Ion channels and channelopathies in glomeruli.

An essential step in renal function entails the formation of an ultrafiltrate that is delivered to the renal tubules for subsequent processing. This process, known as glomerular filtration, is controlled by intrinsic regulatory systems and by paracrine, neuronal, and endocrine signals that converge onto glomerular cells. In addition, the characteristics of glomerular fluid flow, such as the glomerular filtration rate and the glomerular filtration fraction, play an important role in determining blood flow to the rest of the kidney. Consequently, disease processes that initially affect glomeruli are the most likely to lead to end-stage kidney failure. The cells that comprise the glomerular filter, especially podocytes and mesangial cells, express many different types of ion channels that regulate intrinsic aspects of cell function and cellular responses to the local environment, such as changes in glomerular capillary pressure. Dysregulation of glomerular ion channels, such as changes in TRPC6, can lead to devastating glomerular diseases, and a number of channels, including TRPC6, TRPC5, and various ionotropic receptors, are promising targets for drug development. This review discusses glomerular structure and glomerular disease processes. It also describes the types of plasma membrane ion channels that have been identified in glomerular cells, the physiological and pathophysiological contexts in which they operate, and the pathways by which they are regulated and dysregulated. The contributions of these channels to glomerular disease processes, such as focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, as well as the development of drugs that target these channels are also discussed.

INF2 formin variants linked to human inherited kidney disease reprogram the transcriptome, causing mitotic chaos and cell death.

Mutations in the human INF2 gene cause autosomal dominant focal segmental glomerulosclerosis (FSGS)-a condition characterized by podocyte loss, scarring, and subsequent kidney degeneration. To understand INF2-linked pathogenicity, we examined the effect of pathogenic INF2 on renal epithelial cell lines and human primary podocytes. Our study revealed an increased incidence of mitotic cells with surplus microtubule-organizing centers fostering multipolar spindle assembly, leading to nuclear abnormalities, particularly multi-micronucleation. The levels of expression of exogenous pathogenic INF2 were similar to those of endogenous INF2. The aberrant nuclear phenotypes were observed regardless of the expression method used (retrovirus infection or plasmid transfection) or the promoter (LTR or CMV) used, and were absent with exogenous wild type INF2 expression. This indicates that the effect of pathogenic INF2 is not due to overexpression or experimental cell manipulation, but instead to the intrinsic properties of pathogenic INF2. Inactivation of the INF2 catalytic domain prevented aberrant nuclei formation. Pathogenic INF2 triggered the translocation of the transcriptional cofactor MRTF into the nucleus. RNA sequencing revealed a profound alteration in the transcriptome that could be primarily attributed to the sustained activation of the MRTF-SRF transcriptional complex. Cells eventually underwent mitotic catastrophe and death. Reducing MRTF-SRF activation mitigated multi-micronucleation, reducing the extent of cell death. Our results, if validated in animal models, could provide insights into the mechanism driving glomerular degeneration in INF2-linked FSGS and may suggest potential therapeutic strategies for impeding FSGS progression.

Proteomic Analysis of Idiopathic Nephrotic Syndrome Triggered by Primary Podocytopathies in Adults: Regulatory Mechanisms and Diagnostic Implications.

Idiopathic nephrotic syndrome (NS) is a heterogeneous group of glomerular disorders which includes two major phenotypes: minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). MCD and FSGS are classic types of primary podocytopathies. We aimed to explore the molecular mechanisms in NS triggered by primary podocytopathies and evaluate diagnostic value of the selected proteomic signatures by analyzing blood proteome profiling. Totally, we recruited 90 participants in two cohorts. The first cohort was analyzed using label-free quantitative (LFQ) proteomics to discover differential expressed proteins and identify enriched biological process in NS which were further studied in relation to clinical markers of kidney injury. The second cohort was analyzed using parallel reaction monitoring-based quantitative proteomics to verify the data of LFQ proteomics and assess the diagnostic performance of the selected proteins using receiver-operating characteristic curve analysis. Several biological processes (such as immune response, cell adhesion, and response to hypoxia) were found to be associated with kidney injury during MCD and FSGS. Moreover, three proteins (CSF1, APOC3, and LDLR) had over 90% sensitivity and specificity in detecting adult NS triggered by primary podocytopathies. The identified biological processes may play a crucial role in MCD and FSGS pathogenesis. The three blood protein markers are promising for diagnosing adult NS triggered by primary podocytopathies.

