), medium-dose group of P. linteus decoction (PLD-MD), and high-dose group of P. linteus decoction (PLD-HD). Blood and urine analysis were performed after 12 weeks and the molecular indicators of renal function and the renal pathological changes were examined., Results: FSGS developed within 12 weeks in the test group and showed progressive proteinuria and segmental glomerular scarring. Urinary protein, serum creatinine, urea nitrogen, triglycerides and cholesterol were significantly reduced following the 12-week intervention with P.linteus decoction, especially in the PLD-LD group. Renal nephrin and podocin were markedly increased. Moreover, the pathological damage in the renal tissue was alleviated by the PLD-LD intervention., Conclusion: The P. linteus decoction alleviated the podocyte injury in the FSGS rat model, thus minimizing the progression of glomerular sclerosis and improving renal function.

Low-density lipoprotein (LDL) apheresis has been used increasingly in clinical practice for the treatment of renal diseases with nephrotic syndrome (NS), specifically focal segmental glomerulosclerosis (FSGS). Persistent hyperlipidemia for prolonged periods is nephrotoxic and leads to chronic progressive glomerular and tubulointerstitial injury. Effective management of hyperlipidemia with HMG-CoA reductase inhibitors or LDL apheresis in drug-resistant NS patients may prevent the progression of renal disease and, in some patients, resolution of NS symptoms. Available literature reveals beneficial effects of LDL apheresis for NS refractory to drug therapy. Here we update on the current understanding of lipid nephrotoxicity and application of LDL apheresis to prevent progression of renal diseases.

Background: Focal segmental lesions (FSLs) are not uncommon in idiopathic membranous nephropathy (IMN). The reported percentage of IMN patients with focal segmental glomerulosclerosis (FSGS) lesions varies widely between studies. The objective of this study was to differentiate atypical FSL (aFSL) from typical FSGS in IMN and to analyse the clinicopathological predictors of primary outcome of IMN patients., Methods: A total of 716 patients with biopsy-proven IMN between January 1, 2007 and December 31, 2017 were enrolled in the study. An atypical focal segmental lesion was defined as pure synechia, segmental hyperplasia of podocytes or thickening of the GBM accompanied by proliferation of the mesangial matrix, and absence of typical FSGS. The patients were divided into three groups: patients without FSL (FSL - ), patients with typical FSGS (FSGS + ), and patients with aFSL (aFSL + ).The primary outcome was a 50% decline in the initial estimated glomerular filtration rate or end-stage renal disease (ESRD) incidence. Secondary outcomes included all-cause death and ESRD., Results: FSGS was present in 174 patients, while aFSL was noted in 161 patients. Systolic blood pressure was higher in both aFSL + group and FSGS + groups compared with the FSL - group. IMN patients without FSL and with aFSL had lower serum creatinine levels than IMN patients with FSGS. Both the FSGS + and aFSL + groups had higher levels of proteinuria and lower albumin levels than the FSL - group. Renal tissue lesions, including tubulointerstitial fibrosis, glomerular obsolescence, and vascular sclerosis were significantly more severe in the FSGS + group. Cox multivariate analysis showed that older age ≥ 60 years, eGFR< 60 ml/(min·1.73m 2 ), tubulointerstitial fibrosis area ≥ 15% and FSGS at biopsy were independent risk factors for the primary outcome., Conclusions: No significant difference in outcome was found between the FSL - and aFSL + groups, although the patients with aFSL had lower levels of serum albumin and eGFR, higher level of urinary protein, more severe renal lesions with proliferation of the mesangial area,tubulointerstitial fibrosis and vascular sclerosis. FSGS, excluding atypical lesions, was an independent predictor of the primary outcome.

The renal filtration is ensured by the kidney glomeruli selective for filtering the blood. The main actor of the glomerular filter is the podocyte whose interlaced pedicels bear protein complexes (nephrin, podocin, etc.) creating a molecular sieve (slit diaphragm) to achieve the filtration. Alterations of these podocytes lead to massive proteinuria, which characterizes the nephrotic syndrome. The idiopathic form is one of the most malignant and essentially comprises two entities: minimal change disease and focal segmental glomerulosclerosis. Many observations indicated that (1) immune cells are involved and that (2) there are several permeability factors in the blood that affect the morphology and function of podocytes (slit diaphragm with fractional foot processes fusion/effacement). Evidence for a permeability factor was chiefly derived from remission of proteinuria observed after implantation of a kidney with FSGS in healthy recipients or with other kidney diseases. Today, we are moving towards a multifactorial conception of the nephrotic syndrome where all these barely known factors could be associated according to a sequential kinetic mechanism that needs to be determined., (© 2019 médecine/sciences – Inserm.)

