Clinical Features and Outcomes of Immune Checkpoint Inhibitor–Associated AKI: A Multicenter Study
Authors: Cortazar Frank B. , Kibbelaar Zoe A. , Glezerman Ilya G. , Abudayyeh Ala , Mamlouk Omar , Motwani Shveta S. , Murakami Naoka , Herrmann Sandra M. , Manohar Sandhya , Shirali Anushree C. , Kitchlu Abhijat , Shirazian Shayan , Assal Amer , Vijayan Anitha , Renaghan Amanda DeMauro , Ortiz-Melo David I. , Rangarajan Sunil , Malik A. Bilal , Hogan Jonathan J. , Dinh Alex R. , Shin Daniel Sanghoon , Marrone Kristen A. , Mithani Zain , Johnson Douglas B. , Hosseini Afrooz , Uprety Deekchha , Sharma Shreyak , Gupta Shruti , Reynolds Kerry L. , Sise Meghan E. , Leaf David E. 
Published: January 2020

Significance Statement
Kidney toxicity from use of immune checkpoint inhibitors is being recognized as an increasingly frequent complication of treatment. However, existing data on immune checkpoint inhibitor–associated AKI have been limited to small, mostly single-center studies. In this multicenter study of 138 patients with immune checkpoint inhibitor–associated AKI and 276 controls, the authors characterize the clinical features of this complication and identify risk factors associated with its development, clinicopathologic features, and determinants of kidney recovery after an episode. Failure to achieve kidney recovery was associated with worse overall survival, and a minority (23%) of patients who were retreated with immune checkpoint inhibitors had a recurrence of AKI. The study provides insights into immune checkpoint inhibitor–associated AKI, although further study is needed to inform the care of affected patients.

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.