Investigating FSGS-like injury in zebrafish larvae by nifurpirinol: efficacy and molecular insight.

Identifying effective drugs for focal segmental glomerulosclerosis (FSGS) treatment holds significant importance. Our high-content drug screening on zebrafish larvae relies on nitroreductase/metronidazole (NTR/MTZ)-induced podocyte ablation to generate FSGS-like injury. A crucial factor for successful drug screenings is minimizing variability in injury induction. For this, we introduce nifurpirinol (NFP) as a more reliable prodrug for targeted podocyte depletion. NFP showed a 2.3-fold increase in efficiency at concentrations 1,600-fold lower compared with MTZ-mediated injury induction. Integration into the screening workflow validated its suitability for the high-content drug screening. The presence of crucial FSGS hallmarks, such as podocyte foot process effacement, proteinuria, and activation of parietal epithelial cells, was observed. After the isolation of the glomeruli from the larvae, we identified essential pathways by proteomic analysis. This study shows that NFP serves as a highly effective prodrug to induce the FSGS-like disease in zebrafish larvae and is well-suited for a high-content drug screening to identify new candidates for the treatment of FSGS.NEW & NOTEWORTHY This research investigated the use of nifurpirinol in nanomolar amounts as a prodrug to reliably induce focal segmental glomerulosclerosis (FSGS)-like damage in transgenic zebrafish larvae. Through proteomic analysis of isolated zebrafish glomeruli, we were further able to identify proteins that are significantly regulated after the manifestation of FSGS. These results are expected to expand our knowledge of the pathomechanism of FSGS.

Podocyte injury at young age causes premature senescence and worsens glomerular aging.

As life expectancy continues to rise, age-related diseases are becoming more prevalent. For example, proteinuric glomerular diseases typified by podocyte injury have worse outcomes in the elderly compared with young patients. However, the reasons are not well understood. We hypothesized that injury to nonaged podocytes induces senescence, which in turn augments their aging processes. In primary cultured human podocytes, injury induced by a cytopathic antipodocyte antibody, adriamycin, or puromycin aminonucleoside increased the senescence-related genes CDKN2A (p16INK4a/p14ARF), CDKN2D (p19INK4d), and CDKN1A (p21). Podocyte injury in human kidney organoids was accompanied by increased expression of CDKN2A, CDKN2D, and CDKN1A. In young mice, experimental focal segmental glomerulosclerosis (FSGS) induced by adriamycin and antipodocyte antibody increased the glomerular expression of p16, p21, and senescence-associated ß-galactosidase (SA-ß-gal). To assess the long-term effects of early podocyte injury-induced senescence, we temporally followed young mice with experimental FSGS through adulthood (12 m of age) and middle age (18 m of age). p16 and Sudan black staining were higher at middle age in mice with earlier FSGS compared with age-matched mice that did not get FSGS when young. This was accompanied by lower podocyte density, reduced canonical podocyte protein expression, and increased glomerular scarring. These results are consistent with injury-induced senescence in young podocytes, leading to increased senescence of podocytes by middle age accompanied by lower podocyte lifespan and health span.NEW & NOTEWORTHY Glomerular function is decreased by aging. However, little is known about the molecular mechanisms involved in age-related glomerular changes and which factors could contribute to a worse glomerular aging process. Here, we reported that podocyte injury in young mice and culture podocytes induced senescence, a marker of aging, and accelerates glomerular aging when compared with healthy aging mice.

A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis recurrence.

