Rationale & Objective The approved therapeutic indication for immune checkpoint inhibitors (CPIs) are rapidly expanding including treatment in the adjuvant setting, the immune related toxicities associated with CPI can limit the efficacy of these agents. The literature on the nephrotoxicity of CPI is limited. Here, we present cases of biopsy proven acute tubulointerstitial nephritis (ATIN) and glomerulonephritis (GN) induced by CPIs and discuss potential mechanisms of these adverse effects. Study design, setting, & participants We retrospectively reviewed all cancer patients from 2008 to 2018 who were treated with a CPI and subsequently underwent a kidney biopsy at The University of Texas MD Anderson Cancer Center. Results We identified 16 cases diagnosed with advanced solid or hematologic malignancy; 12 patients were male, and the median age was 64 (range 38 to 77 years). The median time to developing acute kidney injury (AKI) from starting CPIs was 14 weeks (range 6–56 weeks). The average time from AKI diagnosis to obtaining renal biopsy was 16 days (range from 1 to 46 days). Fifteen cases occurred post anti-PD-1based therapy. ATIN was the most common pathologic finding on biopsy (14 of 16) and presented in almost all cases as either the major microscopic finding or as a mild form of interstitial inflammation in association with other glomerular pathologies (pauci-immune glomerulonephritis, membranous glomerulonephritis, C3 glomerulonephritis, immunoglobulin A (IgA) nephropathy, or amyloid A (AA) amyloidosis). CPIs were discontinued in 15 out of 16 cases. Steroids and further immunosuppression were used in most cases as indicated for treatment of ATIN and glomerulonephritis (14 of 16), with the majority achieving complete to partial renal recovery. Conclusions Our data demonstrate that CPI related AKI occurs relatively late after CPI therapy. Our biopsy data demonstrate that ATIN is the most common pathological finding; however it can frequently co-occur with other glomerular pathologies, which may require immune suppressive therapy beyond corticosteroids. In the lack of predictive blood or urine biomarker, we recommend obtaining kidney biopsy for CPI related AKI.

Objective: To explore the risk of cardiovascular disease in patients with antineutrophil cytoplasmic antibody–associated vasculitides (AAVs) and to assess contributing risk factors.Methods: In a retrospective matched‐pair cohort study, 113 of 131 patients with AAVs from a vasculitis clinic registry were matched 1:1 for renal function, age at diagnosis, sex, smoking status, and previous history of a cardiovascular disease to patients with noninflammatory chronic kidney disease (CKD). Cardiovascular events were defined as acute coronary syndrome, new‐onset angina, symptomatic peripheral vascular disease, stroke, and transient ischemic attack.Results: Median followup times were 3.4 years for the AAV patients and 4.2 years for the CKD patients. More cardiovascular events occurred in the AAV group (23 of 113) than in the CKD group (16 of 113). Cox regression survival analysis showed a significantly increased risk of a cardiovascular event for AAV patients, with a hazard ratio (HR) of 2.23 (95% confidence interval [95% CI] 1.1–4.4) (P = 0.017). Within the cohort of AAV patients, the most strongly predictive factors were previous history of cardiovascular disease (HR 4 [95% CI 1.7–9.8]), history of dialysis dependency (HR 4.3 [95% CI 1.5–12.1]), ever having smoked (HR 3.9 [95% CI 1.5–10]), age at diagnosis (HR 1.038 [95% CI 1.006–1.072]), estimated glomerular filtration rate at remission (HR 0.977 [95% CI 0.957–0.998]), and serum cholesterol concentration at presentation (HR 0.637 [95% CI 0.441–0.92]).Conclusion: In this retrospective study, patients with AAVs appear at greater risk of cardiovascular disease, with increased risk in those with a previous history of cardiovascular disease, dialysis dependency, poor renal function at remission, or a history of smoking. Measures to reduce the risk of cardiovascular disease should be integral to the management of systemic vasculitis.

Acute tubular interstitial nephritis (ATIN) is the most frequently reported pathology in patients with checkpoint inhibitor (CPI) induced acute kidney injury (AKI). Glucocorticoid (GC) therapy and discontinuation of CPI are the mainstay of treatment to prevent permanent renal dysfunction and dialysis. However, less than 50% of patients have complete kidney recovery and relapse of ATIN can occur. Infliximab is effective in treating other immune-related adverse events but its use for the treatment of CPI-ATIN is not well established. We report the first retrospective study examining the steroid-sparing potential of infliximab in achieving durable and complete renal recovery for patients with CPI-ATIN. Data were collected from medical records of patients diagnosed with CPI-AKI with a kidney biopsy or clinical diagnosis of ATIN that was managed with GC and infliximab. Infliximab-containing regimens were used to treat 10 patients with CPI-ATIN. Four patients relapsing after GC therapy achieved durable and complete renal recovery, four patients experienced partial renal recovery, and two patients showed no improvement in kidney function. This is the first study evaluating clinical outcomes using an infliximab-containing regimen for treatment of relapsed CPI-ATIN in patients or patients failing to achieve complete response after primary therapy. Our data suggest that infliximab may be a treatment option for achieving durable and complete renal recovery in this patient population and represents a potential steroid-sparing strategy in challenging cases of CPI-ATIN. Rigorous clinical studies are warranted to evaluate the risk-benefit analysis for infliximab usage in CPI-ATIN patients.

Vascular endothelial growth factor (VEGF) receptor inhibition is a commonly used tool to prevent vascular proliferation in tumors and retinal diseases. The antiangiogenic effects of these drugs have made them potent adjunct therapies when given systemically for malignancies. They are also useful tools to ameliorate diminishing eyesight in retinopathy. Hypertension and proteinuria have been observed in systemic VEGF inhibitor therapy, with rarer presentations involving nephrotic-range proteinuria due to glomerulopathies. Pharmacokinetic studies have shown detectable blood levels of anti-VEGF inhibitors up to 30 days postintravitreal injection. Animal studies have also demonstrated binding of VEGF inhibitors in simian glomeruli 1 week after a single intravitreal injection. We report three patients who received intravitreal bevacizumab and/or aflibercept with worsening hypertension, proteinuria and renal injury. Data regarding emerging evidence of VEGF inhibitor nephrotoxicity after intravitreal injections are also presented. The clinical data and the existing literature are reviewed to support the hypothesis that intravitreal anti-VEGF agents may be unrecognized nephrotoxins. These agents are given to vulnerable patients with diabetes, hypertension and preexisting nephropathy and proteinuria. This case series is reported to spur further study of the systemic effects of intravitreal VEGF inhibitors.