Focal Segmental Glomerulosclerosis Research Articles

Obinutuzumab as a viable therapeutic strategy in rituximab-refractory childhood frequently relapsing, steroid-dependent nephrotic syndrome that relapsed during B-cell depletion.

A subgroup of children with frequently-relapsing, steroid-dependent nephrotic syndrome relapse during B-cell depletion after rituximab. A 15-year-old boy with focal segmental glomerulosclerosis became rituximab-refractory after 5 courses of treatments, with a relapse-free period shortened to 1month. Circulating total and memory B-cells were undetectable at the time of relapse. A single infusion of obinutuzumab sustained relapse-free remission up to the last follow-up at 18months. There was persistent hypogammaglobulinemia but no infection was observed. Obinutuzumab may be a viable option for attaining long-term remission with reasonable side effect profiles in patients who relapse during B-cell depletion after rituximab.

Management and long-term outcome of recurrent idiopathic FSGS in pediatric kidney transplant recipients

Focal segmental glomerulosclerosis (FSGS) is a major cause of pediatric kidney failure. Most cases of FSGS in children are idiopathic and have a high risk of post-transplantation recurrence and graft loss. Common treatments for recurrent FSGS (rFSGS) post-transplantation include plasmapheresis, immunoadsorption, and/or immunomodulatory therapy. This study retrospectively evaluated the efficacy and safety of early plasmapheresis followed by rituximab for inducing and maintaining remission in rFSGS. Between 2014 and 2023, 8 of 65 pediatric kidney transplant recipients at our center were diagnosed with idiopathic FSGS. rFSGS was diagnosed based on nephrotic range proteinuria with no other cause and managed with plasmapheresis. Rituximab therapy was used for those who did not achieve complete remission with prolonged plasmapheresis or remained plasmapheresis dependent. 6 of 8 (75%) transplant recipients with idiopathic FSGS experienced rFSGS. All patients achieved partial or complete remission with plasmapheresis, with response times ranging from 8 to 379 days (median 13 days). Rituximab therapy was introduced for 5 plasmapheresis-dependent patients, leading to sustained remission and cessation of plasmapheresis in 3 patients, while 2 showed improved proteinuria and reduced plasmapheresis frequency. Adverse effects included rituximab-induced serum sickness in one patient and one mild allergic reaction. One patient experienced graft loss due to humoral rejection, but no grafts were lost to rFSGS, and all other grafts remained functional over an average follow-up of 50 months. Early plasmapheresis followed by rituximab therapy effectively induces remission in most post-transplantation rFSGS cases, is well tolerated, and prevents graft loss. Larger studies are needed to confirm these findings.

APOL1 Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans.

Apolipoprotein L1 gene (APOL1) variants are risk factors for chronic kidney disease (CKD) among Black Americans. Data are sparse on the genetic epidemiology of CKD and the clinical association of APOL1 variants with CKD in West Africans, a major group in the Black population. We conducted a case-control study involving participants from Ghana and Nigeria who had CKD stages 2 through 5, biopsy-proven glomerular disease, or no kidney disease. We analyzed the association of CKD with APOL1 variants among participants with high-risk genotypes (two APOL1 risk alleles) and those with low-risk genotypes (fewer than two APOL1 risk alleles) by fitting logistic-regression models that controlled for covariates, including clinical site, age, and sex. Among 8355 participants (4712 with CKD stages 2 through 5, 866 with glomerular diseases, and 2777 with no kidney disease), the prevalence of monoallelic APOL1 variants was 43.0% and that of biallelic APOL1 variants was 29.7%. Participants with two APOL1 risk alleles had higher odds of having CKD than those with one risk allele or no risk alleles (adjusted odds ratio, 1.25; 95% confidence interval [CI], 1.11 to 1.40), as well as higher odds of focal segmental glomerulosclerosis (adjusted odds ratio, 1.84; 95% CI, 1.30 to 2.61). Participants with one APOL1 risk allele had higher odds of having CKD than those with no risk alleles (adjusted odds ratio, 1.18; 95% CI, 1.04 to 1.33), as well as higher odds of focal segmental glomerulosclerosis (adjusted odds ratio, 1.61; 95% CI, 1.04 to 2.48). The inclusion of covariates did not modify the association of monoallelic and biallelic APOL1 variants with CKD or focal segmental glomerulosclerosis. In this study, monoallelic APOL1 variants were associated with 18% higher odds of CKD and 61% higher odds of focal segmental glomerulosclerosis; biallelic APOL1 variants were associated with 25% higher odds of CKD and 84% higher odds of focal segmental glomerulosclerosis. (Funded by the National Human Genome Research Institute and others.).