Possible roles of anti-nephrin antibodies in post-transplant recurrent focal segmental glomerulosclerosis (FSGS) have been reported recently. To confirm these preliminary results, we performed a multi-institutional study of 22 Japanese pediatric kidney transplant recipients with FSGS including eight genetic FSGS and 14 non-genetic (presumed primary) FSGS. Eleven of the 14 non-genetic FSGS patients had post-transplant recurrent FSGS. Median (interquartile range) plasma levels of anti-nephrin antibodies in post-transplant recurrent FSGS measured using ELISA were markedly high at 899 (831, 1292) U/mL (cutoff 231 U/mL) before transplantation or during recurrence. Graft biopsies during recurrence showed punctate IgG deposition co-localized with nephrin that had altered localization with increased nephrin tyrosine phosphorylation and Src homology and collagen homology A expressions. Graft biopsies after remission showed no signals for IgG and a normal expression pattern of nephrin. Anti-nephrin antibody levels decreased to 155 (53, 367) U/mL in five patients with samples available after remission. In patients with genetic FSGS as in those with non-genetic FSGS without recurrence, anti-nephrin antibody levels were comparable to those of 30 control individuals, and graft biopsies had no signals for IgG and a normal expression pattern of nephrin. Thus, our results suggest that circulating anti-nephrin antibodies are a possible candidate for circulating factors involved in the pathogenesis of post-transplant recurrent FSGS and that this may be mediated by nephrin phosphorylation. Larger studies including other ethnicities are required to confirm this finding.

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 α3α4α5(IV) and α1α1α2(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 α3α4α5(IV) relative to α1α1α2(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.

Post-transplant recurrence of focal segmental glomerular sclerosis: consensus statements.

Focal segmental glomerular sclerosis (FSGS) is 1 of the primary causes of nephrotic syndrome in both pediatric and adult patients, which can lead to end-stage kidney disease. Recurrence of FSGS after kidney transplantation significantly increases allograft loss, leading to morbidity and mortality. Currently, there are no consensus guidelines for identifying those patients who are at risk for recurrence or for the management of recurrent FSGS. Our work group performed a literature search on PubMed/Medline, Embase, and Cochrane, and recommendations were proposed and graded for strength of evidence. Of the 614 initially identified studies, 221 were found suitable to formulate consensus guidelines for recurrent FSGS. These guidelines focus on the definition, epidemiology, risk factors, pathogenesis, and management of recurrent FSGS. We conclude that additional studies are required to strengthen the recommendations proposed in this review.

Differing sensitivities to angiotensin converting enzyme inhibition of kidney disease mediated by APOL1 high-risk variants G1 and G2.

Apolipoprotein L1 (APOL1) variants G1 and G2 contribute to the excess risk of kidney disease in individuals of recent African ancestry. Since disease mechanisms and optimal treatments remain controversial, we study the effect of current standard-of-care drugs in mouse models of APOL1 kidney disease. Experiments were performed in APOL1 BAC-transgenic mice, which develop proteinuria and glomerulosclerosis following injection with a pCpG-free IFNɤ plasmid. Proteinuric, plasmid injected G1/G1 and G2/G2 mice were randomized to drug treatment or no treatment. Lisinopril, dapagliflozin, and hydralazine were administered in drinking water starting day seven. The urine albumin/creatinine ratio was measured twice weekly, and the kidneys examined histologically with the focal segmental glomerulosclerosis score computed from periodic acid-Shiff-stained sections. The angiotensin converting enzyme inhibitor lisinopril, at standard dose, reduced proteinuria by approximately 90-fold and reduced glomerulosclerosis in the APOL1 G1/G1 BAC-transgenic mice. These effects were independent of blood pressure. Dapagliflozin did not alter disease progression in either G1/G1 or G2/G2 mice. Proteinuria reduction and glomerulosclerosis in G2/G2 BAC-transgenic mice required lisinopril doses two times higher than were effective in G1/G1 mice but achieved a much smaller benefit. Therefore, in these BAC-transgenic mouse models of APOL1 disease, the anti-proteinuric and anti-glomerulosclerotic effects of standard dose lisinopril were markedly effective in G1/G1 compared with G2/G2 APOL1 mice. Comparable reduction in blood pressure by hydralazine treatment provided no such protection. Neither G1/G1 or G2/G2 mice showed improvement with the sodium-glucose cotransporter-2 inhibition dapagliflozin. Thus, it remains to be determined if similar differences in ACE inhibitor responsiveness are observed in patients.

Rescue with obinutuzumab and daratumumab as combined B cell/plasma cell targeting approach in severe posttransplant focal segmental glomerulosclerosis recurrence.

