Infliximab for the treatment of patients with checkpoint inhibitor-associated acute tubular interstitial nephritis

Abstract

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.

Keywords: Checkpoint inhibitors; acute interstitial nephritis; immune-related adverse event.

Figure 1.

Time course of events and response to treatment. Panels A-D: Cases 1–4 with complete kidney recovery. Panels E-H: Cases 5–8 with partial kidney recovery. panels I-J: Cases 9–10 no kidney recovery. yellow: checkpoint inhibitor (CPI) therapy. CPI dosing regimens are provided in Table 1. Blue: glucocorticoid (GC) therapy. Purple triangle: infliximab (5 mg/kg IV). Dotted black line represents creatinine level to < 0.35 mg/dL above baseline; complete renal recovery

Figure 2.

Representative images of CPI-induced AKI A. Case 1. hematoxylin and eosin (H&E) stain: moderate to severe tubulointerstitial inflammation with lymphocytes, neutrophils, and tubular microabscesses (arrows). scale bar 50 µm. B. Case 1. Electronic micrograph (EM) of tubule with flattened epithelial cells and intraepithelial lymphocyte (tubulitis, arrow). Scale bar 2 µm. C. Case 2. Periodic acid-Schiff (PAS) stain with acute tubulointerstitial inflammation and focal granuloma with associated tubular basement membrane break (arrow). Scale bar 100 µm. D. Case 7. Masson’s trichrome stain with diffuse moderate interstitial fibrosis. Scale bar 200 µm. E. Case 9, first biopsy. H&E stain: mild to moderate tubulointerstitial inflammation with lymphocytes, plasma cells, and occasional eosinophils. Scale bar 50 µm. F. Case 9, second biopsy. H&E stain: diffuse moderate tubulointerstitial inflammation with lymphocytes, plasma cells, and neutrophils. Scale bar 50 µm