Zand, Ladan

Key Points Baseline kidney function and chronic structural injury strongly predicted both renal recovery and long-term clinical outcomes. Tubulointerstitial nephritis was the predominant lesion in Sjögren syndrome with renal involvement. Early detection and management of renal involvement in Sjögren syndrome are critical to preventing irreversible kidney damage. Background Renal involvement in primary Sjögren syndrome (SS) is uncommon but clinically consequential. Previous studies have been limited by small samples and incomplete biopsy data. We evaluated a large biopsy-confirmed cohort to characterize clinicopathologic features of SS with renal involvement and identify predictors of renal recovery and long-term outcomes. Methods We retrospectively identified adults with SS and kidney biopsy at Mayo Clinic (2012–2025). Clinical, laboratory, and histologic data were extracted. Predictors of complete renal recovery within 6 months, defined as serum creatinine (sCr) returning to within 25% of baseline or <1.4 mg/dl if baseline was unknown, were evaluated using logistic regression. Cox regression assessed long-term risk of a composite end point: newly developed or progressive CKD, ESKD, or all-cause mortality. Results Fifty-six patients were included (median age 57 years; 91% female). Extraglandular manifestations occurred in 76% and baseline CKD in 65%. The median sCr at baseline and biopsy was 1.3 and 1.6 mg/dl, respectively. Anti-Sjogren's syndrome antigen A, often linked with Ro ribonucleoprotein was positive in 80%. Low C3 occurred in 14% and low C4 in 25%. Tubulointerstitial nephritis was the predominant lesion (71%). Moderate/severe interstitial fibrosis/tubular atrophy and arteriosclerosis were present in 36% and 41%, respectively. Immunosuppressive therapy was applied in 84%. Complete recovery occurred in 67%. Over a median 3.9 years (interquartile range, 1.4–7.2), 43% reached the composite end point. Baseline sCr ≥2 mg/dl, 24-hour proteinuria ≥1 g, and presence of segmental glomerulosclerosis were associated with lower odds of recovery (odds ratio=0.16, 0.13 and 0.11, P = 0.02, 0.001 and 0.008, respectively) and higher long-term risk (hazard ratio=4.51, 2.92 and 3.52; P = 0.002, 0.01 and 0.02, respectively). Moderate/severe arteriosclerosis also increased long-term risk (hazard ratio=2.56; P = 0.03). Conclusions In biopsy-confirmed SS-related renal involvement, the severity of kidney dysfunction and the extent of chronic glomerular and vascular injury strongly predict renal prognosis. Early detection and targeted management of high-risk features may improve long-term renal outcomes.

Key Points Our study found a high prevalence of monoclonal gammopathy (MG) in patients diagnosed with ANCA-negative pauci-immune crescentic GN. Patients with MG showed a higher degree of fibrosis on kidney biopsy than those without MG with higher mortality rate. Our data suggest an association between MG and ANCA-negative pauci-immune crescentic GN, emphasizing this population's need for MG testing and monitoring. Background In a small subset of patients with pauci-immune crescentic GN (PICGN), ANCA are not identified, and patients are referred to as having ANCA-negative vasculitis. The cause of the disease in this subset of patients has remained elusive. We explored the role of monoclonal gammopathy (MG) in those with ANCA-negative PICGN. Methods We conducted a retrospective study and identified patients with PICGN who had undergone ANCA and monoclonal testing. Those positive for ANCA were excluded. Results We identified 14 patients with ANCA-negative vasculitis, of whom eight (57%) tested positive for MG with a mean age of 60.3±12.2 years, 75% were female, and with a mean serum creatinine of 4.3±1.92 mg/dl. The most common monoclonal proteins were IgG ( n =4, 50%) and kappa ( n =4, 50%). One patient had diagnosis of multiple myeloma. Most common extra-renal manifestations were skin rash (leukocytoclastic vasculitis) and neuropathy. Kidney biopsy showed a higher degree of interstitial fibrosis and tubular atrophy compared with those without MG. The median follow-up time was 3.2 years, with 50% mortality in those with MG. Conclusions More than 50% of the patients with ANCA-negative PICGN have MG, and patients present with more evidence of fibrosis on kidney biopsy, with higher mortality rate observed in our cohort. Monoclonal proteins may trigger the development of PICGN; their specific role in the pathogenesis of this disease needs further investigation.

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 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

Background and objectives Kidney biopsy is the current gold standard to diagnose membranous nephropathy. Approximately 70%–80% of patients with primary membranous nephropathy have circulating anti-phospholipase A2 receptor antibodies. We previously demonstrated that in proteinuric patients with preserved eGFR and absence of associated conditions ( e.g., autoimmunity, malignancy, infection, drugs, and paraproteinemia), a positive anti-phospholipase A2 receptor antibody test by ELISA and immunofluorescence assay confirms the diagnosis of membranous nephropathy noninvasively. These data have not been externally validated. Design, setting, participants, & measurements The clinical and pathologic characteristics of patients with a positive anti-phospholipase A2 receptor antibody test at the Mayo Clinic, the University Hospital Vall D’Hebron (Barcelona), and the Columbia University Medical Center (New York) were retrospectively reviewed. Biopsy findings and presence or absence of a potential associated condition were assessed. Results From a total of 276 patients with positive anti-phospholipase A2 receptor serology, previously reported patients ( n =33), kidney transplant recipients ( n =9), pediatric patients ( n =2), and patients without kidney biopsy ( n =69) were excluded. Among the 163 remaining patients, associated conditions were identified in 47 patients, and 15 patients had diabetes mellitus. All 101 patients of the final cohort had a primary diagnosis of membranous nephropathy on kidney biopsy. In the 79 patients with eGFR≥60 ml/min per 1.73 m 2 , none of the biopsy findings altered diagnosis or management. Among the 22 patients with decreased eGFR, additional findings included superimposed acute interstitial nephritis ( n =1). Conclusions In patients with preserved eGFR and absence of associated conditions or diabetes, a positive anti-phospholipase A2 receptor test by either ELISA >20 RU/ml or a positive immunofluorescence assay confirms the diagnosis of membranous nephropathy, precluding the requirement for a kidney biopsy.