The recurrence of primary focal segmental glomerulosclerosis (FSGS) after kidney transplantation is associated with a high graft loss rate with standard treatments based on plasmapheresis with/without rituximab. We present 2 consecutive cases of nongenetic early severe recurrent FSGS refractory to rituximab and anti-interleukin 1 treatment and with a partial response to plasmapheresis. Case 1 was a 22-year-old man who was rescue-treated for recurrence 36 weeks after transplantation with obinutuzumab (1000 mg/1.73 m2, 1 dose) and daratumumab (18 mg/kg each dose, 8 doses), resulting in plasmapheresis discontinuation and a drop of proteinuria from 29 to 2.3 g/d. Proteinuria increased with circulating CD38+ plasma cells and responded to an additional daratumumab dose. Currently, the proteinuria is 1.8 g/d, 14.5 months after discontinuing plasmapheresis and starting obinutuzumab and daratumumab therapy. Case 2 was a 15-year-old girl who was plasmapheresis dependent with 2 g/d proteinuria 82 weeks after transplantation, with a Tesio catheter in the right jugular vein as the only possible vascular access. After treatment with obinutuzumab and daratumumab (1 dose each), she achieved stable complete remission (0.3 g/d proteinuria) with persistent plasmapheresis discontinuation. These cases suggest the potential of combining obinutuzumab with daratumumab for the treatment of recurrent FSGS.

Efficacy of combined rituximab and daratumumab treatment in posttransplant recurrent focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is one of the leading causes of kidney failure and it is characterized by a high rate of recurrence after kidney transplant. Moreover, FSGS recurrence is worsened by an increased risk of graft failure. Common therapies for FSGS recurrence mostly consist of plasma exchange treatments, also for prolonged time, and rituximab, with variable efficacy. We report 5 cases of early FSGS recurrence after kidney transplant, resistant to plasma exchange and rituximab treatment that subsequently resolved after combined therapy with rituximab and daratumumab. All cases were negative for genetic FSGS. The combined treatment induced a complete response in all the cases and was well tolerated. We also performed a comprehensive flow cytometry analysis in 2 subjects that may suggest a mechanistic link between plasma cells and disease activity. In conclusion, given the lack of viable treatments for recurrent FSGS, our reports support the rationale for a pilot trial testing the safety/efficacy profile of combined rituximab and daratumumab in posttransplant FSGS recurrence.

Association of Obesity With Kidney and Cardiac Outcomes Among Patients With Glomerular Disease: Findings From the Cure Glomerulonephropathy Network.

RATIONALE & OBJECTIVE: The influence of obesity on cardiorenal outcomes in individuals with glomerular disease is incompletely known. This study examined the association between obesity and kidney and cardiovascular outcomes in children and adults with glomerular kidney disease. STUDY DESIGN: Prospective, multicenter, observational study. SETTING & PARTICIPANTS: Participants in the Cure Glomerulonephropathy Network (CureGN) who were≥5 years of age at enrollment. EXPOSURE: Adult body mass index (BMI) groups: 20-24 (healthy) versus 25-34 (overweight/class 1 obesity) versus≥35 (class 2-3 obesity); and pediatric BMI percentiles: 5th-84th (healthy) versus 85th-94th (overweight) versus≥95th (obese). OUTCOME: A composite kidney outcome (40% estimated glomerular filtration rate [eGFR] decline or kidney failure) and a composite cardiovascular outcome (myocardial infarction, stroke, heart failure, or death). ANALYTICAL APPROACH: Time to composite primary outcomes by BMI strata were estimated using Kaplan-Meier analysis. The adjusted associations between BMI and outcomes were estimated using Cox proportional hazards analysis. RESULTS: The study included 2,301 participants (1,548 adults and 753 children). The incidence of the primary kidney end point was 90.8 per 1,000 person-years in adults with class 2-3 obesity, compared with 58.0 in normal weight comparators. In the univariable analysis, class 2-3 obesity was associated with the primary kidney outcome only in adults (HR, 1.6 [95% CI, 1.1-2.2], P=0.006) compared with the healthy weight groups. In the multivariable adjusted analysis, class 2-3 obesity did not remain significant among adults when controlling for baseline eGFR and proteinuria. Adults with class 2-3 obesity had an incidence of 19.7 cardiovascular events per 1,000 person-years and greater cardiovascular risk (HR, 3.9 [95% CI, 1.4-10.7], P=0.009) in the fully adjusted model. LIMITATIONS: BMI is an imperfect indicator of adiposity. Residual confounding may exist from socioeconomic factors. CONCLUSIONS: Among adult patients in CureGN, class 2-3 obesity is associated with cardiovascular but not kidney outcomes when adjusted for potential confounding factors. PLAIN-LANGUAGE SUMMARY: Obesity is a risk factor for adverse heart and kidney outcomes in patients with chronic kidney disease, but whether it is associated with these outcomes in patients with glomerulonephropathy is not known. This study used existing data from a large sample of adults and children with glomerular diseases to address this question. The findings suggest that obesity increases the risk of cardiovascular but not kidney disease events in adult patients with glomerular disease.