Acute kidney injury in the context of nephrotic syndrome is a serious and alarming clinical problem. Largely, acute kidney injury is a relatively frequent complication among patients with comorbidities while it has been independently associated with an increased risk of adverse outcomes, including death and chronic kidney disease. Nephrotic syndrome, without hematuria or with minimal hematuria, includes a list of certain glomerulopathies; minimal change disease, focal segmental glomerulosclerosis and membranous nephropathy. In the light of primary nephrotic syndrome, pathophysiology of acute kidney injury is differentiated by the nature of the primary disease and the severity of the nephrotic state. This review aims to explore the clinical circumstances and pathogenetic mechanisms of acute kidney injury in patients with nephrotic syndrome due to primary glomerulopathies, focusing on newer perceptions regarding the pathogenesis and management of this complicated condition, for the prompt recognition and timely initiation of appropriate treatment in order to restore renal function to its baseline level. Prompt recognition of the precise cause of acute kidney injury is crucial for renal recovery. Clinical characteristics, laboratory and serological findings along with histopathological findings, if required, will reveal the implicated pathway leading to individualized approach and management.

Chronic kidney disease can be understood as a pathological reduction in the number of functional glomeruli. It is a frequent medical problem and one of the major independent risk factors for cardiovascular morbidity and mortality. In humans, glomeruli/nephrons are generated during the prenatal period (glomerular endowment), which may be impaired by multiple conditions. After birth, glomeruli are progressively lost - mostly due to glomerular scarring (focal segmental glomerulosclerosis; FSGS). Multiple independent studies have shown that significant loss of glomerular visceral epithelial cells (podocytes) is sufficient to induce FSGS. It is generally believed that podocytes cannot renew themselves and it has been generally assumed that their number is determined at birth (podocyte endowment). However, there are several lines of experimental evidence showing that podocytes can be replenished in the postnatal period. First, a limited reserve of podocytes has been reported on Bowman's capsule, which may be associated with body growth and increases in glomerular size between childhood and adulthood. Second, two intrinsic progenitor cell niches have been proposed to replenish podocytes throughout adult life and in association with glomerular injury and podocyte loss: parietal epithelial cells and/or cells of the renin lineage. While there is increasing evidence supporting postnatal podocyte gain, controversy remains about the involved signalling pathways and the efficiency of these sources to prevent nephron loss., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The etiology of steroid-resistant nephrotic syndrome, which manifests as FSGS, is not completely understood. Aberrant glycosylation is an often underestimated factor for pathologic processes, and structural changes in the glomerular endothelial glycocalyx have been correlated with models of nephrotic syndrome. Glycans are frequently capped by sialic acid (Sia), and sialylation's crucial role for kidney function is well known. Human podocytes are highly sialylated; however, sialylation's role in podocyte homeostasis remains unclear., Methods: We generated a podocyte-specific sialylation-deficient mouse model ( PCmas -/- ) by targeting CMP-Sia synthetase, and used histologic and ultrastructural analysis to decipher the phenotype. We applied CRISPR/Cas9 technology to generate immortalized sialylation-deficient podocytes (asialo-podocytes) for functional studies., Results: Progressive loss of sialylation in PCmas -/- mice resulted in onset of proteinuria around postnatal day 28, accompanied by foot process effacement and loss of slit diaphragms. Podocyte injury led to severe glomerular defects, including expanded capillary lumen, mesangial hypercellularity, synechiae formation, and podocyte loss. In vivo , loss of sialylation resulted in mislocalization of slit diaphragm components, whereas podocalyxin localization was preserved. In vitro , asialo-podocytes were viable, able to proliferate and differentiate, but showed impaired adhesion to collagen IV., Conclusions: Loss of cell-surface sialylation in mice resulted in disturbance of podocyte homeostasis and FSGS development. Impaired podocyte adhesion to the glomerular basement membrane most likely contributed to disease development. Our data support the notion that loss of sialylation might be part of the complex process causing FSGS. Sialylation, such as through a Sia supplementation therapy, might provide a new therapeutic strategy to cure or delay FSGS and potentially other glomerulopathies., (Copyright © 2019 by the American Society of Nephrology.)

