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Observational Study
. 2019 Dec 6;14(12):1692-1700.
doi: 10.2215/CJN.00990119. Epub 2019 Oct 31.

The Incidence, Causes, and Risk Factors of Acute Kidney Injury in Patients Receiving Immune Checkpoint Inhibitors

Harish Seethapathy  1 , Sophia Zhao  1 , Donald F Chute  1 , Leyre Zubiri  2 , Yaa Oppong  1 , Ian Strohbehn  1 , Frank B Cortazar  1 , David E Leaf  3 , Meghan J Mooradian  2 , Alexandra-Chloé Villani  4   5 , Ryan J Sullivan  2 , Kerry Reynolds  2 , Meghan E Sise  1
Affiliations
Observational Study

The Incidence, Causes, and Risk Factors of Acute Kidney Injury in Patients Receiving Immune Checkpoint Inhibitors

Harish Seethapathy et al. Clin J Am Soc Nephrol. .

Abstract

Background and objectives: Immune checkpoint inhibitor use in oncology is increasing rapidly. We sought to determine the frequency, severity, cause, and predictors of AKI in a real-world population receiving checkpoint inhibitors.

Design, setting, participants, & measurements: We included all patients who received checkpoint inhibitor therapy from May 2011 to December 2016 at Massachusetts General Hospital. Baseline serum creatinine, averaged 6 months before checkpoint inhibitor start date, was compared with all subsequent creatinine values within 12 months of starting therapy. AKI was defined by Kidney Disease: Improving Global Outcomes criteria for fold changes in creatinine from baseline. Sustained AKI events lasted at least 3 days and was our primary outcome. The cause of sustained AKI was determined by chart review. Cumulative incidence and subdistribution hazard models were used to assess the relationship between baseline demographics, comorbidities, and medications, and sustained AKI and potential checkpoint inhibitor-related AKI.

Results: We included 1016 patients in the analysis. Average age was 63 (SD 13) years, 61% were men, and 91% were white. Mean baseline creatinine was 0.9 mg/dl (SD 0.4 mg/dl), and 169 (17%) had CKD (eGFR<60 ml/min per 1.73 m2) at baseline. A total of 169 patients (17%) experienced AKI, defined by an increase in creatinine at least 1.5 times the baseline within 12 months; 82 patients (8%) experienced sustained AKI and 30 patients (3%) had potential checkpoint inhibitor-related AKI. The first episode of sustained AKI occurred, on average, 106 days (SD 85) after checkpoint inhibitor initiation. Sixteen (2%) patients experienced stage 3 sustained AKI and four patients required dialysis. Proton pump inhibitor use at baseline was associated with sustained AKI.

Conclusions: AKI is common in patients receiving checkpoint inhibitor therapy. The causes of sustained AKI in this population are heterogenous and merit thorough evaluation. The role of PPI and other nephritis-inducing drugs in the development of sustained AKI needs to be better defined.

Keywords: Massachusetts; acute interstitial nephritis; acute kidney injury; acute renal failure; checkpoint inhibitors; chronic renal insufficiency; comorbidity; creatinine; general hospitals; glomerular filtration rate; humans; immune related adverse events; incidence; kidney function tests; male; nephritis; nephrology; onconephrology; proportional hazards models; proton pump inhibitors; renal dialysis; risk factors.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
Patient flow and causes of sustained AKI events. Eighty-two patients (8.1% of the total cohort n=1016) experienced 110 episodes of sustained AKI between them. *The 41 immune checkpoint inhibitor–related sustained AKI events occurred in 30 patients, (3% incidence). **Patient did not have sepsis, nephrotoxin exposure, or a hemodynamic cause, and they did not improve with an intravenous fluid challenge. ICPI, immune checkpoint inhibitor; irAE, immune-related adverse event; MGH, Massachusetts General Hospital; Scr, serum creatinine.
Figure 2.
Figure 2.
Proportion of AKI stages among patients experiencing any and sustained AKI. (A) Any AKI: 169 patients (16.6% of the total cohort n=1016) experienced an AKI event within 12 months of immune checkpoint inhibitor start date. Among these patients, the highest grade of AKI experienced was stage 1 (1.5–2 times the baseline creatinine) in 97 (57%) patients, stage 2 (two to three times the baseline creatinine) in 54 (32%) patients, and stage 3 (more than three times the baseline creatinine) in 18 (11%) patients. (B) Sustained AKI: 82 patients (8% of the total cohort n=1019) experienced a sustained AKI event within 12 months of immune checkpoint inhibitor start date. Among these patients, the highest grade of AKI experienced was stage 1 (1.5–2 times the baseline creatinine) in 30 (37%) patients, stage 2 (two to three times the baseline creatinine) in 36 (44%) patients, and stage 3 (more than three times the baseline creatinine) in 16 (19%) patients. *Of the 16 patients with stage 3 AKI, four required dialysis.
Figure 3.
Figure 3.
Cumulative incidence curve for death and sustained AKI. Patients were censored at the time of sustained AKI or their last serum creatinine measurement, which served as a proxy for death if laboratory testing suddenly ceased. The breakdown of sustained AKI by those who died and those who were alive at 1 year is shown in Supplemental Figure 4.
Figure 4.
Figure 4.
Cumulative incidence curve for sustained AKI by PPI use. There was a significant difference in the cumulative incidence of sustained AKI by baseline PPI, which began after 2.5 months of follow- up. There was a significant interaction of PPI and follow-up time (P=0.01). Data were censored at the time of death, loss of follow-up, or at the end of the 12-month observation period, whichever happened first. A breakdown of events (death, AKI) is provided in Supplemental Table 5C.
Figure 5.
Figure 5.
Proportion of KDIGO stages of sustained AKI and immune checkpoint inhibitor-related AKI by immune checkpoint inhibitor type. (A) Sustained AKI: A total of 80% of stage 1 AKI occurred in patients receiving PD1 inhibitors (nivolumab, pembrolizumab), whereas 56% of stage 3 AKI occurred in patients receiving the CTLA4 inhibitor ipilimumab. (B) Immune checkpoint inhibitor-related AKI: A total of 73% of stage 1 AKI occurred in patients receiving PD1 inhibitors (nivolumab, pembrolizumab), whereas 60% of stage 3 AKI occurred in patients receiving the CTLA4 inhibitor ipilimumab.
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