Association of COVID-19 Versus COVID-19 Vaccination With Kidney Function and Disease Activity in Primary Glomerular Disease: A Report of the Cure Glomerulonephropathy Study.

RATIONALE & OBJECTIVE: Patients with glomerular disease (GN) may be at increased risk of severe COVID-19, yet concerns over vaccines causing disease relapse may lead to vaccine hesitancy. We examined the associations of COVID-19 with longitudinal kidney function and proteinuria and compared these with similar associations with COVID-19 vaccination. STUDY DESIGN: Observational cohort study from July 1, 2021, to January 1, 2023. SETTING & PARTICIPANTS: A prospective observational study network of 71 centers from North America and Europe (CureGN) with children and adults with primary minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy. EXPOSURE: COVID-19 and COVID-19 vaccination. OUTCOME: Repeated measure of estimated glomerular filtration rate (eGFR); recurrent time-to-event outcome of GN disease worsening as defined by doubling of the urinary protein-creatinine ratio (UPCR) to at least 1.5g/g or increase in dipstick urine protein by 2 ordinal levels to 3+(300mg/dL) or above. ANALYTICAL APPROACH: Interrupted time series analysis for eGFR. Prognostic matched sequential stratification recurrent event analysis for GN disease worsening. RESULTS: Among 2,055 participants, 722 (35%) reported COVID-19 infection; of these, 92 (13%) were hospitalized, and 3 died (<1%). The eGFR slope before COVID-19 infection was-1.40mL/min/1.73m2 (± 0.29 SD); within 6 months after COVID-19 infection, the eGFR slope was-4.26mL/min/1.73m2 (± 3.02 SD), which was not significantly different (P=0.34). COVID-19 was associated with increased risk of worsening GN disease activity (HR, 1.35 [95% CI, 1.01-1.80]). Vaccination was not associated with a change in eGFR (-1.34mL/min/1.73m2±0.15 SD vs-2.16mL/min/1.73m2±1.74 SD; P=0.6) or subsequent GN disease worsening (HR 1.02 [95% CI, 0.79-1.33]) in this cohort. LIMITATIONS: Infrequent or short follow-up. CONCLUSIONS: Among patients with primary GN, COVID-19 infection was severe for 1 in 8 cases and was associated with subsequent worsening of GN disease activity, as defined by proteinuria. By contrast, vaccination against COVID-19 was not associated with change in disease activity or kidney function decline. These results support COVID-19 vaccination for patients with GN. PLAIN-LANGUAGE SUMMARY: In this cohort study of 2,055 patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy, COVID-19 resulted in hospitalization or death for 1 in 8 cases and was associated with a 35% increase in risk for worsening proteinuria. By contrast, vaccination did not appear to adversely affect kidney function or proteinuria. Our data support vaccination for COVID-19 in patients with glomerular disease.

Efficacy of Rituximab for Minimal Change Disease and Focal Segmental Glomerulosclerosis with Frequently Relapsing or Steroid-Dependent Nephrotic Syndrome in Adults: A Chinese Multicenter Retrospective Study.