Collapsing glomerulopathy (CG) is a rare entity as a glomerular disease. Although it has been considered as a variant of focal segmental glomerulosclerosis, the fact is that the podocyte lesions show different features with respect to the typical focal segmental glomerulosclerosis, an aspect that has been attributed to a type of podocytopathy. In CG, the podocyte lesion is typically characterised by a dysregulated podocyte phenotype, reflected by the loss of expression of mature podocyte markers. CG can be a primary disease or it can be associated with several causal factors that develop a common histopathological entity. The clinical expressiveness of CG is often characterised by the presence of a nephrotic syndrome and a rapid deterioration of the renal function than other variants of the focal segmental glomerulosclerosis. The prognosis of these patients is a rapid progression towards end-stage renal disease with poor response to treatment., (Copyright © 2018 Elsevier España, S.L.U. All rights reserved.)

Renal disease is a common medical problem in Saudi Arabia. Varieties of renal lesions if not treated properly or not discovered early will lead to a chronic kidney disease. Identifying the types of renal lesions can help in identifying the high-risk patients and appropriate treatment can be provided. Glomerulonephritis (GN) is considered one of the leading causes of end-stage renal disease in Saudi Arabia. The prevalence of different renal lesions were identified by different reports; however, these reports showed inconsistency. One important reason for such differences is related to the lack of unified methods in diagnosing and processing renal tissues and to the fact that different reports were reported by different pathologists. In addition, the differences in the reported results may reflect patient selection biases for renal biopsy or to the different policies and protocols adopted by different nephrologists. This is a prospective, multicenter study that involves different patients from different institutes and from different regions in Saudi Arabia to delineate the pattern of renal diseases based on renal biopsies. Four hundred and five cases were selected and studied over two years. This preliminary report shows that the most common primary renal lesion in Saudi Arabia is focal segmental glomerulosclerosis in 24.1%, followed by IgA nephropathy (15.2%), mesangioproliferative non-IgA, (13.2%), and membranoproliferative GN (12.4%). Lupus nephritis was the most common cause of secondary GN in 66% of the secondary causes.

Background: The increase of circulating urokinase plasminogen activator receptor (suPAR) was demonstrated in various diseases showing its prognostic value as well as the link to the inflammatory reaction. In glomerular diseases, suPAR was considered a causative factor of proteinuria. In the present study we aimed to evaluate serum concentration of suPAR in children with primary and secondary glomerulonephritis (GN) and its association with disease severity., Methods: The study involved 22 children with minimal change disease (MCD), nine with primary focal segmental glomerulosclerosis (FSGS), seven with Henoch-Schönlein nephritis, seven with lupus nephritis (LN) and 16 controls., Results: Serum suPAR was significantly higher in children with FSGS and LN than controls (4.47±1.39 ng/mL vs. 3.23±0.76 ng/mL; P=0.011 and 6.17±1.12 ng/mL vs. 3.23±0.76 ng/mL, respectively; P<0.0001). Further, suPAR was increased in LN when compared to FSGS (P=0.031). In the total group suPAR showed negative correlation with eGFR, serum complement C3 and positive with left ventricular mass index. In children with MCD and FSGS the inverse association of suPAR with eGFR was also shown., Conclusions: In children with primary and secondary glomerulonephritis suPAR levels are not associated with proteinuria. In primary GN elevated suPAR levels may result from reduced eGFR reflecting renal damage. In LN circulating suPAR can be increased further indicating both multi-organ involvement and systemic inflammation reflecting disease severity.

Finding new therapeutic targets of glomerulosclerosis treatment is an ongoing quest. Due to a living environment of various stresses and pathological stimuli, podocytes are prone to injuries; moreover, as a cell without proliferative potential, loss of podocytes is vital in the pathogenesis of glomerulosclerosis. Thus, sufficient understanding of factors and underlying mechanisms of podocyte injury facilitates the advancement of treating and prevention of glomerulosclerosis. The clinical symptom of podocyte injury is proteinuria, sometimes with loss of kidney functions progressing to glomerulosclerosis. Injury-induced changes in podocyte physiology and function are actually not a simple passive process, but a complex interaction of proteins that comprise the anatomical structure of podocytes at molecular levels. This chapter lists several aspects of podocyte injuries along with potential mechanisms, including glucose and lipid metabolism disorder, hypertension, RAS activation, micro-inflammation, immune disorder, and other factors. These aspects are not technically separated items, but intertwined with each other in the pathogenesis of podocyte injuries.

