BackgroundNon-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis.MethodsA retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression ofIL2RA,IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls.ResultssIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9–3.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5–0.9, p<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7–1.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve >96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions forIL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls.ConclusionElevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.

Background Glomerular involvement in rheumatoid arthritis has been known to be associated with treatment side effects from medications and secondary amyloidosis. However, limited basic science and clinical studies have been performed to address the potential disease specific immune-mediated mechanisms causing secondary glomerular pathology, its various types of presentation, and the potential treatments. Case presentation A 41-year-old man with chronic active rheumatoid arthritis presented with nephrotic syndrome and was found to have membranous nephropathy with eosinophilic intracapillary thrombi on renal biopsy. Proteinuria persisted despite complete withdrawal from non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs). Throughout the disease course, he developed cryoglobulinemic vasculitis and pulmonary sarcoidosis, both of which achieved clinical resolution with glucocorticoids. However, only partial improvement was observed in proteinuria with treatment of steroids and Rituximab. Conclusion Our case presented a unique and complicated clinical phenotype of active rheumatoid arthritis, with clinical features of cryoglobulinemic vasculitis, histopathologic features of membranous and cryoglobulinemic nephropathy in the absence of DMARDs use, as well as pulmonary sarcoidosis. We speculate that there is a wider spectrum of glomerular disease in patients with untreated rheumatoid arthritis. In addition, the potential association between rheumatoid arthritis and cryoglobulinemic vasculitis should probably be revisited and requires further studies to elucidate the underlying mechanisms and treatment options.

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Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, ICIs can be limited by inflammatory toxicities referred to as immune related-adverse events (irAEs). Clinical presentation of acute kidney injury (AKI) with corresponding pathological features of acute interstitial nephritis (AIN) is the most common manifestation of kidney irAE. Case discussion: A 74-year-old man with invasive squamous cell carcinoma (SCC) and chronic kidney disease (CKD) developed progressive kidney function decline after initiating treatment with cemiplimab (a programmed death protein 1 inhibitor). Because of the outstanding treatment response, and the fact that the patient had no other irAEs, cemiplimab was continued with close monitoring of kidney function. Over the course of 2 years, his creatinine increased from 2.1 to 3.1 mg/dL. Two years into treatment, he presented to the clinic with nausea, vomiting and diarrhea. He was hospitalized and underwent endoscopic examination that led to the diagnosis ICI-associated enterocolitis. After initiation of high dose glucocorticoids, his serum creatinine rapidly improved to his pre-ICI baseline. Conclusion: ICI-associated nephrotoxicity should be considered as a possible cause of rapidly progressive CKD; clinicians must keep a high suspicion for irAEs even in patients who have been receiving ICIs for over 1 year.

Capillary leak syndrome (CLS) is a rare condition typically presenting with profound hypotension, edema, and hemoconcentration. While there are some known, yet rare causes of CLS described, there is very limited data available with use of monoclonal antibodies and immune checkpoint inhibitors. This study aimed to look for the reported side effect of CLS with the use of targeted monoclonal antibodies and immune checkpoint inhibitors (ICI). FDA adverse event reporting system (FAERS) database was searched from first quarter 2010 to fourth quarter 2021 for targeted monoclonal antibodies and ICI. Other literature search including PubMed and case reports/series were also performed. Only 22 cases of CLS with novel anti-cancer treatments were reported in FAERS. Anti-CD20 was the most common class with nine cases of CLS with Rituximab. Six cases with ICI and four cases of CLS with anti-VEGF therapy were also documented. PubMed search showed anti-programmed cell death protein 1 (anti-PD1) as the most common class associated with CLS with five reported cases. CLS is a known complication of anticancer agents such as gemcitabine, clofarabine, cyclophosphamide, platinum-based therapy, colony stimulating factors, and CAR-T therapy, however CLS is not that common with newer monoclonal antibodies and ICIs. This study demonstrates that clinicians need to be aware of this rare fatal side effect of these drugs.