Role of baseline soluble tumor necrosis factor receptor 2 as a biomarker in primary podocytopathy: Implications for renal impairment and disease progression

BackgroundPodocytopathies, including minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and collapsing glomerulopathy (CG), are kidney diseases that damage glomerular podocytes, leading to heavy proteinuria and nephrotic syndrome (NS). Inflammation plays a critical role in the progression of chronic kidney disease (CKD), with recent studies linking inflammatory biomarkers to declining kidney function. Tumor necrosis factor-alpha (TNF-α), an essential inflammatory cytokine, interacts with its circulating receptors, TNFR1 and TNFR2. The TNF-α pathway has been implicated in the pathogenesis of FSGS and MCD. Increased circulating TNFR2 levels have been associated with worsening renal function in podocytopathies, suggesting that the TNF-α inflammatory pathway significantly contributes to disease progression.MethodsWe conducted a study involving 53 patients with biopsy-proven MCD or FSGS and 53 healthy, age- and gender-matched controls. All patients were followed for 18 months. We analyzed serum and urine TNFR2 levels and gene expression at baseline and after three months. To assess the ability of TNFR2 to predict persistent decline in estimated glomerular filtration rate (eGFR < 30 mL/min/1.73m2), remission, and relapse, we employed Cox regression analysis. Additionally, we evaluated its prognostic utility for predicting progression to stage 4 CKD using ROC curve analysis.ResultsSerum and urine TNFR2 levels were significantly elevated in patients compared to controls. Serum TNFR2 was a significant predictor in univariate Cox regression analysis for persistent eGFR decline (HR 1.017, 95% CI: 1.003 to 1.032, p = 0.018), remission (HR 0.995, 95% CI: 0.992 to 0.999, p = 0.006), and relapse (HR 1.005, 95% CI: 1.001 to 1.010, p = 0.029). The ROC curve analysis demonstrated that serum TNFR2 levels had a strong prognostic ability for predicting progression to stage 4 CKD, with an AUC of 0.848 (95% CI: 0.737—0.960), sensitivity of 81%, and specificity of 71%.ConclusionThis study underscores the critical role of circulating TNFR2 in kidney injury among patients with primary podocytopathy. Elevated TNFR2 levels are significant predictors of persistent eGFR decline and disease relapse, highlighting their potential as biomarkers for disease progression and prognosis.

The clinical course of SARS-CoV-2 infection in patients with glomerular diseases and evaluation of the subsequent risk of relapse