INTRODUCTION: Rituximab has been proven effective and safe in pediatric patients with frequently relapsing or steroid-dependent nephrotic syndrome (FR/SDNS). We aimed to analyze the efficacy and safety of rituximab in adult FR/SDNS patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). METHODS: A retrospective cohort study at three nephrology centers in China included adult FR/SDNS patients with biopsy-proven MCD or FSGS. Primary outcomes were relapse frequency and first relapse-free survival time. Adverse events were well recorded, and logistic regression analyses were used to investigate the risk factors of relapse. RESULTS: Eighty-one patients (age, 25.0 years; interquartile range, 20.0-40.5; 67% males; 82.7% MCD) received an average rituximab dose of 1,393.8 ± 618.7 mg/2 years during the 2-year follow-up period. The relapse frequency, calculated as the ratio of relapse times to follow-up years, significantly decreased after rituximab treatment (0.04 [0.00, 0.08] vs. 1.71 [1.00, 2.45], p < 0.001). The first relapse-free survival time was 16.7 ± 8.0 months. Fifty-seven patients (70.4%) achieved cessation of corticosteroids and immunosuppressants within 3 months after the first rituximab infusion. Adverse events were mostly mild, and no severe treatment-related adverse events were observed. Low serum albumin level before rituximab and high CD56+CD16+ natural killer cell count after rituximab were independent risk factors of relapse within 2 years after rituximab treatment. CONCLUSION: Rituximab was proven an effective and safe treatment option for adult FR/SDNS patients with MCD or FSGS in maintaining disease remission and minimizing corticosteroid exposure.

Prophylactic treatment of FSGS recurrence in patients who relapsed in a previous kidney graft.

BACKGROUND AND HYPOTHESIS: Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation and is classically associated with a significant decrease in graft survival. A major risk factor is a prior history of FSGS recurrence on a previous graft. This analysis reports the impact of a prophylactic treatment of FSGS recurrence in very high-risk patients who experienced a recurrence on a previous graft. METHODS: We performed a retrospective multicentre observational study in 25 French transplantation centres. The inclusion criteria were patients aged more than 18 years who had undergone kidney transplant between December 31, 2004, and December 31, 2020, and who had a history of FSGS recurrence on a previous graft. RESULTS: We identified 66 patients: 40 received prophylactic treatment (PT+), including intravenous cyclosporine and/or rituximab and/or plasmapheresis, and 26 did not receive any prophylactic treatment (PT-). The time to progression to end-stage kidney disease was similar between groups. The PT + group was younger at FSGS diagnosis and at the time of kidney retransplantation and lost their previous graft faster. The overall recurrence rate was 72.7% (76.9% in the PT- group and 70.0% in the PT + group, P = 0.54). At least partial remission was achieved in 87.5% of patients. The 5-year graft survival was 67.7% (95% CI: 53.4 to 78.4%): 65.1% (95%CI: 48.7 to 77.4%) in patients with FSGS recurrence vs. 77.3% (95% CI: 43.8 to 92.3%) in patients without recurrence (P = 0.48). CONCLUSION: Our study suggests that prophylactic treatment should not be used routinely in patients receiving a second transplantation after recurrence of FSGS on a previous graft. The recurrence rate is high regardless of the use of prophylactic treatment. However, the 5-year graft survival remains satisfactory.

Design and baseline characteristics of the Finerenone, in addition to standard of care, on the progression of kidney disease in patients with Non-Diabetic Chronic Kidney Disease (FIND-CKD) randomized trial.

BACKGROUND AND HYPOTHESIS: Finerenone, a non-steroidal mineralocorticoid receptor antagonist, improved kidney, and cardiovascular outcomes in patients with CKD and T2D in two Phase 3 outcome trials. The FIND-CKD study investigates the effect of finerenone in adults with CKD without diabetes. METHODS: FIND-CKD (NCT05047263 and EU CT 2023-506897-11-00) is a randomized, double-blind, placebo-controlled Phase 3 trial in patients with CKD of non-diabetic aetiology. Adults with a urinary albumin-creatinine ratio (UACR) of ≥ 200 to ≤3500 mg/g and eGFR ≥ 25 to <90 mL/min/1.73 m2 receiving a maximum tolerated dose of a renin-angiotensin-system (RAS) inhibitor were randomized 1:1 to once daily placebo or finerenone 10 or 20 mg depending on eGFR above or below 60 mL/min/1.73 m2. The primary efficacy outcome is total eGFR slope, defined as the mean annual rate of change in eGFR from baseline to Month 32. Secondary efficacy outcomes include a combined cardiorenal composite outcome comprising time to kidney failure, sustained ≥57% decrease in eGFR, hospitalization for heart failure, or cardiovascular death, as well as separate kidney and cardiovascular composite outcomes. Adverse events are recorded to assess tolerability and safety. RESULTS: Across 24 countries, 3231 patients were screened and 1584 were randomized to study treatment. The most common causes of CKD were chronic glomerulonephritis (57.0%) and hypertensive/ischaemic nephropathy (29.0%). Immunoglobulin A nephropathy was the most common glomerulonephritis (26.3% of the total population). At baseline, mean eGFR and median UACR were 46.7 mL/min/1.73 m2 and 818.9 mg/g, respectively. Diuretics were used by 282 participants (17.8%), statins by 851 (53.7%), and calcium channel blockers by 794 (50.1%). SGLT2 inhibitors were used in 16.9% of patients; these individuals had a similar mean eGFR (45.6 vs 46.8 mL/min/1.73 m2) and slightly higher median UACR (871.9 vs 808.3 mg/g) compared to those not using SGLT2 inhibitors at baseline. CONCLUSIONS: FIND-CKD is the first Phase 3 trial of finerenone in patients with CKD of non-diabetic aetiology.

