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.

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.

Epilepsy in Qatar: Causes, treatment, and outcome.

OBJECTIVE: Qatar is a small country on the Eastern coast of the Arabian Peninsula. Its population is a unique mixture of native citizens and immigrants. We aimed to describe the features of epilepsy in Qatar as such information is virtually lacking from the current literature. METHODS: We summarized information retrospectively collected from 468 patients with epilepsy seen through the national health system adult neurology clinic. RESULTS: Epilepsy was classified as focal in 65.5% of the cases and generalized in 23%. Common causes of epilepsy were as follows: stroke (9%), hippocampal sclerosis (7%), infections (6%), and trauma (6%). Sixty-six percent of patients were receiving a single antiepileptic drug, with levetiracetam being the most frequently prescribed drug (41% of subjects). When the patients were divided by geographical background, remote infections caused the epilepsy in 15% of Asian patients (with neurocysticercosis accounting for 10%) but only in 1% of Qatari and 3% of Middle East/North African subjects (with no reported neurocysticercosis) (p<0.001). Cerebrovascular and neurodegenerative etiologies were the most prominent in Qataris, accounting for 14% (p=0.005) and 4% (p=0.03) of cases, respectively. The choice of antiepileptic drugs varied also according to the regional background, but the seizure freedom rate did not, averaging at 54% on the last clinic visit. SIGNIFICANCE: To our knowledge, this is the first detailed information about epilepsy in Qatar. The geographical origin of patients adds to the heterogeneity of this disorder. Neurocysticercosis should be in the etiological differential diagnosis of epilepsy in patients coming from Southeast Asian countries, despite the fact that it is not endemic to Qatar. The choice of antiepileptic drugs is influenced by the availability of individual agents in the patients' native countries but had no bearing on the final seizure outcome.

Pneumocystis jirovecii Pneumonia Prophylaxis in Patients with ANCA Vasculitis on Rituximab Maintenance Therapy.

Introduction: Although an increased risk of Pneumocystis jirovecii pneumonia (PJP) has been reported in adults receiving rituximab for induction therapy, current evidence is lacking on the utility of PJP prophylaxis in ANCA-associated vasculitis (AAV) patients on maintenance rituximab therapy. The purpose of this study was to compare the incidence of PJP pneumonia and the outcomes of AAV patients with and without PJP prophylaxis. Methods: We performed an observational, single-center, retrospective study examining patients with AAV in clinical remission and on rituximab maintenance therapy. We divided the patients into two groups: those with and without PJP prophylaxis. We explored factors associated with PJP prophylaxis use. We additionally looked at several outcomes, including PJP infections, infections requiring hospitalizations, end-stage kidney disease (ESKD), and death. Data were analyzed using T test, Fisher's exact test, univariate, and multivariate logistic regression as appropriate. Results: A total of 129 patients with mean follow-up time of 7.2 (5.4) years were included: 44% received PJP prophylaxis and 56% of patients did not. There were no PJP infections in the entire cohort. Lung involvement was associated with increased odds of prescribing PJP prophylaxis (OR: 4.09 [95% CI: 1.8-9.82]). PJP prophylaxis did not decrease infection rates requiring hospitalizations, ESKD, or death. Glucocorticoid use, however, was associated with increased rates of infections requiring hospitalizations (OR: 5.54 [95% CI: 2.01-15.4]) and death (OR: 4.67 [95% CI: 1.36-15.71]) even after adjustment for age, gender, and use of PJP prophylaxis. Conclusion: Regardless of the use of PJP prophylaxis during the maintenance phase of AAV management, PJP pneumonia was not observed. AAV patients with lung involvement were more likely to be on PJP prophylaxis.

Real-World Experience With Avacopan in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Introduction: Postmarketing data on outcomes of avacopan use in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) are lacking. Methods: We performed a multicenter retrospective analysis of 92 patients with newly diagnosed or relapsing AAV who received therapy with avacopan. The coprimary outcome measures were clinical remission at 26 and 52 weeks. We use descriptive statistics and univariate logistic regression to assess outcomes and predictors of remission, respectively. Results: Of the 92 patients, 23% (n = 21) had a baseline estimated glomerular filtration rate (eGFR) < 15 ml/min per 1.73 m2 and 10% on kidney replacement therapy at baseline. Among those with kidney involvement, mean (SD) enrollment eGFR was 33 (27) ml/min per 1.73 m2 with a mean (SD) change of +12 (25) and +20 (23) ml/min per 1.73 m2 at weeks 26 and 52, respectively. In addition to avacopan, 47% of patients received combination therapy of rituximab and low-dose cyclophosphamide, and 14% of patients received plasma exchange (PLEX). After induction, the median (interquartile range [IQR]) time to start avacopan was 3.6 (2.1-7.7) weeks, and the median time to discontinue prednisone after starting avacopan was 5.6 (3.3-9.5) weeks. Clinical remission was achieved in 90% of patients at week 26 and 84% of patients at week 52. Of the patients, 20% stopped avacopan due to adverse events, with the most common being elevated serum aminotransferases (4.3%). Conclusion: A high rate of remission and an acceptable safety profile were observed with the use of avacopan in the treatment of AAV in this postmarketing analysis, including the populations excluded from the ADVOCATE trial.

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.

Renal Involvement of CD20-Negative Intravascular Large B Cell Lymphoma with Neurological Manifestations.

The involvement of hematological tumors such as lymphoma in the kidneys is a well-recognized phenomenon. Some of the distinct reported pathological processes resulting in kidney dysfunction include minimal change disease, lymphocytic invasion of the parenchyma, immune complex disposition, immunotactoid glomerulopathy, membranous glomerulopathy, and acute tubular injury. We report a rare case of CD20-negative intravascular lymphoma found on a kidney biopsy in a male with primary angiitis of the central nervous system (CNS) who presented with acute kidney injury and proteinuria. After the initiation of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP), kidney function improved and proteinuria resolved.

Hypercalcemia, Acute Kidney Injury, and Metabolic Alkalosis.

Calcium regulation is tightly controlled in the body. Multiple causes of hypercalcemia have been studied including primary hyperparathyroidism, hypercalcemia of malignancy, and chronic granulomatous disorders. Among the less studied causes is calcium-alkali syndrome. Here, we discuss a case of hypercalcemia secondary to calcium-alkali syndrome, presenting with hypercalcemia, metabolic alkalosis, and acute kidney injury as a result of ingestion of a large amount of calcium supplements. Hypercalcemia can result in impaired collecting duct system sensitivity to antidiuretic hormone, afferent arteriole constriction, and activation of calcium sensor receptors in multiple tissues. The net effect is an increase in calcium reabsorption with a salt and water diuresis which leads to volume depletion, acute kidney injury, and metabolic alkalosis.