IntroductionThis study aimed to describe the clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with glomerular diseases (GDs) and its impact on the probability of relapse.MethodsPatients with biopsy-proven GD and positive PCR test for SARS-CoV-2 from glomerular clinics across Greece were studied retrospectively. Those who received the GD diagnosis after the SARS-CoV-2 vaccination or coronavirus disease 2019 (COVID-19) or ended in ESKD prior to infection were excluded. Demographics, histopathological diagnoses, past medical history, immunosuppression, and GD activity status were recorded.ResultsA total of 219 patients with GDs and documented SARS-CoV-2 infection were included. The mean time from the diagnostic kidney biopsy to SARS-CoV-2 infection was 67.6 ( ± 59.3) months. Among the participants, 82.5% had been vaccinated against SARS-CoV-2 with three doses (range: 2.5–3) without subsequent GD reactivation in 96.2% of them. Twenty-two patients (10%) were hospitalized for COVID-19 and one (0.5%) required mechanical ventilation. Four (1.8%) died due to COVID-19 and one (0.5%) had long COVID-19 symptoms. Among patients in remission prior to SARS-CoV-2 infection, 22 (11.2%) experienced a GD relapse within 2.2 (range: 1.5–3.7) months from the diagnostic test. The relapse-free survival after COVID-19 was significantly shorter for patients with minimal change disease, pauci-immune glomerulonephritis, and focal segmental glomerulosclerosis. No difference was observed in the relapse-free survival post-COVID-19 based on the history of SARS-CoV-2 vaccination.ConclusionsSARS-CoV-2 infection appears to have a symptomatic but uncomplicated sequence in vaccinated patients with GDs, with a significant impact on the clinical course of GD, associated with an increased probability of relapse in certain histopathological types.

Long-Term Outcomes of Rituximab-Treated Adult Patients with Podocytopathies

Background: Long-term outcomes of rituximab-treated adult patients with podocytopathies (either minimal change disease or focal segmental glomerulosclerosis) are largely unknown. Methods: A retrospective study at 30 nephrology departments from 15 countries worldwide included rituximab-treated adults with primary podocytopathies and a minimum clinical follow-up of 36 months. The primary outcome was relapse-free survival at 36 months. Results: 183 adult patients (n=64 with focal segmental glomerulosclerosis and n=119 with minimal change disease) with difficult-to-treat nephrotic syndrome (68% steroid-dependent/frequently relapsing, 22% steroid-resistant, 85% previously treated with two or more lines of immunosuppressive therapy) were treated with rituximab as part of a remission induction regimen. Complete or partial remission at 6 months after rituximab treatment was achieved in 82%. Eighty-three of 151 (55%) initial responders achieved long-term relapse-free survival over three years. Maintenance therapy with rituximab was associated with a better relapse-free survival (HR 2.05, 95% CI: 1.07-3.91), irrespective of the dosing regimen. At 36 months, 61% of initial responders receiving maintenance therapy with rituximab achieved long-term relapse-free survival and withdrawal of all concomitant immunosuppressive medication compared to 36% of patients without maintenance treatment (OR 2.69, 95% CI: 1.27-5.73). Relapses per year were reduced from an annual relapse rate of 1.0 (95% CI: 1.0-1.7) before to 0.17 (95% CI: 0.00-0.24) relapses/year after rituximab initiation. Over the 36 months of follow-up, a stable course of estimated glomerular filtration rate (eGFR) was observed in those who initially responded with either complete or partial remission, whereas non-responders experienced a reduction in eGFR reaching -11 (95% CI: -18 to -8) mL/min/1.73m2 . Conclusions: Rituximab facilitated achievement of initial and long-term response in a majority of adult patients with difficult-to-treat podocytopathies. Maintenance treatment with rituximab further associated with long-term relapse-free survival over three years. Non-response to initial rituximab treatment was associated with poor kidney prognosis.

Evaluating Predictive Factors for Lymphocele Formation Following Kidney Transplantation.

Lymphocele is a common complication post-kidney transplantation, influenced by various factors including surgical technique, graft vessel count, operator experience, body mass index, ischemia time, and immunotherapy regimens. The purpose of this study was to evaluate lymphocele risk factors, particularly focusing on the role of end-stage kidney disease. A retrospective study was conducted on renal transplant recipients from a single center (March 2020 to December 2022). Patients were categorized into those developing lymphocele and those without during the postoperative period. Data, including sociodemographic, personal history, graft-related variables, intervention, and postoperative outcomes, were collected from electronic medical records. Out of 291 renal transplant recipients, 57 (19.6%) developed postoperative lymphocele, with 15 (5.1%) being symptomatic. Patients with body mass index <24.9 kg/m2 have lower risk of developing lymphocele with an Odds Ratio of 0.538 (P=0.046). Higher lymphocele prevalence was noted in patients with chronic tubulointerstitial nephritis (46.2%; OR 3.815; P=0.024). Focal segmental glomerulosclerosis patients showed no lymphocele (0.0%; OR 0.123; P=0.048). Other factors, including autosomal dominant polycystic kidney disease, did not exhibit significant differences in lymphocele prevalence. The etiology of end-stage kidney disease can serve as a significant predictor of lymphocele development during the postoperative period following renal transplantation. Further larger prospective studies are required to comprehensively assess risk factors and explore end-stage kidney disease potential role in predicting lymphocele formation.

