Key PointsThe presence of cellular segmental sclerosis and crescents predicts a favorable response to glucocorticoid therapy in patients with IgA nephropathy.Glucocorticoid therapy was associated with lower risk of kidney failure across histologic subtypes, with the greatest benefit in cellular segmental sclerosis.The study highlights that there is a need for further subclassification of segmental sclerosis lesions that may guide therapeutic decisions.BackgroundThe Oxford Classification is widely accepted as a histopathology tool to predict kidney outcomes in IgA nephropathy. However, it remains unclear whether the mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescents (C) scores can predict therapeutic response. This study aims to determine the predictive value of mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescents (C) scores on the efficacy of glucocorticoid therapy using the Therapeutic Effects of Steroids in IgA Nephropathy Global trial.MethodsThree hundred and seventy-nine Chinese participants were enrolled in the Therapeutic Effects of Steroids in IgA Nephropathy Global trial, of whom 279 had kidney biopsy slides available for central pathology review. The primary outcomes were a composite of >= 40% reduction in eGFR, kidney failure, or death due to kidney disease. Multivariable Cox regression analysis was used to determine the effects of glucocorticoid therapy across pathologic subgroups, and the interaction between glucocorticoid therapy and pathology scores was evaluated.ResultsAmong 279 participants selected for this study, the median (interquartile range) time from kidney biopsy to randomization was 4 (3-7) months. The median (interquartile range) follow-up was 4.7 (3.0-6.4) and 5.1 (3.1-6.8) years for the placebo and glucocorticoid-treated group. Glucocorticoid therapy showed benefits across all histologic subtypes. Participants with crescents (C1/C2) showed a trend toward greater benefit from glucocorticoid therapy (C1/2: hazard ratio [HR], 0.05 [95% confidence interval (CI), 0.008 to 0.3]; C0: HR, 0.6 [95% CI, 0.4 to 0.9]; P for interaction = 0.4). Participants with hypercellularity within segmental sclerosis lesions (cellular segmental sclerosis) demonstrated a significant reduction in the risk of kidney failure compared with those without (HR, 0.2 [95% CI, 0.07 to 0.4] versus HR, 0.6 [95% CI, 0.4 to 1.0]; P for interaction = 0.03). Analysis of local pathologists' scores of all 379 Chinese participants demonstrated a significantly greater benefit from glucocorticoid therapy in participants with crescents (C0: HR, 0.7 [95% CI, 0.4 to 1.2]; C1: HR, 0.3 [95% CI, 0.2 to 0.6]; C2: HR, 0.2 [95% CI, 0.08 to 0.7]; P for interaction = 0.05).ConclusionsThe presence of crescents and cellular segmental sclerosis in patients with IgA nephropathy was associated with a favorable response to glucocorticoid therapy.

Background: In patients with anti-phospholipase A2 receptor (PLA2R) antibody associated membranous nephropathy, there is currently no accepted method to predict an individual's probability of remission after treatment with immunosuppression or supportive therapy using changes in antibody levels and clinical variables during the first 3-6 months of therapy. Methods: Using a cohort of 187 patients from the GEMRITUX, MENTOR and STARMEN clinical trials with antibody levels at baseline >= 14 RU/ml, we derived logistic regression models to predict proteinuria remission at 12 months that can be used at baseline or after three or six months of treatment. Treatment exposures in the trials included supportive therapy, rituximab, calcineurin inhibitors and cyclophosphamide. Predictors in the models included male sex, and baseline and changes in serum albumin, proteinuria, and antibody levels, with or without changes in eGFR. Results: Proteinuria remission at 12 months was achieved in 107 patients. Compared to the model at baseline, the three- and six-month models had better model fit with lower Akaike Information Criterion (186/158 vs 225) and higher R-2 (52.7%/62.4% vs 25.8%), better discrimination with higher C-statistic (0.87 and 0.91 vs 0.75, P<0.001), and better calibration with lower integrated calibration index (0.89%/2.22% vs 2.51%). The three- and six-month models had no consistent difference in prediction performance and decision curve analysis demonstrated similar net benefit for treatment decisions based on either model up to a threshold probability of 31%. Prediction performance was similar after internal validation using optimism correction. Prediction performance was maintained within subgroups of different treatment regimens, including supportive therapy, rituximab, calcineurin inhibitors and cyclophosphamide. Conclusions: Either the three- or six-month models can be used in patients with anti-PLA2R antibody associated membranous nephropathy after three or six months of treatment with a variety of immunosuppression or supportive therapy to predict remission status at 12 months.

[This corrects the article DOI: 10.1016/j.ekir.2025.01.025.].

