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 extra-renal 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 one 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 two 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.

Nivolumab‐induced severe acute kidney injury with a long latent phase in a patient with non‐small‐cell lung cancer: A case report

“…ICI rechallenging was undertaken following improvement of AKI in three cases and AKI recurrence developed in one case 2, 4. In that case, serum creatinine level was elevated to 1.7 mg/dL from a baseline level of 1.2 mg/dL, while our patient showed more severe AKI requiring hemodialysis.…”

“…The organ most frequently affected with irAEs is the skin, followed by the gastrointestinal tract, endocrine system, liver, lung, and kidney 1. The incidence of nephritis secondary to irAEs was very low in comparison with other organs; Cortazar FB et al reported that the overall incidence of AKI was 2.2% among a total of 3695 patients treated with ICI monotherapy 2. In this review, all the patients who underwent kidney biopsy after ICI‐induced AKI showed histological features of AIN which resembled those of drug‐induced AIN.…”

“…However, kidney injury is not often detected until an increase in serum creatinine is manifested, which might take 7‐10 days after exposure 3. The time from initiation of ICI to AKI was much longer than that of other medications; Cortazar FB et al reported that the median time was 91 (range, 21‐245) days 2. In our case, the duration from initiation of nivolumab to onset of AKI was 377 days, which was longer than any other cases in that paper.…”

“…The plausible reason for delayed onset of AKI is that ICI, itself, is not likely to be the antigen responsible for triggering the AKI, in contrast to other medications. ICI may reprogram the immune system, leading to loss of tolerance against endogenous kidney antigens 2. Shirali et  al reported six lung cancer patients with biopsy‐proven AIN during treatment with nivolumab or pembrolizumab 4.…”

“…ICIs have a unique adverse event known as immune‐related adverse event (irAE) which manifest most frequently as a skin disorder, and very rarely as a renal disorder 1. Recently, it has been known that the histopathology of acute kidney injury (AKI) associated with irAE show acute interstitial nephritis (AIN) in most cases 2. It is speculated that the mechanism of ICI‐induced AIN differs from other medications‐induced AIN.…”