Incidence and Proportion of Primary Focal Segmental Glomerulosclerosis (FSGS) among a Racially and Ethnically Diverse Adult Patient Population between 2010-2021.

Focal segmental glomerulosclerosis (FSGS) refers to a pattern of glomerular injury but also includes primary FSGS which is considered as an immune mediated glomerulopathy. We sought to determine the incidence of primary FSGS and proportion of FSGS patients with primary FSGS among a large diverse patient population in the United States. A cross-sectional study (2010-2021) was performed within an integrated health system in patients (age ≥18yrs) with biopsy-proven FSGS. Among biopsies with FSGS as the first diagnosis on pathology report, chart reviews were performed to determine primary FSGS, defined as podocyte foot process effacement ≥80% on electron microscopy. The proportion of patients with primary FSGS and annual incidence rates (per 100,000 patient-years) were calculated. Standardized incidence rates were determined by age, sex, and race and ethnicity based on US population structure of the five-year (2018-2022) American Community Survey estimates. We identified 3,838 patients with FSGS reported on biopsy. Among 1,502 with FSGS as the principal diagnosis, 637 met criteria for primary FSGS (mean [SD] age 55.5 years [17.9], 56.5% male, 35.6% Hispanic, 28.7% White, 17.9% Asian/Pacific Islander, and 16.0% Black). The mean standardized incidence rate [CI] of primary FSGS was 1.7 [0.9, 2.5] per 100,000 patient-years during the study period. The standardized annual incidence rates ranged from 1.3 - 2.4 per 100,000 patient-years. Incidence rates (per 100,000 patient-years) were highest among Black (3.2), Asian (2.7), and Pacific Islander (2.8) patients. Primary FSGS accounted for 16.6% of biopsy-proven FSGS. Primary FSGS is a likely a rare disease with incidence highest among Black, Asian, and Pacific Islander people. More precise identification of primary FSGS may facilitate work to improve understanding of this glomerulopathy and improve kidney outcomes.

Endothelin Inhibitors in Chronic Kidney Disease: New Treatment Prospects.

The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease. In the kidney, endothelins are produced in mesangial cells and the glomerular basement membrane by the endothelium and podocytes. The endothelin system regulates glomerular function by inducing proliferation, increasing permeability and in effect proteinuria, and stimulating inflammation, tubular fibrosis, and glomerular scarring. Endothelin A receptor antagonists have been proven to delay the progression of chronic kidney disease and play a protective role in immunoglobulin A nephropathy, focal segmental glomerulosclerosis, and diabetic nephropathy. There are several ongoing research studies with ETAR antagonists in nondiabetic nephropathy, Alport disease, vasculitis and scleroderma nephropathy, which results are promising. Some reports suggest that the endothelin system might contribute to ischemia-reperfusion injury, acute graft rejection and deterioration of graft function. Endothelin inhibition in renal transplantation and its influence on graft survival is the future direction needing further research. The most frequent side effects associated with ETAR antagonists is fluid retention. Additionally, it should be considered if selective ETAR antagonists therapy needs to be co-administered with sodium-glucose co-transporter 2 inhibitors, renin-angiotensin-aldosterone inhibitors or diuretics and which patients should be recruited to such treatment to minimize the risk of adverse outcomes.

