Zand, Ladan

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.

Background Little is known about the prognostic significance of monoclonal gammopathy of undetermined and renal significance (MGUS and MGRS) in patients with CKD. The objective of this study was to determine the clinical and kidney outcomes of patients with CKD with either MGUS or MGRS compared with those with CKD without MGUS or MGRS. Methods We conducted a retrospective cohort study from 2013 to 2018. Patients who had both CKD diagnosis and monoclonal testing were identified. Patients were divided into MGRS, MGUS, and no monoclonal gammopathy groups. Cumulative incidence functions and Cox proportional hazards regression were used to model time to event data and to evaluate the association between monoclonal gammopathy status and risk of kidney failure, with death treated as a competing risk. Results Among 1535 patients, 59 (4%) had MGRS, 648 (42%) had MGUS, and 828 (54%) had no monoclonal gammopathy. Unadjusted analysis showed that compared with no monoclonal gammopathy patients, patients with MGRS were at higher risk of kidney failure (hazard ratio [HR] [95% confidence interval]: 2.5 [1.5 to 4.2] but not patients with MGUS (HR [95% confidence interval]: 1.3 [0.97 to 1.6]), after taking death into account as a competing risk. However, in the multivariable analysis, after adjusting for age, sex, eGFR, proteinuria, and Charlson Comorbidity Index, the risk of progression to kidney failure (with death as competing risk) in the MGRS group was no longer statistically significant (HR: 0.9 [0.5 to 1.8]). The same was also true for the MGUS group compared with the group with no monoclonal gammopathy (HR: 1.3 [0.95 to 1.6]). When evaluating the association between MGUS/MGRS status and overall survival, MGRS was significantly associated with mortality in fully adjusted models compared with the group with no monoclonal gammopathy, while MGUS was not. Conclusions After adjusting for traditional risk factors, MGUS/MGRS status was not associated with a greater risk of kidney failure, but MGRS was associated with a higher risk of mortality compared with patients with no monoclonal gammopathy.

ABSTRACT Membranous nephropathy (MN) is characterized by deposition of immune complexes leading to thickening of glomerular basement membranes. Over time, the understanding of MN has evolved, with the identification of specific autoantibodies against novel podocyte antigens and the unraveling of intricate pathogenic pathways. Although the anti-CD20 monoclonal antibody rituximab is favored as part of the initial therapy in MN, a subgroup of MN patients may be resistant to rituximab necessitating the use of alternative agents such as cytotoxic therapies. In addition, newer agents such as novel anti-CD20 monoclonal antibodies, therapies targeting the CD38-positive plasma cells and anti-complement therapy are being studied in patients who are resistant to traditional treatment strategies. This manuscript furnishes a review of the novel developments in the pathophysiology of MN including the identification of target antigens and current treatment standards for MN, concentrating on evidenced-based interventions designed to attain remission and to prevent disease progression.

ABSTRACT Hematuria—either macroscopic hematuria or asymptomatic microscopic hematuria—is a clinical feature typical but not specific for immunoglobulin A nephropathy (IgAN). The only biomarker supported by the Kidney Disease: Improving Global Outcomes group as a predictor of progression, identifying patients needing treatment, is proteinuria >1 g/day persistent despite maximized supportive care. However, proteinuria can occur in the setting of active glomerulonephritis or secondary to sclerotic renal lesions. Microscopic hematuria is observed in experimental models of IgAN after IgA–IgG immunocomplex deposition, activation of inflammation and complement pathways. Oxidative damage, triggered by hemoglobin release, is thought to contribute to the development of proteinuria and progression. Despite being a clinical hallmark of IgAN and having a rational relationship with its pathophysiology, the value of microscopic hematuria in assessing activity and predicting outcomes in patients with IgAN is still debated. This was partly due to a lack of standardization and day-to-day variability of microhematuria, which discouraged the inclusion of microhematuria in large multicenter studies. More recently, several studies from Asia, Europe and the USA have highlighted the importance of microhematuria assessment over longitudinal follow-up, using a systematic approach with either experienced personnel or automated techniques. We report lights and shadows of microhematuria evaluation in IgAN, looking for evidence for a more consistent consensus on its value as a marker of clinical and histological activity, risk assessment and prediction of treatment response. We propose that hematuria should be included as part of the clinical decision-making process when considering when to use immunosuppressive therapy and as part of criteria for enrollment into clinical trials to test drugs targeting the inflammatory reaction elicited by immune pathway activation in IgAN.