Background: Focal segmental glomerulosclerosis (FSGS) is considered one of the most severe glomerular diseases and around 80% of cases are resistant to steroid treatment. Since a large proportion of steroid-resistant (SR) FSGS patients progress to end-stage renal disease, other therapeutic strategies may benefit this population. However, identification of non-invasive biomarkers to predict this high-risk population is needed., Objective: We aimed to identify the biomarker candidates to distinguish SR from steroid-sensitive (SS) patients using metabolomics approach and to identify the possible molecular mechanism of resistance., Methods: Urine was collected from biopsy-proven FSGS patients eligible for monotherapy with prednisolone. Patients were followed for 6-8 weeks and categorized as SS or SR. Metabolite profile of urine samples was analyzed by one-dimensional 1 H-nuclear magnetic resonance ( 1 H-NMR). Predictive biomarker candidates and their diagnostic importance impaired molecular pathways in SR patients, and the common target molecules between biomarker candidates and drug were predicted., Results: Homovanillic acid, 4-methylcatechol, and tyrosine were suggested as the significant predictive biomarker candidates, while L-3,4-dihydroxyphenylalanine, norepinephrine, and gentisic acid had high accuracy as well. Tyrosine metabolism was the most important pathway that is perturbed in SR patients. Common targets of the action of biomarker candidates and prednisolone were molecules that contributed in apoptosis., Conclusion: Urine metabolites including homovanillic acid, 4-methylcatechol, and tyrosine may serve as potential non-invasive predictive biomarkers for evaluating the responsiveness of FSGS patients., (Copyright: © 2019 SecretarÍa de Salud.)

Background: To compare the efficacy of glucocorticoids in primary focal segmental glomerulosclerosis (pFSGS) patients with moderate proteinuria. Registered at http://www.chictr.org.cn/ , study No. ChiCTR-OPN-17012789., Methods: pFSGS patients with urine protein between 1.0 and 3.5 g/24 h were recruited from 2006 to 2016. No decline in urine protein > 50% was observed after 2 months of run-in angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEI/ARB) treatment. Patients were assigned to study group (glucocorticoids with ACEI/ARB) or control group (ACEI/ARB without glucocorticoids). Variables including 24-h urinary protein, serum albumin and serum creatinine during the trial were recorded. Remission was defined as proteinuria < 0.3 g/24 h or declined > 50%, and our composite end point as > 30% decrease of eGFR or eGFR < 30 ml/min., Results: A total of 102 patients were enrolled (study group N = 52, control group N = 50), and the median follow-up time was 36 (12-117) months without significant difference between groups. During the 12-month follow-up, the remission rate was significantly higher in study group [73.1 vs 50.0% (P = 0.01)], and the initial median response time was 3 months in the study group while 6 in the control group. The end point was reached by 22.2% cases in study group, and 42.0% in control. The medium survival times were study group 72 months and control 57 (P = 0.03). Minor adverse reactions were observed in 10 patients (study group N = 8, control group N = 2)., Conclusions: Additional glucocorticoids therapy is more efficacious compared to ACEI/ARB alone in the treatment of patients with pFSGS and moderate proteinuria.

Idiopathic nephrotic syndrome represents up to 30% of adult glomerulopathies. However, its prognosis according to remission, relapse and renal failure remains unchanged since the 80s and prediction remains difficult. Physiopathology of adult idiopathic nephrotic syndrome is complex and multifactorial, including immunologic and environmental factors and a putative permeability-circulating factor, still unknown. In this point of view, we propose to summarize actual knowledge about idiopathic minimal change disease and focal and segmental glomerulosclerosis physiopathology., (Copyright © 2018 Association Société de néphrologie. Published by Elsevier Masson SAS. All rights reserved.)