Clinical relevance of proteinuria selectivity index and fractional excretion of sodium in patients with nephrotic syndrome

Proteinuria selectivity index (PSI) is a potential tool for histological classification and prediction of treatment response in nephrotic syndrome, but evidence is insufficient. Clinical relevance of fractional excretion of sodium (FENa) in nephrotic syndrome remains largely unexplored. This multicenter retrospective study included patients with nephrotic syndrome who underwent kidney biopsy between January 2012 and June 2022. Optimal cutoffs for predicting complete remission based on PSI and FENa were determined using receiver operating characteristic curves. Patients were divided into two groups using these cutoffs and followed until complete remission. Of the 611 patients included, 177 had minimal change disease (MCD), 52 had focal segmental glomerulosclerosis (FSGS), and 149 had membranous nephropathy (MN). Median (interquartile range) PSI were 0.14 (0.09–0.19) for MCD, 0.33 (0.23–0.40) for FSGS, and 0.20 (0.14–0.30) for MN. FENa were 0.24 (0.09–0.68), 1.03 (0.50–2.14), and 0.78 (0.41–1.28). Patients with low PSI and FENa had a higher incidence of complete remission. Cox regression analyses demonstrated that both parameters were associated with achieving complete remission (HR 2.73 [95% CI 1.97–3.81] and HR 1.93 [95% CI 1.46–2.55], respectively). PSI and FENa may be useful for histological classification and predicting remission in nephrotic syndrome.

The contribution of the sphingosine 1-phosphate signaling pathway to chronic kidney diseases: recent findings and new perspectives.

Chronic kidney disease (CKD) is a multifactorial condition with diverse etiologies, such as diabetes mellitus, hypertension, and genetic disorders, often culminating in end-stage renal disease (ESRD). A hallmark of CKD progression is kidney fibrosis, characterized by the excessive accumulation of extracellular matrix components, for which there is currently no effective anti-fibrotic therapy. Recent literature highlights the critical role of sphingosine 1-phosphate (S1P) signaling in CKD pathogenesis and renal fibrosis. This review provides an in-depth analysis of the latest findings on S1P metabolism and signaling in renal fibrosis and in specific CKDs, including diabetic nephropathy (DN), lupus nephritis (LN), focal segmental glomerulosclerosis (FSGS), Fabry disease (FD), and IgA nephropathy (IgAN). Emerging studies underscore the therapeutic potential of modulating S1P signaling with receptor modulators and inhibitors, such as fingolimod (FTY720) and more selective agents like ozanimod and cenerimod. Additionally, the current knowledge about the effects of established kidney protective therapies such as glucocorticoids and SGLT2 and ACE inhibitors on S1P signaling will be summarized. Furthermore, the review highlights the potential role of S1P as a biomarker for disease progression in CKD models, particularly in Fabry disease and diabetic nephropathy. Advanced technologies, including spatial transcriptomics, are further refining our understanding of S1P's role within specific kidney compartments. Collectively, these insights emphasize the need for continued research into S1P signaling pathways as promising targets for CKD treatment strategies.

Is It a Tumor or Not? A Case of Focal Segmental Glomerulosclerosis Secondary to Type 2 Diabetes with a Concomitant Renal Pseudotumor

Background: Focal segmental glomerulosclerosis (FSGS) is a histologic pattern of glomerular injury that can be primary or secondary to various conditions, including obesity, diabetes, and hypertension. Renal masses, often detected incidentally, can be benign or malignant, with renal cell carcinoma (RCC) being the most common. This case report presents a patient with FSGS secondary to type 2 diabetes and a concomitant renal pseudotumor, initially suspected to be RCC. Case presentation: A 60-year-old woman presented with weakness, fever, and weight loss. Imaging revealed a renal mass, initially suspected to be RCC. A kidney biopsy revealed FSGS, and further evaluation confirmed type 2 diabetes. After controlling her diabetes and hypertension, the renal mass regressed, suggesting a pseudotumor. Conclusion: This case highlights the importance of considering pseudotumors in the differential diagnosis of renal masses, especially in patients with comorbidities such as diabetes. A kidney biopsy can help avoid unnecessary invasive procedures like nephrectomy.

