Kidney Failure in Pauci-immune Crescentic Glomerulonephritis: Rationale for Immunosuppression to Improve Kidney Outcome.

PURPOSE OF REVIEW: Pauci-immune crescentic glomerulonephritis is the hallmark finding in ANCA-associated vasculitis (AAV) when the kidneys are affected. The rationale for immunosuppression in AAV is based on the underlying autoimmune nature of the disease. Overall remission rates, kidney outcomes, and the burden of disease have greatly improved since the discovery of various immunosuppressive therapies, but relapses remain common, and a significant proportion of patients continue to progress to end-stage kidney disease. Here, we review the role of immunosuppressive therapies for the treatment of pauci-immune crescentic glomerulonephritis. RECENT FINDINGS: Besides the recognized role of B and T cells in the pathogenies of AAV, the focus on the contribution of inflammatory cytokines, neutrophil extracellular traps (NETs), and the complement system allowed the discovery of new therapies. Specifically, the C5a receptor blocker (avacopan) has been approved as a glucocorticoid-sparing agent. Additionally, based on observational data, more clinicians are now using combination therapies during the induction phase. There is also an evolving understanding of the role of plasma exchange in removing ANCA antibodies. Furthermore, the recent development of risk score systems provides physicians with valuable prognostic information that can influence decisions on immunosuppression, although future validation from larger cohorts is needed. The over-activation of various immune pathways plays a significant role in the pathogenesis of pauci-immune crescentic glomerulonephritis in AAV. Immunosuppression is, therefore, an important strategy to halt disease progression and improve overall outcomes. Relapse prevention while minimizing adverse events of immunosuppression is a major long-term goal in AAV management.

Histologic and Clinical Factors Associated with Kidney Outcomes in IgA Vasculitis Nephritis.

BACKGROUND: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. METHODS: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2-5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. RESULTS: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. CONCLUSIONS: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

COVID vaccine-induced lupus nephritis: Case report and review of the literature.

Vaccines offer an effective strategy to prevent infectious diseases with minimal adverse effects. On rare occasions, vaccination can disrupt the immune response leading to induction of autoimmune diseases. We describe a case of new-onset lupus nephritis following COVID-19 vaccination with the first dose of the Pfizer vaccine. Her symptoms and lab values improved with steroids, hydroxychloroquine, and mycophenolate mofetil.

Efficacy and safety of avacopan in patients with ANCA-associated vasculitis receiving rituximab in a randomised trial.

OBJECTIVES: To evaluate the efficacy and safety of avacopan in the subgroup of patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis receiving background induction therapy with rituximab in the phase 3 ADVOCATE trial. METHODS: Key efficacy outcomes were remission at week 26 and sustained remission at week 52. Additional outcomes included the Glucocorticoid Toxicity Index, estimated glomerular filtration rate, urinary albumin to creatinine ratio, health-related quality of life and safety. RESULTS: Of the 330 patients who received study medication, 214 (64.8%) received rituximab (once weekly for 4 weeks), with a mean age of 59.8 years; 163 (76.2%) had renal vasculitis and 125 (58.4%) were newly diagnosed. Remission at week 26 and sustained remission at week 52 were achieved by 83/107 (77.6%) and 76/107 (71.0%) patients in the avacopan group and 81/107 (75.7%) and 60/107 (56.1%) in the prednisone taper group, respectively. The relapse rate, recovery of renal function, speed of reduction in albuminuria and glucocorticoid toxicity favoured the avacopan group. Serious adverse events occurred in 34.6% and 39.3% of patients in the avacopan and prednisone taper groups, respectively. CONCLUSIONS: These data suggest that in patients with ANCA-associated vasculitis receiving rituximab, efficacy of treatment with avacopan compared with a prednisone taper was similar at week 26 and greater at week 52, with a favourable safety profile. In addition, avacopan was associated with improved renal outcomes and lower glucocorticoid toxicity. These results demonstrate the efficacy and safety of avacopan in patients receiving background induction therapy with rituximab. TRIAL REGISTRATION NUMBER: NCT02994927.

Glomerular Diseases Across Lifespan: Key Differences in Diagnostic and Therapeutic Approaches.