Clinical Course of Nonresponders With Recurrent Focal Segmental Glomerulosclerosis After Pediatric Kidney Transplantation: A Retrospective Multicenter Study.

BACKGROUND: Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation and is associated with poor graft survival. Patients who do not achieve remission (nonresponders) have an especially poor graft survival. However, the characteristics that may affect graft survival in nonresponders are unknown. This study aimed to determine the clinical characteristics associated with graft survival in nonresponders. METHODS: We retrospectively collected the clinical records of patients with FSGS and an age at onset <16 years who experienced posttransplant recurrence of FSGS at six hospitals in Japan from 1993 to 2018. RESULTS: Eight nonresponders with recurrent FSGS were enrolled in this study. The median time to recurrence after kidney transplantation was 1 day (interquartile range, 1-2 days). All patients received therapeutic plasma exchange and methylprednisolone pulse therapy. Rituximab was used as an add-on therapy in three patients. Five patients lost their graft within 2 years after kidney transplantation (rapid group). In contrast, three patients had much longer graft survival (nonrapid group). We compared the clinical characteristics of the rapid and nonrapid groups. Proteinuria tended to be lower in the nonrapid group at the third and subsequent months of therapy. The rapid group had persistent nephrotic syndrome. The rate of reduction in proteinuria was lower in the rapid group than in the nonrapid group. CONCLUSIONS: Our study suggests that persistent nephrotic syndrome and a low rate of reduction in proteinuria may predict rapid progression to graft failure in nonresponders.

Identification of Plasma hsa_circ_0001230 and hsa_circ_0023879 as Potential Novel Biomarkers for Focal Segmental Glomerulosclerosis and circRNA-miRNA-mRNA Network Analysis.

INTRODUCTION: Focal segmental glomerulosclerosis (FSGS) is a common glomerulopathy with an unclear mechanism. The demand for FSGS clinical diagnostic biomarkers has not yet been met. Circular RNA (circRNA) is a novel non-coding RNA with multiple functions, but its diagnostic value for FSGS remains unexplored. This study aimed to identify circRNAs that could aid in early clinical diagnosis and to investigate their mechanisms in podocyte injury. METHODS: The signature of plasma circRNAs for FSGS was identified by circRNA microarray. The existence of circRNAs was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR), RNase R assay, and DNA sequencing. Plasma levels of circRNAs were evaluated by qRT-PCR. The diagnostic value was appraised by the receiver operating characteristic curve. The circRNA-miRNA-mRNA network was built with Cytoscape 7.3.2. Statistically significant differences were calculated by the Mann-Whitney U test. RESULTS: A total of 493 circRNAs (165 upregulated, 328 downregulated) were differentially expressed in the plasma of FSGS patients (n = 3) and normal controls (n = 3). Eight candidate circRNAs were demonstrated to be circular and stable transcripts. Among them, hsa_circ_0001230 and hsa_circ_0023879 were significantly upregulated in FSGS patients (n = 29) compared to normal controls (n = 51). The areas under the curve value of hsa_circ_0001230 and hsa_circ_0023879 were 0.668 and 0.753, respectively, while that of the two-circRNA panel was 0.763. The RNA pull-down analysis revealed that hsa_circ_0001230 and hsa_circ_0023879 could sponge hsa-miR-106a. Additionally, hsa_circ_0001230 and hsa_circ_0023879 positively regulated hsa-miR-106a target genes phosphatase and tensin homolog (PTEN) and Bcl-2-like protein 11 (BCL2L11) in podocytes. CONCLUSION: hsa_circ_0001230 and hsa_circ_0023879 are novel blood biomarkers for FSGS. They may regulate podocyte apoptosis by competitively binding to hsa-miR-106a.