Lipoprotein Apheresis: Utility, Outcomes, and Implementation in Clinical Practice: A Scientific Statement From the American Heart Association.

Despite the availability of multiple classes of lipoprotein-lowering medications, some high-risk patients have persistent hypercholesterolemia and may require nonpharmacologic therapy. Lipoprotein apheresis (LA) is a valuable but underused adjunctive therapeutic option for low-density lipoprotein cholesterol and lipoprotein(a) lowering, particularly in children and adults with familial hypercholesterolemia. In addition to lipid lowering, LA reduces serum levels of proinflammatory and prothrombotic factors, reduces blood viscosity, increases microvascular myocardial perfusion, and may provide beneficial effects on endothelial function. Multiple observational studies demonstrate strong evidence for improved cardiovascular outcomes with LA; however, use in the United States is limited to a fraction of its Food and Drug Administration-approved indications. In addition, there are limited data regarding LA benefit for refractory focal segmental glomerulosclerosis. In this scientific statement, we review the history of LA, mechanisms of action, cardiovascular and renal outcomes data, indications, and options for treatment.

8533 Salt on the Kidneys A case of DDAVP induced arginine vasopressin resistance

Abstract Disclosure: M.M. Jordan: None. J.R. Islam: None. R. Hassan: None. A 63-year old female with a history of head trauma complicated by polyuria and excessive fatigue diagnosed with central DI and started on treatment with oral Desmopressin. She had no other known pertinent medical history. Patient was lost to follow-up with an eventual visit to the emergency department with complaints of bilateral leg cramps, nausea and persistent headaches. She was noted to have been initiated intranasal desmopressin in addition to oral DDAVP. On initial lab work, Sodium was 114 along with acute kidney injury. She was admitted to ICU and treated with hypertonic saline. DDAVP was withheld until sodium normalized and stabilization of renal functions. GFR still remained impaired on discharge at 40 mL/min/1.73m*2. She was then discharged on DDAVP with reestablished follow up in the endocrinology clinic with complaints of persistent polyuria. Once more, she was sent to the emergency room and was admitted for acute renal injury secondary to dehydration in the setting of polyuria and altered mentation. Upon review of her medications, the patient continued both oral and inhaled DDAVP. No other medications or supplements were reported. During this subsequent hospitalization, sodium remained between 131-135 with urine output 4.5L/ day despite increasing doses of oral DDAVP and oral sodium supplementation. At which point, suspicion for mixed DI was hypothesized (central DI and arginine vasopressin resistance). Other causes of polyuria were ruled out. Labs for persistent AKI revealed gross proteinuria. Renal biopsy was performed during hospitalization which showed acute to chronic vascular thrombotic microangiopathy and focal segmental glomerulosclerosis with collapsing features. Extensive workup for chronic infections, autoimmune conditions and hematological malignancies were negative. This showed concerns for possible DDAVP induced renal injury. Presentation: 6/2/2024

An Updated Comprehensive Review on Diseases Associated with Nephrotic Syndromes.

There have been exciting advances in our knowledge of primary glomerular diseases and nephrotic syndromes in recent years. Beyond the histological pattern from renal biopsy, more precise phenotyping of the diseases and the use of modern nephrogenetics helps to improve treatment decisions and sometimes also avoid unnecessary exposure to potentially toxic immunosuppression. New biomarkers have led to easier and more accurate diagnoses and more targeted therapeutic decisions. The treatment landscape is becoming wider with a pipeline of promising new therapeutic agents with more sophisticated approaches. This review focuses on all aspects of entities that are associated with nephrotic syndromes with updated information on recent advances in each field. This includes podocytopathies (focal segmental glomerulosclerosis and minimal-change disease), membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, fibrillary glomerulonephritis, amyloidosis, and monoclonal gammopathy of renal significance in the context of the nephrotic syndrome, but also renal involvement in systemic diseases, diabetic nephropathy, and drugs that are associated with nephrotic syndromes.