Planar cell polarity (PCP) pathways control the orientation and alignment of epithelial cells within tissues. Van Gogh-like 2 (Vangl2) is a key PCP protein that is required for the normal differentiation of kidney glomeruli and tubules. Vangl2 has also been implicated in modifying the course of acquired glomerular disease, and here, we further explored how Vangl2 impacts on glomerular pathobiology in this context. Targeted genetic deletion of Vangl2 in mouse glomerular epithelial podocytes enhanced the severity of not only irreversible accelerated nephrotoxic nephritis but also lipopolysaccharide-induced reversible glomerular damage. In each proteinuric model, genetic deletion of Vangl2 in podocytes was associated with an increased ratio of active-MMP9 to inactive MMP9, an enzyme involved in tissue remodelling. In addition, by interrogating microarray data from two cohorts of renal patients, we report increased VANGL2 transcript levels in the glomeruli of individuals with focal segmental glomerulosclerosis, suggesting that the molecule may also be involved in certain human glomerular diseases. These observations support the conclusion that Vangl2 modulates glomerular injury, at least in part by acting as a brake on MMP9, a potentially harmful endogenous enzyme. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Background: In glomerular injury dendrin translocates from the slit diaphragm to the podocyte nucleus, inducing apoptosis. We analyzed dendrin expression in IgA glomerulonephritis and Henoch Schönlein purpura (IgAN/HSP) versus in podocytopathies minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), and compared it to pathohistological findings and renal function at the time of biopsy and the last follow-up., Methods: Twenty males and 13 females with median of age 35 years (min-max: 3-76) who underwent percutaneous renal biopsy and had diagnosis of glomerular disease (GD) were included in this retrospective study. Fifteen patients had IgAN/HSP and eighteen podocytopathy. Control group consisted of ten patients who underwent nephrectomy due to renal cancer. Dendrin expression pattern (membranous, dual, nuclear or negative), number of dendrin positive nuclei and proportion of dendrin negative glomeruli were analyzed., Results: In GD and the control group significant differences in number of dendrin positive nuclei and proportion of dendrin negative glomeruli were found (P = 0.004 and P = 0.003, respectively). Number of dendrin positive nuclei was higher in podocytopathies than in IgAN/HSP, 3.90 versus 1.67 (P = 0.028). Proportion of dendrin negative glomeruli correlated to higher rates of interstitial fibrosis (P = 0.038), tubular atrophy (P = 0.011) and globally sclerotic glomeruli (P = 0.008). Dual and nuclear dendrin expression pattern were connected with lower rate of interstitial fibrosis and tubular atrophy than negative dendrin expression pattern (P = 0.024 and P = 0.017, respectively). Proportion of dendrin negative glomeruli correlated with lower creatinine clearance (CC) at the time of biopsy and the last follow-up (P = 0.010 and P < 0.001, respectively). Dendrin expression pattern correlated to CC at the last follow-up (P = 0.009), being lower in patients with negative than nuclear or dual dendrin expression (P = 0.034 and P = 0.004, respectively)., Conclusion: In this pilot study the number of dendrin positive nuclei was higher in podocytopathies than in inflammatory GD. Negative dendrin expression pattern correlated to chronic tubulointerstitial changes and lower CC, which needs to be confirmed in a larger series.

Apolipoprotein (apo) E5 is a rare apoE isoform. The apoE5 (Glu3Lys) variant, which is caused by the substitution of lysine with glutamic acid at codon 3, has a relative frequency of 0.1% in Japan. Previous studies have reported that apoE5 (Glu3Lys) is associated with hyperlipidemia and cardiovascular diseases, but this isoform has higher LDL receptor-binding activity than that of normal apoE3. Nephropathy associated with apoE5 (Glu3Lys) alone has not yet been reported. We present a case of a 51-year-old man with nephrotic syndrome. On renal biopsy, three glomeruli showed segmental sclerosis with hypertrophy of podocytes and intracapillary marked infiltration of intraglomerular foam cells. These findings were compatible with focal segmental glomerulosclerosis (FSGS). The patient had mild diabetes mellitus and monoclonal gammopathy of undetermined significance, but there were no specific findings of nephrolopathy related to these diseases. Various factors are involved in the pathogenesis of FSGS, including dyslipidemia and apoE activity. Our findings suggest that abnormal lipid metabolism by ApoE5 (Glu3Lys) is involved in the onset of FSGS.

