Acute kidney injury (AKI) commonly occurs in patients taking immune checkpoint inhibitors to treat cancer, a new study shows.
In an analysis of 1016 patients who received checkpoint inhibitor therapy during 2011 to 2016 at Massachusetts General Hospital in Boston, 17% experienced any AKI within 12 months of initiating an inhibitor, 8% had sustained AKI lasting 3 days or longer, and 3% had AKI potentially related to immune checkpoint inhibitor use, Meghan Sise, MD, MS, of Massachusetts General Hospital, and colleagues reported in the Clinical Journal of the American Society of Nephrology. The first episode of sustained AKI occurred a mean 106 days after checkpoint inhibitor initiation.
Patients received either a CTLA-4 inhibitor (ipilimumab), PD-1 inhibitor (pembrolizumab, nivolumab) or a PD-L1 inhibitor (atezolizumab, avelumab, durvalumab), with only a few receiving a combination of CTLA-4 or PD-1 (ipilimumab and nivolumab).
Among confirmed inhibitor-related AKI cases, 80% of stage 1 AKI occurred in patients receiving PD-1 inhibitors, whereas 56% of stage 3 AKI occurred in patients receiving ipilimumab. Among cases potentially related to immune checkpoint inhibitors, 73% of stage 1 AKI occurred in patients receiving PD-1 inhibitors, while 60% of stage 3 AKI occurred in patients receiving ipilimumab. In all, 4 patients required dialysis. Results were not significant. Potential checkpoint inhibitor-related AKI was based on subspecialist evaluation, unexplained sustained AKI concurrent with another immune-related adverse event, or kidney biopsy.
Previous research has shown that acute interstitial nephritis (AIN) is the most common biopsy-proven diagnosis in patients on checkpoint inhibitors who develop AKI. The American Society of Clinical Oncology guidelines recommend interrupting checkpoint inhibitor therapy and evaluating any patient whose serum creatinine rises 1.5-fold above baseline (i.e., stage 1 or higher AKI).
The investigators also examined use of concomitant medications that may cause AKI. Proton pump inhibitor (PPI) use at baseline was associated with a 2.85-fold higher risk for sustained AKI. By comparison, immune checkpoint inhibitor use was associated with a 2.24-fold higher risk.
“As the clinical spectrum of checkpoint inhibitor use continues to grow, the study of associated toxicities becomes increasingly important,” Dr Sise and colleagues commented.
According to the investigators, there are neither consistent symptoms nor urinary findings to facilitate a non-invasive diagnosis of immune checkpoint inhibitor-acute interstitial nephritis. Accurately diagnosing these events may sometimes require kidney biopsy. In this cohort, mean estimated glomerular filtration rate (eGFR) at baseline was 82 mL/min/1.73 m2, and very few patients had an eGFR less than 30 mL/min/1.73 m2.
“It is important for nephrologists and oncologists to recognize the incidence and factors that associate with AKI and checkpoint nephritis in patients receiving immunotherapy for cancer,” Dr Sise said in an American Society of Nephrology news release. “We believe that nephrologists are going to be increasingly called upon to determine the cause of AKI in patients on immune checkpoint inhibitors, and making an accurate diagnosis has huge implications for therapy for a patient’s cancer treatment going forward.”
In an accompanying editorial, Christopher Carlos, MD, MAS, and Raymond K. Hsu, MD, MAS, of the University of California, San Francisco, commented that the study “represents a significant step forward in the field of immune checkpoint inhibitor-associated nephrotoxicity and in onconephrology in general.” They agreed that certain questions about diagnosis and management still need to be answered.
“Prospective studies with standardized collection of sera and urine may help to establish biomarkers to help identify AIN in this setting without tissue diagnosis. In terms of treatment of checkpoint inhibitor-associated AKI/AIN, we also need more data on optimal steroid dosing/length/tapering, along with answers on if (and when and how) to re-challenge patients with checkpoint inhibitors after AKI, especially when potential oncologic benefits of treatment may outweigh kidney function preservation.”
Seethapathy H, Zhao S, Chute DF, et al. The incidence, causes, and risk factors of acute kidney injury in patients receiving immune checkpoint inhibitors [published online October 31, 2019]. Clin J Am Soc Nephrol. doi:10.2215/CJN.00990119
Carlos CA, Hsu RK. AKI with immune checkpoint inhibitors: A push beyond case reports [published online October 31, 2019]. Clin J Am Soc Nephrol. doi:10.2215/CJN.12621019
Study examines kidney injury in patients taking immunotherapy cancer medications [news release]. American Society of Nephrology; October 31, 2019.