The clinical characteristics and genotype analysis of LAMB2 gene mutation.

To report a case of steroid-resistant nephrotic syndrome caused by a LAMB2 gene mutation, examine the associated literature, outline the clinical and genetic features of Pierson syndrome, and deepen the clinical comprehension of this condition. The study involved retrospective summary and analysis of the clinical presentations, genetic mutation features, and prognosis of one case involving a LAMB2 gene mutation. PubMed, Medline, Web of Science, CNKI, and Wanfang databases were searched to gather and summarize information on the pathological phenotypes and genotypic alterations associated with LAMB2 mutations. A 9-month-old infant presented with edema and massive proteinuria, along with horizontal nystagmus and miosis, manifesting clinically as steroid-resistant nephrotic syndrome. Ocular symptoms prompted both a kidney biopsy and genetic testing. The biopsy revealed minimal change disease, while genetic testing identified compound heterozygous mutations in the LAMB2 gene: c.1405C > T (p.R469X) and c.1066 T > A (p.C356S), inherited from the father and mother, respectively. These mutations were determined to be novel. The diagnosis was confirmed as a LAMB2 gene mutation. A literature review of 26 cases with LAMB2 mutations indicated these typically presented as steroid-resistant or congenital nephrotic syndrome, with 14 cases also displaying ocular symptoms. Among the 18 cases undergoing kidney biopsy, findings included focal segmental glomerulosclerosis in 10 cases, minimal change disease in 4 cases, diffuse mesangial sclerosis in 2 cases, IgM nephropathy in 1 case, and mesangial proliferation in 1 case. Electron microscopy in 10 cases showed basement membrane splitting. Genetic analysis revealed 15 cases with compound heterozygous mutations, 5 with homozygous mutations, 3 with heterozygous mutations, 2 with frame-shift mutations, and 1 with a truncating mutation. 16 out of the 26 reported cases progressed to end-stage kidney disease. Mutations in the LAMB2 gene primarily manifest as steroid-resistant or congenital nephrotic syndrome, often accompanied by ocular abnormalities, suggesting a strong likelihood of this disease. The results of genetic testing offer a foundational basis for clinical diagnosis. The identification of a new mutation site in this case expands the known spectrum of mutations in the LAMB2 gene. Unfortunately, the prognosis associated with this condition is generally poor.

Anti-slit diaphragm antibodies on kidney biopsy identify pediatric patients with steroid-resistant nephrotic syndrome responsive to second-line immunosuppressants

Podocytopathies represent a group of glomerular disorders associated with minimal changes (MC) or focal segmental glomerulosclerosis (FSGS) lesion patterns at biopsy and heterogeneous responses to steroids. Anti-nephrin antibodies were previously found in such patients, suggesting an autoimmune form of podocytopathy. High resolution confocal microscopy on kidney biopsies of a cohort of 128 pediatric patients revealed localization of IgG along the slit diaphragm in 30% of patients with MC and 25% of those with FSGS, but not in other lesion patterns. Anti-nephrin IgG ELISA assay in the serum and stimulated emission depletion microscopy of kidney biopsies showed IgG-nephrin co-localization only in 77.8% of cases. Similar observations were obtained in a cohort of 48 adult patients with MC or FSGS at kidney biopsy, where IgG-nephrin colocalization was only 44.4%, suggesting the existence of autoantibodies binding to other slit proteins. Patients with anti-slit antibodies showed nephrotic syndrome at onset in 94.4% of cases. Patients with primary steroid-resistance had anti-slit antibodies in 27%, while those with secondary steroid-resistance in 87.5% of cases, irrespective of the histopathological lesion pattern. Steroid-resistant patients with anti-slit antibodies responded to second-line immunosuppressants in 92.3% vs. only 20% of patients that were anti-slit negative. No patient with anti-slit antibodies developed kidney failure vs. 51.7% of those negative for antibodies (66.7% with a genetic cause and 41.2% with a non-genetic cause). Thus, the detection of anti-slit antibodies can identify patients with an autoimmune podocytopathy responsive to treatment with second-line immunosuppressants, irrespective of the histopathological lesion pattern at biopsy.