Introduction:Rituximab (RTX) therapy has become the standard of care for treatment of membranous nephropathy (MN). However, data on hard outcomes such as end-stage kidney disease (ESKD) and loss of estimated glomerular filtration rate (eGFR), are lacking. Methods:This was a retrospective study on all patients with MN treated with RTX between January 2000 and December 2022. The primary outcomes were ESKD and eGFR loss > 50%. Clinical outcomes were complete remission (CR), partial remission (PR) (reduction in baseline proteinuria ≥ 50% and proteinuria ≤ 3.5 g/24 h), and immunological remission (IR) (serum antiphospholipase A receptor antibody [PLA2R-Ab] depletion). Results:A total of 159 patients were included (75.5% male, 87.4% White, median age: 58 years); 52.8% had previous immunosuppression (IS). Baseline serum creatinine was 1.50 (1.1-1.9) mg/dl, eGFR was 54.6 (37.4-72.5) ml/min per 1.73 m2, proteinuria was 9.2 (6.7-11.9) g/24 h, and serum albumin was 2.7 (2.2-3.2) g/dl; Of the patients, 108 (75.5%) had PLA2R-Ab-associated MN (PLA2R-MN); and 140 of 159 (88.1%) attained CR or PR. Median (interquartile range [IQR]) time to CR and PR were 22.6 (15.5-37.4) and 6.8 (3.6-12.1) months, respectively. Failure to respond to RTX was observed in 11.9% of patients. Previous IS and interstitial fibrosis/tubular atrophy (IFTA) ≥ 25% were independent factors associated with failure to respond to RTX. Patients treated only with RTX with a median follow-up of 62.6 months; 7 of 159 (4.4%) developed ESKD with an estimated renal survival of 97% (95% confidence interval [CI]: 94%-100%) and 95.4% (95% CI: 91.2%-99%) at 5 and 10 years, respectively. Conclusion:RTX treatment is associated with excellent long-term renal survival that compares favorably with historical survival rates using the cyclic corticosteroids/cyclophosphamide regimen.

BACKGROUND:IgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran is an investigational RNA interference therapeutic that suppresses hepatic production of complement component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease progression. METHODS:In this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein ≥1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in combination with the standard of care. The primary end point was percentage change from baseline at week 32 in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments. RESULTS:Thirty-one patients were randomized (cemdisiran, N =22; placebo, N =9). Cemdisiran-treated patients had a placebo-adjusted geometric mean change in 24-hour UPCR of -37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-adjusted change of -45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD) change in serum C5 level from baseline at week 32 was -98.7% (1.2) with cemdisiran and 25.2% (57.7) with placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse event after cemdisiran treatment was injection-site reaction (41%). CONCLUSIONS:These findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated.

The pediatric International IgA Nephropathy (IgAN) Prediction Tool comprises two models with and without ethnicity and is the first method to predict the risk of a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure in children at the time of biopsy using clinical risk factors and Oxford MEST histology scores. However, it is unknown if the Prediction Tool can be applied after a period of observation post-biopsy. Using an international multi-ethnic cohort of 947 children with IgAN, 38% of whom were followed into adulthood, the Prediction Tool was updated for use one year after biopsy. Compared to the original pediatric Prediction Tool, the updated post-biopsy Prediction Tool had a better model fit with higher R2D (51%/50% vs 20%), significant increase in 4-year C-statistics (0.83 vs 0.73/0.69, ΔC 0.09 [95% confidence interval 0.07-0.10] and ΔC 0.14 [0.12-0.15]) and better 4-year calibration with lower integrated calibration indices (0.74/0.54 vs 2.45/1.01). Results were similar after internal validation and when the models were applied two years after biopsy. Trajectories of eGFR after a baseline one year post-biopsy were non-linear and those at higher predicted risk started with a lower eGFR and experienced a more rapid decline over time. In children, eGFR had a variable rate of increase until 15-18 years old and then decreased linearly with a more rapid decline in higher risk groups that was similar to young adults of comparable risk. Thus, the original pediatric Prediction Tool should be used in children at the time of biopsy, and the updated pediatric Prediction Tool should be used to re-evaluate risk one or two years after biopsy.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%e90% of cases of MN. Many of the forms of MN asso-ciated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen -based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Abstract Background Although the clinical benefit of obtaining a remission in proteinuria in nephrotic patients with focal segmental glomerulosclerosis (FSGS) is recognized, the long-term value of maintaining it and the impact of relapses on outcome are not well described. Methods We examined the impact of remissions and relapses on either a 50% decline in kidney function or end-stage kidney disease (combined event) using time-dependent and landmark analyses in a retrospective study of all patients from the Toronto Glomerulonephritis Registry with biopsy-proven FSGS, established nephrotic-range proteinuria and at least one remission. Results In the 203 FSGS individuals with a remission, 89 never relapsed and 114 experienced at least one relapse. The first recurrence was often followed by a repeating pattern of remission and relapse. The 10-year survival from a combined event was 15% higher in those with no relapse versus those with any relapse. This smaller than anticipated difference was related to the favourable outcome in individuals whose relapses quickly remitted. Relapsers who ultimately ended in remission (n = 46) versus in relapse (n = 68) experienced a 91% and 32% 7-year event survival (P < .001), respectively. Using time-varying survival analyses that considered all periods of remission and relapse in every patient and adjusting for each period's initial estimated glomerular filtration rate, the state of relapse was associated with a 2.17 (95% confidence interval 1.32–3.58; P = .002) greater risk of experiencing a combined event even in this FSGS remission cohort. Conclusion In FSGS, unless remissions are maintained and relapses avoided, long-term renal survival remains poor. Treatment strategies addressing remission duration remain poorly defined and should be an essential question in future trials.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