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

Abstract Background and Aims A significant number of patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) with glomerulonephritis (AAV-GN) still progress to end-stage kidney disease (ESKD, eGFR<15mL/min/1.73m2) despite advances in remission-induction treatment. Method A retrospective cohort study on MPO- or PR3-ANCA positive patients with AAV (MPA or GPA) and ESKD at presentation. Renal recovery, dialysis discontinuation and maintenance in ESKD after standard remission-induction, with or without the use of PLEX were compared. Results We analyzed 166 patients with biopsy proven active kidney involvement and eGFR <15mL/min/1.73m2 at the time of AAV-GN diagnosis. Patients received glucocorticoids with CYC (n = 84) or with RTX (n = 72) for remission-induction, and 49 also received PLEX. The predictors for renal recovery were erythrocyte sedimentation rate, SCr at diagnosis and minimal or mild chronicity changes. We analyzed 71 patients who started dialysis with or without PLEX within 4 weeks from AAV-GN diagnosis. The predictors for dialysis discontinuation were minimal chronicity changes in kidney biopsy at the time of diagnosis (OR 6.138, [95%CI 1.389-27.118],p = 0.017) and focal glomerular involvement (OR 5.017,[95%CI 1.287-19.567],p = 0.020). Predictors for maintenance in ESKD at 12 months included higher serum creatinine (SCr) at the time of diagnosis (IRR 1.086, [95%CI 1.005-1.173],p = 0.037), moderate (IRR 3.797,[95%CI 1.090-13.225],p = 0.036), or severe chronicity changes in kidney biopsy (IRR 5.883,[95%CI 1.542–22.439],p = 0.009). Conclusion In our cohort, kidney recovery, dialysis discontinuation, and maintenance of ESKD in patients with AAV-GN and eGFR<15mL/min/1.73m2 depended on SCr and histologic findings on kidney biopsies at the time of diagnosis and was not affected by the addition of PLEX.

ABSTRACT Membranous nephropathy (MN) is a common cause of nephrotic syndrome (NS) in adults and if untreated can progress to endstage kidney disease. Factors considered to place a patient at high or very high risk for progression include elevated serum creatinine at baseline, declining kidney function, persistent heavy proteinuria (>8 g/24 h), or persistent NS, presence of life-threatening complications related to NS (such as venous thromboembolic events), or very high anti-PLA2R antibody titers (>150 RU/ml). Patients who are at high or very high risk of progression should be treated with immunosuppression therapy to induce remission of proteinuria and to avoid progressive loss of kidney function. Traditional forms of immunosuppression for patients with MN have included the use of cyclic courses of corticosteroids with cyclophosphamide or calcineurin inhibitors. These forms of therapy are associated with significant toxicity, e.g. corticosteroids (infections, diabetes, weight gain), cyclophosphamide (infertility, severe leukopenia, malignancy), and calcineurin inhibitors (hypertension, nephrotoxicity). The introduction of anti-CD20+ B-cell therapies in the late 1990s has changed the landscape. In this article we will argue that anti-CD20+ B therapy should be the treatment of choice for patients at high/very high risk of progression when considering its efficacy and side-effect profile.

Background The optimal strategy for remission-maintenance therapy in patients with myeloperoxidase-ANCA (MPO-ANCA)–associated vasculitis is not established. Defining parameters to guide maintenance therapy is required. Methods This was a retrospective cohort study of all patients with MPO-ANCA–associated vasculitis (microscopic with polyangiitis and granulomatosis with polyangiitis) and GN followed at the Mayo Clinic between 1996 and 2015. Relapse rate, MPO-ANCA status, and remission-maintenance therapies were reviewed. Logistic regression models, Kaplan–Meier method, and Cox proportional hazards regression models were applied. Results We analyzed 159 patients with active MPO-ANCA–associated vasculitis with GN. Sixty-six (42%) patients had at least one relapse, and 52 (33%) relapsed before 60 months. Patients with MPO-ANCA who became persistently negative did not relapse (hazard ratio [HR], 0.03; 95% confidence interval [95% CI], 0.002 to 0.431; P =0.01). The reappearance of MPO-ANCA was associated with a higher risk of relapse (HR, 1.91; 95% CI, 1.109 to 3.293; P =0.02). Immunosuppression was withdrawn in 80 (50%) patients, and this was less likely in those who received cyclophosphamide for remission induction or in patients with persistently positive MPO-ANCA (odds ratio [OR], 0.44; 95% CI, 0.228 to 0.861; P =0.02 and OR, 0.42; 95% CI, 0.213 to 0.820; P =0.01, respectively). Relapse frequency was not different between patients with persistently positive MPO-ANCA and patients with MPO-ANCA reappearance (44% versus 39%, P =0.49), irrespective of remission-maintenance treatment. Ear, nose, and throat involvement (OR, 6.10; 95% CI, 1.280 to 29.010; P =0.02) and MPO-ANCA reappearance (OR, 9.25; 95% CI, 3.126 to 27.361; P <0.001) were independently associated with relapse after treatment withdrawal. Conclusions Patients persistently MPO-ANCA negative are at low risk for relapse even without remission-maintenance therapy. Persistence or subsequent reappearance of MPO-ANCA is associated with a higher risk of relapse. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast.aspx?p=CJASN&e=2023_01_10_CJN06460622.mp3