Anti-nephrin autoantibodies: novel predictors of post-transplant recurrence of focal segmental glomerular sclerosis.

Post-transplant recurrence of focal segmental glomerular sclerosis (FSGS) is a major challenge in the field of kidney transplantation. Currently, the most reliable predictor of FSGS recurrence is disease recurrence in a previous allograft. Recent studies suggest a possible causal role of anti-nephrin autoantibodies in the primary disease (primary FSGS and minimal change disease), as well as post-transplant recurrence of FSGS. In this issue of Kidney International, Batal etal. evaluate pretransplant anti-nephrin autoantibodies as a specific predictor of FSGS recurrence and demonstrate colocalization of nephrin and punctate IgG in anti-nephrin-positive patients with disease recurrence.

Proteinuria as an Endpoint in Clinical Trials of Focal Segmental Glomerulosclerosis

Focal Segmental Glomerulosclerosis (FSGS) is a characteristic histopathological lesion that is indicative of underlying glomerular dysfunction. It is not a single disease entity but rather a heterogeneous disorder that is an important cause of nephrotic syndrome and kidney failure in children and adults. The aim of this Kidney Health Initiative project was to evaluate potential endpoints for clinical trials in FSGS. This paper focuses on the data supporting proteinuria as a surrogate endpoint. Available data support the use of complete remission of proteinuria in patients with heavy proteinuria as a surrogate endpoint for progression to kidney failure. While substantial treatment effects on proteinuria that are short of a complete remission may also predict the effect of a treatment on progression to kidney failure, further work is needed to determine how such an endpoint should be defined. Fortunately, efforts are underway to bring together patient-level data from randomized controlled trials, observational studies, and registries to address this issue.

An international, multi-center study evaluated rituximab therapy in childhood steroid-resistant nephrotic syndrome

The efficacy and safety of rituximab in childhood steroid-resistant nephrotic syndrome (SRNS) remains unclear. Therefore, we conducted a retrospective cohort study at 28 pediatric nephrology centers from 19 countries in Asia, Europe, North America and Oceania to evaluate this. Children with SRNS treated with rituximab were analyzed according to the duration of calcineurin inhibitors (CNIs) treatment before rituximab [6 months or more (CNI-resistant) and under 6 months]. Primary outcome was complete/partial remission (CR/PR) as defined by IPNA/KDIGO guidelines. Secondary outcomes included kidney failure and adverse events. Two-hundred-forty-six children (mean age, 6.9 years; 136 boys; 57% focal segmental glomerulosclerosis, FSGS) were followed a median of 32.4 months after rituximab. All patients were in non-remission before rituximab. (146 and 100 children received CNIs for 6 month or more or under 6 months before rituximab, respectively). In patients with CNI-resistant SRNS, the remission rates (CR/PR) at 3-, 6-, 12- and 24-months were 26% (95% confidence interval 19.3-34.1), 35.6% (28.0-44.0), 35.1% (27.2-43.8) and 39.1% (29.2-49.9), respectively. Twenty-five patients were in PR at 12-months, of which 22 had over 50% reduction in proteinuria from baseline. The remission rates among children treated with CNIs under 6 months before rituximab were 42% (32.3-52.3), 52% (41.8-62.0), 54% (44.3-64.5) and 60% (47.6-71.3) at 3-, 6-, 12-, and 24-months. Upon Kaplan-Meier analysis, non-remission and PR at 12-months after rituximab, compared to CR, were associated with significantly worse kidney survival Adverse events occurred in 30.5% and most were mild. Thus, rituximab enhances remission in a subset of children with SRNS, is generally safe and CR following rituximab is associated with favorable kidney outcome.