Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study

Abstract

Background: Despite increasing recognition of the importance of immune checkpoint inhibitor-associated AKI, data on this complication of immunotherapy are sparse.

Methods: We conducted a multicenter study of 138 patients with immune checkpoint inhibitor-associated AKI, defined as a ≥2-fold increase in serum creatinine or new dialysis requirement directly attributed to an immune checkpoint inhibitor. We also collected data on 276 control patients who received these drugs but did not develop AKI.

Results: Lower baseline eGFR, proton pump inhibitor use, and combination immune checkpoint inhibitor therapy were each independently associated with an increased risk of immune checkpoint inhibitor-associated AKI. Median (interquartile range) time from immune checkpoint inhibitor initiation to AKI was 14 (6-37) weeks. Most patients had subnephrotic proteinuria, and approximately half had pyuria. Extrarenal immune-related adverse events occurred in 43% of patients; 69% were concurrently receiving a potential tubulointerstitial nephritis-causing medication. Tubulointerstitial nephritis was the dominant lesion in 93% of the 60 patients biopsied. Most patients (86%) were treated with steroids. Complete, partial, or no kidney recovery occurred in 40%, 45%, and 15% of patients, respectively. Concomitant extrarenal immune-related adverse events were associated with worse renal prognosis, whereas concomitant tubulointerstitial nephritis-causing medications and treatment with steroids were each associated with improved renal prognosis. Failure to achieve kidney recovery after immune checkpoint inhibitor-associated AKI was independently associated with higher mortality. Immune checkpoint inhibitor rechallenge occurred in 22% of patients, of whom 23% developed recurrent associated AKI.

Conclusions: This multicenter study identifies insights into the risk factors, clinical features, histopathologic findings, and renal and overall outcomes in patients with immune checkpoint inhibitor-associated AKI.

Keywords: acute kidney injury; immune checkpoint inhibitors; tubulointerstitial nephritis.

Figure 1.

Clinical features of ICPi-AKI. (A) The number of weeks between ICPi initiation and AKI diagnosis. (B) The number of weeks between the last ICPi cycle and AKI diagnosis. (C) The distribution of AKI severity according to the Kidney Disease Improving Global Outcomes criteria. (D) The SCr trend (mean±SEM). Baseline SCr refers to the value immediately preceding ICPi initiation; diagnosis SCr refers to the value when the patient first fulfilled criteria for ICPi-AKI (doubling of SCr or need for RRT); peak SCr refers to the highest value during the AKI episode; and nadir SCr refers to the lowest value achieved within 3 months after the AKI episode (excluding values obtained during RRT). (E) The frequency of extrarenal irAEs occurring before (>14 days before) or concomitantly (within 14 days before or after) with the AKI.

Figure 2.

Clinical features of ICPi-AKI, stratified by AKI severity. (A) The frequency of concomitant potential TIN-causing medications taken within 2 weeks preceding ICPi-AKI. (B–F) The distribution of eosinophilia, proteinuria, dipstick hematuria, leukocyte esterase, and pyuria in patients with ICPi-AKI, respectively. Abx, antibiotic; HPF, high-power field; Neg, negative; UA, urinalysis; UPCR, urine protein-to-creatinine ratio; WBCs, white blood cells.

Figure 3.

Renal recovery after ICPi-AKI. (A) The frequency of complete, partial, and no kidney recovery after an episode of ICPi-AKI. Complete recovery was defined as a return of SCr to <0.35 mg/dl of the baseline value, and partial recovery was defined as a return of SCr to >0.35 mg/dl but less than twice the baseline value, or liberation from RRT. (B) Univariate and multivariable adjusted odds ratios (and 95% confidence intervals) for achievement of complete kidney recovery. ¹Combination ICPi therapy refers to treatment with both an anti–CTLA-4 and an anti–PD-1/PD-L1 antibody. ²Refers to concomitant use of potential TIN-causing medications, including antibiotics, NSAIDs, and PPIs within 2 weeks prior to the diagnosis of ICPi-AKI. 95% CI, confidence interval; CTLA-4, cytotoxic T lymphocyte–associated antigen 4; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1.

Figure 4.

Flow chart indicating rates of treatment with steroids, kidney recovery, rechallenge, and recurrence of ICPi-AKI.

Figure 5.

Kidney recovery status predicts overall survival. (A) Kaplan–Meier 6-month overall survival curves, stratified by kidney recovery status, starting at the time of development of ICPi-AKI (median duration of follow-up was 29 [IQR, 10–67] weeks). (B) Similar Kaplan–Meier survival curves but limited to patients who survived for at least 2 weeks after the development of ICPi-AKI. (C and D) Univariate and multivariable adjusted hazard ratios for 6-month mortality. ¹Refers to per 30 ml/min per 1.73 m² decline. ²The reference group is partial or complete recovery of AKI. 95% CI, 95% confidence interval; NR, no recovery; R, recovery.