Hidden genetics behind glomerular scars: an opportunity to understand the heterogeneity of focal segmental glomerulosclerosis?

Focal segmental glomerulosclerosis (FSGS) is a complex disease which describes different kinds of kidney defects, not exclusively linked with podocyte defects. Since nephrin mutation was first described in association with early-onset nephrotic syndrome (NS), many advancements have been made in understanding genetic patterns associated with FSGS. New genetic causes of FSGS have been discovered, displaying unexpected genotypes, and recognizing possible site of damage. Many recent large-scale sequencing analyses on patients affected by idiopathic chronic kidney disease (CKD), kidney failure (KF) of unknown origin, or classified as FSGS, have revealed collagen alpha IV genes, as one of the most frequent sites of pathogenic mutations. Also, recent interest in complex and systemic lysosomal storage diseases, such as Fabry disease, has highlighted GLA mutations as possible causes of FSGS. Tubulointerstitial disease, recently classified by KDIGO based on genetic subtypes, when associated with UMOD variants, may phenotypically gain FSGS features, as well as ciliopathy genes or others, otherwise leading to completely different phenotypes, but found carrying pathogenic variants with associated FSGS phenotype. Thus, glomerulosclerosis may conceal different heterogeneous conditions. When a kidney biopsy is performed, the principal objective is to provide an accurate diagnosis. The broad spectrum of phenotypic expression and genetic complexity is demonstrating that a combined path of management needs to be applied. Genetic investigation should not be reserved only to selected cases, but rather part of medical management, integrating with clinical and renal pathology records. FSGS heterogeneity should be interpreted as an interesting opportunity to discover new pathways of CKD, requiring prompt genotype-phenotype correlation. In this review, we aim to highlight how FSGS represents a peculiar kidney condition, demanding multidisciplinary management, and in which genetic analysis may solve some otherwise unrevealed idiopathic cases. Unfortunately there is not a uniform correlation between specific mutations and FSGS morphological classes, as the same variants may be identified in familial cases or sporadic FSGS/NS or manifest a variable spectrum of the same disease. These non-specific features make diagnosis challenging. The complexity of FSGS genotypes requires new directions. Old morphological classification does not provide much information about the responsible cause of disease and misdiagnoses may expose patients to immunosuppressive therapy side effects, mistaken genetic counseling, and misguided kidney transplant programs.

Clinical characteristics and favorable treatment responses of recurrent focal segmental glomerulosclerosis or steroid-resistant nephrotic syndrome in children after kidney transplantation.

BACKGROUND: Recurrence of focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) after kidney transplant leads to significant morbidity and potentially earlier allograft loss. To date however, reported rates, risk factors and treatment outcomes have varied widely. METHODS: We applied computational phenotypes to a multicenter aggregation of electronic health records data from 7 large pediatric health systems in the USA, to identify recurrence rates, risk factors, and treatment outcomes. We refined the data collection by chart review. RESULTS: From > 7 million patients, we compared children with primary FSGS/SRNS who received a kidney transplant between 2009 and 2020 and who either developed recurrence (n = 67/165; 40.6%) or did not (n = 98/165). Serum albumin level at time of transplant was significantly lower and recipient HLA DR7 presence was significantly higher in the recurrence group. By 36 months post-transplant, complete remission occurred in 58.2% and partial remission in 17.9%. Through 6 years post-transplant, no remission after recurrence was associated with an increased risk of allograft loss over time (p < 0.0001), but any remission showed similar allograft survival and function decline to those with no recurrence. Since treatments were used in non-random fashion, using spline curves and multivariable non-linear analyses, complete + partial remission chance was significantly higher with greater plasmapheresis sessions, CTLA4-Ig doses or LDL-apheresis sessions. Only treatment with anti-CD20, CTLA4-Ig agents, or LDL-apheresis sessions were associated with complete remission. Excluding 25 patients with mutations did not significantly change our results. CONCLUSIONS: Our contemporary high-risk cohort had higher favorable response rates than most prior reports, from combinations of agents.