Cofilin is a actin-binding protein in eukaryotic cells. It plays a role in maintaining the steady state of the internal environment through regulating actin dynamics, which contributes to the development of various kinds of diseases. In recent 20 years, cofilin has been widely attracted due to its regulatory effect on cell phenotype, gene transcription, apoptosis and inflammation in renal tissue. Cofilin plays a regulatory role in pathological changes in proteinuria diseases such as minimal change nephropathy, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy. It could be one of the diagnosis index for glomerular podocyte injury. At the same time, cofilin plays a key role in maintaining the polarity and function of proximal tubular epithelial cells and it is involved in the regulation of kidney inflammation in a variety of kidney diseases, such as renal ischemia/reperfusion injury, diabetic nephropathy, and hypertensive nephropathy reaction. In addition, cofilin plays an important role in epithelial-to-mesenchymal transition (EMT) of tumor cells and epithelial cells in various tissues, suggesting that cofilin may be involved in the regulation of peritoneal dialysis-related EMT and fibrosis. Cofilin might turn into the new diagnosis and treatment target of kidney diseases.

Background: We previously reported that mutations in the anillin ( ANLN ) gene cause familial forms of FSGS. ANLN is an F-actin binding protein that modulates podocyte cell motility and interacts with the phosphoinositide 3-kinase (PI3K) pathway through the slit diaphragm adaptor protein CD2-associated protein (CD2AP). However, it is unclear how the ANLN mutations cause the FSGS phenotype. We hypothesized that the R431C mutation exerts its pathogenic effects by uncoupling ANLN from CD2AP., Methods: We conducted in vivo complementation assays in zebrafish to determine the effect of the previously identified missense ANLN variants, ANLN R431C and ANLN G618C during development. We also performed in vitro functional assays using human podocyte cell lines stably expressing wild-type ANLN ( ANLN WT ) or ANLN R431C ., Results: Experiments in anln -deficient zebrafish embryos showed a loss-of-function effect for each ANLN variant. In human podocyte lines, expression of ANLN R431C increased cell migration, proliferation, and apoptosis. Biochemical characterization of ANLN R431C -expressing podocytes revealed hyperactivation of the PI3K/AKT/mTOR/p70S6K/Rac1 signaling axis and activation of mTOR-driven endoplasmic reticulum stress in ANLN R431C -expressing podocytes. Inhibition of mTOR, GSK-3 β , Rac1, or calcineurin ameliorated the effects of ANLN R431C . Additionally, inhibition of the calcineurin/NFAT pathway reduced the expression of endogenous ANLN and mTOR., Conclusions: The ANLN R431C mutation causes multiple derangements in podocyte function through hyperactivation of PI3K/AKT/mTOR/p70S6K/Rac1 signaling. Our findings suggest that the benefits of calcineurin inhibition in FSGS may be due, in part, to the suppression of ANLN and mTOR. Moreover, these studies illustrate that rational therapeutic targets for familial FSGS can be identified through biochemical characterization of dysregulated podocyte phenotypes., (Copyright © 2018 by the American Society of Nephrology.)

Focal segmental glomerulosclerosis (FSGS) is a histologically defined form of kidney injury typically mediated by podocyte dysfunction. Podocytes rely on their intricate actin-based cytoskeleton to maintain the glomerular filtration barrier in the face of mechanical challenges resulting from pulsatile blood flow and filtration of this blood flow. This review summarizes the mechanical challenges faced by podocytes in the form of stretch and shear stress, both of which may play a role in the progression of podocyte dysfunction and detachment. It also reviews how podocytes respond to these mechanical challenges in dynamic fashion through rearranging their cytoskeleton, triggering various biochemical pathways, and, in some disease states, altering their morphology in the form of foot process effacement. Furthermore, this review highlights the growing body of evidence identifying several mutations of important cytoskeleton proteins as causes of FSGS. Lastly, it synthesizes the above evidence to show that a better understanding of how these mutations leave podocytes vulnerable to the mechanical challenges they face is essential to better understanding the mechanisms by which they lead to disease. The review concludes with future research directions to fill this gap and some novel techniques with which to pursue these directions.

