Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal immune-related adverse event occurred prior to the onset of AKI in 7 patients. Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4 patients requiring hemodialysis. The prevalent pathologic lesion was acute tubulointerstitial nephritis in 12 patients, with 3 having granulomatous features, and 1 thrombotic microangiopathy. Among the 12 patients with acute tubulointerstitial nephritis, 10 received treatment with glucocorticoids, resulting in complete or partial improvement in renal function in 2 and 7 patients, respectively. However, the 2 patients with acute tubulointerstitial nephritis not given glucocorticoids had no improvement in renal function. Thus, CPI-induced AKI is a new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance.

Keywords: acute kidney injury; ipilimumab; nivolumab; pembrolizumab.

Figure 1. Representative images of CPI-induced AKI

Panels A-C, core needle-biopsy specimens from patient 9, show “typical” features of AIN; panel D, from patient 2, shows granulomatous AIN; panels E and F, from patient 8, show acute thrombotic microangiopathy. A) Periodic acid-Schiff (PAS) stain shows diffuse interstitial inflammation and focal severe tubulitis with infiltrating lymphocytes (arrows, ×200; scale bar, 50μm). B) Hematoxylin and eosin stain shows diffuse interstitial infiltrates predominantly composed of lymphocytes, with several eosinophils (arrows, ×400; scale bar, 25μm). C) Immunohistochemistry reveals the lymphocytic infiltrates in the interstitium to be predominantly CD4+ T cells (×40; scale bar, 100μm). D) PAS stain shows a non-caseating granuloma with multi-nucleated giant cells (yellow arrows), severe interstitial inflammation and tubulitis (blue arrows), and severe glomerulitis (black arrow, ×200; scale bar, 50μm). E) Silver stain shows diffusely wrinkled glomerular basement membranes and “onion-skin” lesion of small arteries (arrow, ×200; scale bar, 50μm). F) Electron microscopy shows swollen endothellium and subintimal widening filled with electron-lucent “fluffy” material (arrows, ×1400; scale bar, 4μm). Larger versions of these images are shown in Supplemental Figure 1.

Figure 2. Time course of events and response to treatment

Solid black arrows indicate initiation of steroids (dosing regimens are provided in Table 3). Open arrows indicate initiation of hemodialysis (patients 3 and 12 received three sessions of hemodialysis and subsequently recovered; patients 6 and 8 remained dialysis-dependent). Day 0 refers to CPI initiation.

Figure 2. Time course of events and response to treatment

Solid black arrows indicate initiation of steroids (dosing regimens are provided in Table 3). Open arrows indicate initiation of hemodialysis (patients 3 and 12 received three sessions of hemodialysis and subsequently recovered; patients 6 and 8 remained dialysis-dependent). Day 0 refers to CPI initiation.

Figure 2. Time course of events and response to treatment

Solid black arrows indicate initiation of steroids (dosing regimens are provided in Table 3). Open arrows indicate initiation of hemodialysis (patients 3 and 12 received three sessions of hemodialysis and subsequently recovered; patients 6 and 8 remained dialysis-dependent). Day 0 refers to CPI initiation.

Figure 3. Estimated incidence of CPI-associated AKI

Abbreviations: Ipi, ipilimumab; Nivo, nivolumab; Pembro, pembrolizumab. *P<0.01 for each of the following comparisons: Ipi+Nivo compared to Ipi alone, Nivo alone, and Pembro alone.