BACKGROUND:The 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend following anti-phospholipase A2 receptor (PLA2R) antibody levels as a marker of treatment response in membranous nephropathy; however, the optimal timing to evaluate antibody levels and how to combine them with other clinical variables are currently unknown. METHODS:We used a cohort of 85 patients from the Membranous Nephropathy Trial Of Rituximab (MENTOR) with anti-PLA2R antibodies ≥14 RU/ml to identify risk factors for not experiencing proteinuria remission after 12 months of treatment with cyclosporine or rituximab. Three landmark times were considered: at baseline and after 3 and 6 months of treatment. Logistic regression model performance was evaluated using C-statistics and model fit (Akaike information criterion [AIC], R 2 ). RESULTS:The model at baseline that best predicted no remission included anti-PLA2R antibodies >323 RU/ml and creatinine clearance; the best model after 3 months included the change from baseline in both antibody and albumin levels; and the best model after 6 months included antibody levels >14 RU/ml, creatinine clearance, and the change from baseline in albumin. Compared with the model at baseline, the model at 3 months had better model fit (AIC 70.9 versus 96.4, R 2 51.8% versus 30.1%) and higher C-statistic (0.93 versus 0.83, P = 0.008). The model at 6 months had no difference in performance compared with the model at 3 months (AIC 68.6, R 2 53.0%, C-statistic 0.94, P = 0.67). CONCLUSIONS:In patients with membranous nephropathy treated with cyclosporine or rituximab in the MENTOR trial, we found that the optimal method to evaluate risk factors for the probability of treatment response was to use anti-PLA2R antibody levels combined with albumin levels after 3 months of treatment, which was significantly better than using antibody levels alone or risk factor evaluation at baseline, with no added benefit of waiting until 6 months of treatment. PODCAST:This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_10_09_CJN0000000000000237.mp3.

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

Rationale & Objective: The effects of race, ethnicity, socioeconomic status (SES), and dis-ease severity on acute care utilization in patients with glomerular disease are unknown.Study Design: Prospective cohort study.Setting & Participants: 1,456 adults and 768 children with biopsy-proven glomerular disease enrolled in the Cure Glomerulonephropathy (CureGN) cohort.Exposure: Race and ethnicity as a participant-reported social factor.Outcome: Acute care utilization defined as hos -pit alizations or emergency department visits.Analytical Approach: Multivariable recurrent event proportional rate models were used to es-timate associations between race and ethnicity and acute care utilization.Results: Black or Hispanic participants had lower SES and more severe glomerular dis-ease than White or Asian participants. Acute care utilization rates were 45.6, 29.5, 25.8, and 19.2 per 100 person-years in Black, Hispanic, White, and Asian adults, respectively, and 55.8, 42.5, 40.8, and 13.0, respectively, for children. Compared with the White race (reference group), Black race was significantly associated with acute care utilization in adults (rate ratio [RR], 1.76 [95% CI, 1.37-2.27]), although this finding was attenuated after multivariable adjustment (RR, 1.31 [95% CI, 1.03-1.68]). Black race was not significantly associated with acute care utilization in children; Asian race was significantly associated with lower acute care utilization in children (RR, 0.32 [95% CI 0.14-0.70]); no significant associations between Hispanic ethnicity and acute care utilization were identified.Limitations: We used proxies for SES and lacked direct information on income, household unemployment, or disability.Conclusions: Significant differences in acute care utilization rates were observed across racial and ethnic groups in persons with prevalent glomerular disease, although many of these dif-ference were explained by differences in SES and disease severity. Measures to combat so-cioeconomic disadvantage in Black patients and to more effectively prevent and treat glomerular disease are needed to reduce disparities in acute care utilization, improve patient wellbeing, and reduce health care costs.

The highly variable rate of decline in kidney function in patients with immunoglobulin A nephropathy (IgAN) provides a major clinical challenge. Predicting which patients will progress to kidney failure, and how quickly, is difficult. Multiple novel therapies are likely to be approved in the short-term, but clinicians lack the tools to identify patients most likely to benefit from specific treatments at the right time. Noninvasive and validated markers for selecting at-risk patients and longitudinal monitoring are urgently needed.This review summarizes what is known about demographic, clinical, and histopathologic prognostic markers in the clinician’s toolkit, including the International IgAN Prediction Tool. We also briefly review what is known on these topics in children and adolescents with IgAN. Although helpful, currently used markers leave clinicians heavily reliant on histologic features from the diagnostic kidney biopsy and standard clinical data to guide treatment choice, and very few noninvasive markers reflect treatment efficacy over time. Novel prognostic and predictive markers are under clinical investigation, with considerable progress being made in markers of complement activation. Other areas of research are the interplay between gut microbiota and galactose-deficient IgA1 expression; microRNAs; imaging; artificial intelligence; and markers of fibrosis.Given the rate of therapeutic advancement, the remaining gaps in biomarker research need to be addressed. We finish by describing our route to clinical utility of predictive and prognostic markers in IgAN. This route will provide us with the chance to improve IgAN prognosis by using robust, clinically practical markers to inform patient care.