Glomerular diseases are common causes of chronic kidney disease in childhood, adolescence, and adulthood. The epidemiology of glomerular diseases differs between different age groups, with minimal change disease being the leading cause of nephrotic syndrome in childhood, while membranous nephropathy and focal segmental glomerulosclerosis are more common in adulthood. IgA vasculitis is also more common in childhood. Moreover, there is a difference in disease severity with more children presenting with a relapsing form of nephrotic syndrome and a more acute presentation of antineutrophil cytoplasmic antibody-associated vasculitis and concomitant glomerulonephritis, as highlighted by the higher percentage of cellular crescents on kidney biopsy specimens in comparison with older patients. There is also a female preponderance in antineutrophil cytoplasmic antibody-associated vasculitis and more children present with tracheobroncholaryngeal disease. This article aims to summarize differences in the presentation of different glomerular diseases that are encountered commonly by pediatric and adult nephrologists and potential differences in the management.

COVID-19 outcomes in patients with a history of immune-mediated glomerular diseases.

Introduction: Patients with immune-mediated glomerular diseases are considered at high risk for severe COVID-19 outcomes. However, conclusive evidence for this patient population is scarce. Methods: We created a global registry and retrospectively collected clinical data of patients with COVID-19 and a previously diagnosed immune-mediated glomerular disease to characterize specific risk factors for severe COVID-19 outcomes. Results: Fifty-nine patients with a history of immune-mediated glomerular diseases were diagnosed with COVID-19 between 01.03.2020 and 31.08.2021. Over a mean follow-up period of 24.79 ± 18.89 days, ten patients (16.9%) developed acute kidney injury. Overall, 44.1% of patients were managed in an outpatient setting and therefore considered as having "non-severe" COVID-19, while 55.9% of patients had severe COVID-19 requiring hospitalization including worse outcomes. Comparing both groups, patients with severe COVID-19 were significantly older (53.55 ± 17.91 versus 39.77 ± 14.95 years, p = .003), had lower serum albumin levels at presentation (3.00 ± 0.80 g/dL versus 3.99 ± 0.68 g/dL, p = .016) and had a higher risk of developing acute kidney injury (27% versus 4%, p = .018). Male sex (p <.001) and ongoing intake of corticosteroids at presentation (p = .047) were also significantly associated with severe COVID-19 outcomes, while the overall use of ongoing immunosuppressive agents and glomerular disease remission status showed no significant association with the severity of COVID-19 (p = .430 and p = .326, respectively). Conclusion: Older age, male sex, ongoing intake of corticosteroids and lower serum albumin levels at presentation were identified as risk factors for severe COVID-19 outcomes in patients with a history of various immune-mediated glomerular diseases.

Challenges of defining renal response in ANCA-associated vasculitis: call to action?

Avoiding end-stage kidney disease in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has a high therapeutic priority. Although renal response is a crucial measure to capture clinically relevant changes, clinal trials have used various definitions and no well-studied key surrogate markers to predict renal outcome in AAV exist. Differences in clinical features and histopathologic and therapeutic approaches will influence the course of kidney function. Its assessment through traditional surrogates (i.e. serum creatinine, glomerular filtration rate, proteinuria, hematuria and disease activity scores) has limitations. Refinement of these markers and the incorporation of novel approaches such as the assessment of histopathological changes using cutting-edge molecular and machine learning mechanisms or new biomarkers could significantly improve prognostication. The timing is favourable since large datasets of trials conducted in AAV are available and provide a valuable resource to establish renal surrogate markers and, likely, aim to investigate optimized and tailored treatment approaches according to a renal response score. In this review we discuss important points missed in the assessment of kidney function in patients with AAV and point towards the importance of defining renal response and clinically important short- and long-term predictors of renal outcome.

KDOQI US Commentary on the 2021 KDIGO Clinical Practice Guideline for the Management of Glomerular Diseases.

The KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases represents the first update to this set of recommendations since the initial set of KDIGO guideline recommendations was published in 2012. The pace of growth in our molecular understanding of glomerular disease has quickened and a number of newer immunosuppressive and targeted therapies have been introduced since the original set of guideline recommendations, making such an update necessary. Despite these updates, many areas of controversy remain. In addition, further updates since the publication of KDIGO 2021 have occurred which this guideline does not encompass. With this commentary, the KDOQI work group has generated a chapter-by-chapter companion opinion article that provides commentary specific to the implementation of the KDIGO 2021 guideline in the United States.

Management of antineutrophil cytoplasmic antibody-associated vasculitis with glomerulonephritis as proposed by the ACR 2021, EULAR 2022 and KDIGO 2021 guidelines/recommendations.

Updated guidelines on the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were released in 2021 by the American College of Rheumatology jointly with the Vasculitis Foundation and, subsequently, in 2022 by the European Alliance of Associations for Rheumatology. In addition, in 2021, the Kidney Disease: Improving Global Outcomes had released updated recommendations on the treatment of AAV with glomerulonephritis (AAV-GN). Kidney involvement is particularly relevant in microscopic polyangiitis and granulomatosis with polyangiitis, but is less frequent in eosinophilic granulomatosis with polyangiitis. The management of AAV-GN has been a focus for drug development and change over the past 10 years. Avoidance of progression to end-stage kidney disease (ESKD) or kidney failure is one of the main unmet needs in the management of AAV, with ESKD having a major impact on morbidity, health costs and mortality risk. Relevant changes in AAV-GN management are related to remission-induction treatment of patients with severe kidney disease, the use of glucocorticoids and avacopan, and remission-maintenance treatment. All the documents provide guidance in accordance with the evidence-based standard of care available at the time of their release. With our work we aim to (i) show the progress made and identify the differences between guidelines and recommendations, (ii) discuss the supporting rationale for those, and (iii) identify gaps in knowledge that could benefit from additional research and should be revised in subsequent updates.

Advances in remission induction therapy for ANCA-associated vasculitis.

Since its first description 40 years ago, huge strides have been made in the management of ANCA-associated vasculitis with improved patient outcomes. The use of cyclophosphamide and/or B-cell depleting therapy alongside glucocorticoids remains the cornerstone of therapy in organ or life-threatening disease, but recent trials have re-evaluated existing treatment strategies, alongside the development of new treatment targets. This has led to refinement of the role of plasma exchange, the use of reduced dosing of oral glucocorticoids with improved patient outcomes, as well as other treatment adjuvants/options of steroid minimization including C5a receptor antagonism and IL-5 inhibition. In this review we examine developments in remission induction therapy for ANCA-associated vasculitis.

Outcomes of remission induction therapy for ANCA-associated vasculitis in the elderly.

OBJECTIVE: Treatment regimens combining glucocorticoids with cyclophosphamide or rituximab or both are used to induce remission in ANCA-associated glomerulonephritis (ANCA-GN). There is a paucity of data on the efficacy and safety of these regimens in elderly patients with ANCA-GN. This study aimed to examine outcomes and adverse events in elderly AAV patients with three induction regimens: cyclophosphamide (CYC), cyclophosphamide and rituximab (CYC + RTX), and rituximab (RTX). METHODS: This single-center retrospective cohort study included patients 60 years and older diagnosed with ANCA-GN. Baseline characteristics and outcomes across several clinical parameters were recorded and compared for significance using Kruskal-Wallis test, Chi-squared test, Fisher exact test, univariate, and multivariate logistic regression as appropriate. Cox proportional hazard regression model was used for survival analysis. RESULTS: Seventy-five patients were included. The mean (SD) age at diagnosis was 70 (± 6) years. The mean (SD) follow-up duration was 5.17 (± 3.47) years. Remission induction therapy with glucocorticoids plus CYC was used in 25 patients, glucocorticoids plus CYC and RTX in 12 patients, and glucocorticoids plus RTX in 38 patients. RTX-treated patients had a higher baseline estimated glomerular filtration ratio (eGFR) (p = 0.00009). High remission rates were achieved in all groups (100% vs. 100% vs. 94.6% respectively, p = 0.368). The incidence of end-stage renal disease (ESRD) at one year was 8% among all groups (p = 0.999). There was no difference in the number of infections requiring hospitalization (p = 0.822), but a statistical difference in leukopenia was noted (32% vs. 25% vs. 3% respectively, p = 0.005). The use of RTX only was associated with reduced leukopenia (aOR = 0.1, 95% CI = 0.005-0.8) after adjusting for other variables. CONCLUSIONS: CYC, CYC + RTX, and RTX are equally effective for remission induction in elderly patients with ANCA-GN. Induction therapy with RTX only was associated with a lower risk of leukopenia compared to CYC-containing regimens. Infections requiring hospitalization were similar among all groups. End-stage kidney disease at one year was comparable among the 3 groups. Key Points • Cyclophosphamide, Rituximab, and Cyclophosphamide+Rituximab are equally effective in remission induction in elderly patients with ANCA glomerulonephritis. • The use of Rituximab only was associated with a lower risk of bone marrow suppression compared to Cyclophosphamide only. • More information is needed on the comparative safety of induction therapy strategies in elderly ANCA glomerulonephritis patients.