Globally sclerotic glomeruli (GSG) occur with both normal aging and kidney disease. However, it is unknown whether any GSG or only GSG exceeding that expected for age is clinically important. To evaluate this, we identified patients with a glomerulopathy that often presents with nephrotic syndrome (focal segmental glomerulosclerosis, membranous nephropathy, or minimal change disease) in the setting of the Nephrotic Syndrome Study Network (NEPTUNE), China-Digital Kidney Pathology (DiKiP), and the Southeast Minnesota cohorts. Age-based thresholds (95th percentile) for GSG based on normotensive living kidney donors were used to classify each patient into one of three groups; no GSG, GSG normal for age, or GSG abnormal for age. The risk of end-stage renal disease or a 40% decline in glomerular filtration rate during follow-up was then compared between groups. Among the 425 patients studied, 170 had no GSG, 107 had GSG normal for age, and 148 had GSG abnormal for age. Compared to those with no GSG, the risk of kidney disease progression with GSG normal for age was similar but was significantly higher with GSG abnormal for age. This increased risk with GSG abnormal for age remained significant after adjustment for interstitial fibrosis, arteriosclerosis, age, hypertension, diabetes, body mass index, glomerulopathy type, glomerular filtration rate, and proteinuria. Thus, in patients with glomerulopathy that often presents with nephrotic syndrome, global glomerulosclerosis is clinically important only if it exceeds that expected for age., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Proteinuria is used as an indicator of FSGS disease activity, but its use as a clinical trial end point is not universally accepted. The goal of this study was to refine proteinuria definitions associated with long-term kidney survival., Design, Setting, Participants, & Measurements: Data on 466 patients with primary FSGS with proteinuria (urine protein-to-creatinine ratio >1 g/g) were analyzed from five independent cohorts. Proteinuria by months 1, 4, and 8 after study baseline was categorized by conventional definitions of complete (<0.3 g/g) and partial remission (<3.5 g/g and 50% reduction in proteinuria). Novel remission definitions were explored using receiver operating curves. Kaplan-Meier methods were used to estimate the associations of proteinuria with progression to ESRD or a 50% loss in kidney function. Propensity score-adjusted Cox proportional hazards models were used to adjust for baseline proteinuria, eGFR, and therapy., Results: In the initial derivation cohort, conventional partial remission was not associated with kidney survival. A novel definition of partial remission (40% proteinuria reduction and proteinuria<1.5 g/g) on the basis of receiver operating curve analyses of 89 patients was identified (Sensitivity=0.70; Specificity=0.77). In the validation cohort analyses, complete remission was associated with better prognosis (6 out of 41 patients progressed to kidney failure; 6.6 per 100 patient-years) as was the novel partial remission (13 out of 71 progressed; 8.5 per 100 patient-years), compared with those with no response (51 out of 116 progressed; 20.1 per 100 patient-years). Conventional partial remission at month 8, but not month 4, was also associated with better response (19 out of 85 patients progressed; risk=10.4 per 100 patient-years). Propensity score-adjusted analyses showed the novel partial remission was associated with less progression at months 4 and 8 (month 4: hazard ratio, 0.50; P =0.01; month 8: hazard ratio, 0.30; P =0.002)., Conclusions: Reaching either a complete or partial remission using a novel or conventional definition was associated with better long-term outcomes in patients with FSGS., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018&#95;02&#95;20&#95;CJASNPodcast&#95;18&#95;3&#95;T.mp3., (Copyright © 2018 by the American Society of Nephrology.)

Focal segmental glomerulosclerosis (FSGS) is an important cause of nondiabetic chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibition (SGLT2i) therapy attenuates the progression of diabetic nephropathy, but it remains unclear whether SGLT2i provides renoprotection in nondiabetic CKD such as FSGS. The primary aim of this pilot study was to determine the effect of 8 wk of dapagliflozin on glomerular filtration rate (GFR) in humans and in experimental FSGS. Secondary end points were related to changes in renal hemodynamic function, proteinuria, and blood pressure (BP). GFR (inulin) and renal plasma flow (para-aminohippurate), proteinuria, and BP were measured in patients with FSGS ( n = 10), and similar parameters were measured in subtotally nephrectomized (SNx) rats. In response to dapagliflozin, changes in GFR, renal plasma flow, and 24-h urine protein excretion were not statistically significant in humans or rats. Systolic BP (SBP) decreased in SNx rats (196 ± 26 vs. 165 ± 33 mmHg; P < 0.001), whereas changes were not statistically significant in humans (SBP 112.7 ± 8.5 to 112.8 ± 11.2 mmHg, diastolic BP 71.8 ± 6.5 to 69.6 ± 8.4 mmHg; P = not significant), although hematocrit increased (0.40 ± 0.05 to 0.42 ± 0.05%; P = 0.03). In archival kidney tissue from a separate patient cohort, renal parenchymal SGLT2 mRNA expression was decreased in individuals with FSGS compared with controls. Short-term treatment with the SGLT2i dapagliflozin did not modify renal hemodynamic function or attenuate proteinuria in humans or in experimental FSGS. This may be related to downregulation of renal SGLT2 expression. Studies examining the impact of SGLT2i on markers of kidney disease in patients with other causes of nondiabetic CKD are needed.

Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder caused by a partial deletion of chromosome 4 (4p16.3p16.2). We describe a case of a male 9 years old children with WHS proteinuria and hypertension. Laboratory data showed creatinine 1.05 mg/dl, GFR 65.9 ml/min/1.73 m 2 , cholesterol 280 mg/dl, triglyceride 125 mg/dl with electrolytes in the normal range. Urine collection showed protein 2.72 g/L with a urine protein/creatinine ratio (U P /U Cr ratio) of 4.2 and diuresis of 1,100 ml. Renal ultrasound showed reduced kidney dimensions with diffusely hyperechogenic cortex and poorly visualized pyramids. Renal biopsy showed oligonephronia with focal segmental glomerulosclerosis associated with initial tubulointerstitial sclerotic atrophy. The child began therapy with Angiotensin-converting enzyme inhibitors (ACE-inhibitors) to reduce proteinuria and progression of chronic kidney disease. In the literature the anomalies of number of glomeruli oligonephronia and oligomeganephronia (OMN) are described in two forms, one without any associated anomalies, sporadic, and solitary and the other with one or more anomalies. Our review of the literature shows that the pathogenesis of this anomaly is unknown but the role of chromosome 4 is very relevant. Many cases of OMN are associated with anomalies on this chromosome, in the literature cases series we observed this association in 14/48 cases (29.2%) and in 7 of these 14 cases with WHS. Our case and the review of literature demonstrate how periodic urinalysis and renal ultrasound monitoring is recommended in patients affected by WHS and the renal biopsy must be performed when there is the onset of proteinuria., (© 2017 Wiley Periodicals, Inc.)

Focal and segmental glomerulosclerosis (FSGS) is a histological pattern clinically characterized by nephrotic proteinuria, hypoalbuminemia, edema and dyslipidemia. Approximately 50% of patients progress to end-stage renal disease within 5-10 years, particularly those not responding to the therapies. FSGS pathogenesis is largely unknown and therapy is symptomatic and unspecific. The podocyte is considered as the pathogenetic main target and FSGS is now categorized as a podocytopathy together with minimal change disease, diffuse mesangial proliferation and collapsing glomerulonephritis. This paper provides an overview on the treatment of idiopathic FSGS in adults, citing the latest published trials and the most reliable pathogenetic hypotheses of the disease. A large part of the review then focuses on emerging therapies, specifying for each new drug the assumed mechanism of action and the data available in the literature on the drug's use in experimental animals and humans.

The glomerulus functions as the filtration unit of the kidney. The mesangial, endothelial, and podocyte cells of the glomerulus exhibit the three clinically most important cell types, which are involved in diverse pathologic processes. Cell death has hardly been investigated in these cells but may be of critical importance to the pathogenesis of nephrotic syndrome, nephritic syndrome, focal segmental glomerulosclerosis (FSGS), mesangial proliferation, and thrombonic microangiopathy (which involves dysfunction and death of glomerular endothelial cells). The complexity of the glomerulus is frequently affected in autoimmune disorders, which may elicit cell death in mesangial cells and glomerular endothelia. Artificial antisera are used to induce anti-mesangial cell serum-induced mesangiolysis and selective endothelial cell injury, respectively. Genetic variations result in loss of function of podocytes and nephrotic syndrome, which may encompass similar cell death mechanisms as the ones that are observed in the model of secondary focal segmental glomerulosclerosis (FSGS). The following protocols describe our current arsenal to target glomerular cells in vivo.