Study protocol of a randomized controlled trial of fistula vs. graft arteriovenous vascular access in older adults with end-stage kidney disease on hemodialysis: the AV access trial.

BACKGROUND: Treatment of end-stage kidney disease (ESKD) with hemodialysis requires surgical creation of an arteriovenous (AV) vascular access-fistula (AVF) or graft (AVG)-to avoid (or limit) the use of a central venous catheter (CVC). AVFs have long been considered the first-line vascular access option, with AVGs as second best. Recent studies have suggested that, in older adults, AVGs may be a better strategy than AVFs. Lacking evidence from well-powered randomized clinical trials, integration of these results into clinical decision making is challenging. The main objective of the AV Access Study is to compare, between the two types of AV access, clinical outcomes that are important to patients, physicians, and policy makers. METHODS: This is a prospective, multicenter, randomized controlled trial in adults ≥ 60 years old receiving chronic hemodialysis via a CVC. Eligible participants must have co-existing cardiovascular disease, peripheral arterial disease, and/or diabetes mellitus; and vascular anatomy suitable for placement of either type of AV access. Participants are randomized, in a 1:1 ratio, to a strategy of AVG or AVF creation. An estimated 262 participants will be recruited across 7 healthcare systems, with average follow-up of 2 years. Questionnaires will be administered at baseline and semi-annually. The primary outcome is the rate of CVC-free days per 100 patient-days. The primary safety outcome is the cumulative incidence of vascular access (CVC or AV access)-related severe infections-defined as access infections that lead to hospitalization or death. Secondary outcomes include access-related healthcare costs and patients' experiences with vascular access care between the two treatment groups. DISCUSSION: In the absence of studies using robust and unbiased research methodology to address vascular access care for hemodialysis patients, clinical decisions are limited to inferences from observational studies. The goal of the AV Access Study is to generate evidence to optimize vascular access care, based on objective, age-specific criteria, while incorporating goals of care and patient preference for vascular access type in clinical decision-making. TRIAL REGISTRATION: This study is being conducted in accordance with the tenets of the Helsinki Declaration, and has been approved by the central institutional review board (IRB) of Wake Forest University Health Sciences (approval number: 00069593) and local IRB of each participating clinical center; and was registered on Nov 27, 2020, at ClinicalTrials.gov (NCT04646226).

Traditional and Disease-Specific Risk Factors for Cardiovascular Events in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Multinational Retrospective Study.

OBJECTIVE: To investigate the occurrence of cardiovascular events (CVEs) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, China, Turkey, Russia, the United Kingdom, and the USA. METHODS: Patients with a definite diagnosis of AAV who were followed for ≥ 3 months and had sufficient documentation were included. Data on myocardial infarction (MI) and stroke were collected retrospectively from tertiary vasculitis centers. Univariate and multivariate Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: Over a median follow-up of 62.0 months (IQR 22.6-100.0), CVEs (mostly MIs) occurred in 245 (10.7%) of 2286 patients with AAV, with a higher frequency in China and the UK. On multivariate regression analysis, older age (55-64.9 yrs, HR 2.93, 95% CI 1.99-4.31), smoking (HR 1.98, 95% CI 1.48-2.64), Chinese origin (HR 4.24, 95% CI 3.07-5.85), and pulmonary (HR 1.50, 95% CI 1.09-2.06) and kidney (HR 3.02, 95% CI 2.08-4.37) involvement were independent variables associated with a higher occurrence of CVEs. CONCLUSION: We showed that geographic region and both traditional and disease-specific (kidney involvement in particular) factors were independently associated with CVEs. Proper assessment and management of modifiable cardiovascular (CV) risk factors are essential for prevention of CV morbidity in patients with AAV.

A Meta-Analysis and Cohort Study of Histopathologic and Clinical Outcomes in ANCA-Negative versus -Positive Vasculitis.

BACKGROUND: ANCA-negative pauci-immune glomerulonephritis (PIGN) represents a rare and often under-studied subgroup of the vasculitides. This study aims to investigate differences in the clinical phenotype, renal histological features, and clinical outcomes of patients with PIGN, with and without serum ANCA positivity. METHODS: A cohort of biopsy-proven PIGN with and without detectable circulating ANCA was constructed from a single center between 2006 and 2016. Primary outcomes compared clinical presentation and histopathological features according to ANCA status, with multivariate Cox regression to compare mortality and ESKD. A systematic review and meta-analysis of the published literature was undertaken. RESULTS: In our cohort of 146 patients, 22% (n=32) had ANCA-negative disease, with a comparatively younger mean age at diagnosis; 51.4 versus 65.6 years (P<0.001). In total, 14 studies, inclusive of our cohort, were eligible for meta-analysis, totaling 301 patients who were ANCA negative. Those with ANCA-negative disease tended to have fewer extrarenal symptoms and a higher frequency of renal-limited disease, but both failed to reach statistical significance (P=0.92 and P=0.07). The risk of ESKD was significantly higher in seronegative disease (RR, 2.28; 95% confidence interval, 1.42 to 3.65; P<0.001), reflecting our experience, with a fivefold increased risk of ESKD in ANCA-negative disease (P<0.001). No significant difference in the chronicity of histopathological findings was seen and the meta-analysis showed no difference in morality (RR, 1.22; 95% confidence interval, 0.63 to 2.38; P=0.55). CONCLUSION: Our findings demonstrate that ANCA-negative PIGN presents in younger patients, with fewer extrarenal manifestations and higher ESKD risk, despite a lack of difference in histopathology. This study provides the impetus for further research into the pathogenesis, treatment response, and duration of immunotherapy in ANCA-negative disease. We suggest that the absence of positive ANCA serology should not discourage treatment and for clinical trials to include patients who are ANCA negative.

Risk factors for serious infections in ANCA-associated vasculitis.

OBJECTIVES: Severe infections contribute to morbidity and mortality in antineutrophil cytoplasm antibody-associated vasculitis (AAV). This study aimed to identify risk factors associated with severe infections in participants of the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial. METHODS: Data on 197 patients recruited into the RAVE trial were analysed. Participants received either rituximab (RTX) or cyclophosphamide (CYC), followed by azathioprine (AZA). Clinical and laboratory data of patients with and without severe infections (≥grade 3, according to the Common Terminology Criteria for Adverse Events version 3.0) were compared. Risk factors for severe infections were investigated using Cox-regression models. RESULTS: Eighteen of 22 (82%) severe infections occurred within 6 months after trial entry, most commonly respiratory tract infections (15/22, 68%). At baseline, lower absolute numbers of CD19+ cells were observed in patients with severe infections either receiving RTX or CYC/AZA at baseline, while CD5+B and CD3+T cells did not differ between groups. In Cox-regression analysis, higher baseline serum immunoglobulin M levels were associated with the risk of severe infections, whereby a higher baseline total CD19+B cell number and prophylaxis against Pneumocystis jirovecii with trimethoprim-sulfamethoxazole (TMP/SMX) with decreased risk of severe infections. Use of TMP/SMX was associated with lower risk of severe infections in both groups, receiving either RTX or CYC/AZA. CONCLUSIONS: The use of low-dose TMP/SMX is associated with reduced risk of severe infections in patients with AAV treated with either RTX or CYC/AZA. Reduced B cell subpopulations at start of treatment might be a useful correlate of reduced immunocompetence.

Novel aspects in the pathophysiology and diagnosis of glomerular diseases.

Immune deposits/complexes are detected in a multitude of tissues in autoimmune disorders, but no organ has attracted as much attention as the kidney. Several kidney diseases are characterised by the presence of specific configurations of such deposits, and many of them are under a 'shared care' between rheumatologists and nephrologists. This review focuses on five different diseases commonly encountered in rheumatological and nephrological practice, namely IgA vasculitis, lupus nephritis, cryoglobulinaemia, anti-glomerular basement membrane disease and anti-neutrophil cytoplasm-antibody glomerulonephritis. They differ in disease aetiopathogenesis, but also the potential speed of kidney function decline, the responsiveness to immunosuppression/immunomodulation and the deposition of immune deposits/complexes. To date, it remains unclear if deposits are causing a specific disease or aim to abrogate inflammatory cascades responsible for tissue damage, such as neutrophil extracellular traps or the complement system. In principle, immunosuppressive therapies have not been developed to tackle immune deposits/complexes, and repeated kidney biopsy studies found persistence of deposits despite reduction of active inflammation, again highlighting the uncertainty about their involvement in tissue damage. In these studies, a progression of active lesions to chronic changes such as glomerulosclerosis was frequently reported. Novel therapeutic approaches aim to mitigate these changes more efficiently and rapidly. Several new agents, such as avacopan, an oral C5aR1 inhibitor, or imlifidase, that dissolves IgG within minutes, are more specifically reducing inflammatory cascades in the kidney and repeat tissue sampling might help to understand their impact on immune cell deposition and finally kidney function recovery and potential impact of immune complexes/deposits.

Risk Stratification to Predict Renal Survival in Anti-Glomerular Basement Membrane Disease.

SIGNIFICANCE STATEMENT: Most patients with anti-glomerular basement membrane (GBM) disease present with rapidly progressive glomerulonephritis, and more than half develop ESKD. Currently, no tools are available to aid in the prognostication or management of this rare disease. In one of the largest assembled cohorts of patients with anti-GBM disease (with 174 patients included in the final analysis), the authors demonstrated that the renal risk score for ANCA-associated vasculitis is transferable to anti-GBM disease and the renal histology is strongly predictive of renal survival and recovery. Stratifying patients according to the percentage of normal glomeruli in the kidney biopsy and the need for RRT at the time of diagnosis improves outcome prediction. Such stratification may assist in the management of anti-GBM disease. BACKGROUND: Prospective randomized trials investigating treatments and outcomes in anti-glomerular basement membrane (anti-GBM) disease are sparse, and validated tools to aid prognostication or management are lacking. METHODS: In a retrospective, multicenter, international cohort study, we investigated clinical and histologic parameters predicting kidney outcome and sought to identify patients who benefit from rescue immunosuppressive therapy. We also explored applying the concept of the renal risk score (RRS), currently used to predict renal outcomes in ANCA-associated vasculitis, to anti-GBM disease. RESULTS: The final analysis included 174 patients (out of a total of 191). Using Cox and Kaplan-Meier methods, we found that the RRS was a strong predictor for ESKD. The 36-month renal survival was 100%, 62.4%, and 20.7% in the low-risk, moderate-risk, and high-risk groups, respectively. The need for renal replacement therapy (RRT) at diagnosis and the percentage of normal glomeruli in the biopsy were independent predictors of ESKD. The best predictor for renal recovery was the percentage of normal glomeruli, with a cut point of 10% normal glomeruli providing good stratification. A model with the predictors RRT and normal glomeruli ( N ) achieved superior discrimination for significant differences in renal survival. Dividing patients into four risk groups led to a 36-month renal survival of 96.4% (no RRT, N ≥10%), 74.0% (no RRT, N <10%), 42.3% (RRT, N ≥10%), and 14.1% (RRT, N <10%), respectively. CONCLUSIONS: These findings demonstrate that the RRS concept is transferrable to anti-GBM disease. Stratifying patients according to the need for RRT at diagnosis and renal histology improves prediction, highlighting the importance of normal glomeruli. Such stratification may assist in the management of anti-GBM disease. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_02_27_JASN0000000000000060.mp3.