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

Abstract

Background and objectivesImmune 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, & measurementsWe 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.ResultsWe 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.ConclusionsAKI 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.

Clinical recommendations on diagnosis and treatment of immune checkpoint inhibitor‐induced renal immune‐related adverse events

“…In a recently published study by Seethapathy et al . 1016 patients received ICI therapy at Massachusetts General Hospital, although the incidence of ICI‐related AKI was 2.95% which is similar to other reports, but surprisingly there was 17% patients who experienced AKI (defined as ≥1.5‐fold increase in creatinine from baseline), and 8.07% experienced sustained AKI (defined as an AKI event which lasted ≥3 days) …”

Kidney Biopsy Should Be Performed to Document the Cause of Immune Checkpoint Inhibitor–Associated Acute Kidney Injury: PRO

“…There was no documented period of hypotension or other prominent cause for this finding. He used a proton pump inhibitor given the gastric location of a large metastasis which could be a risk factor for AKI during CPIT (6). Despite these findings, high-dose steroids (1 mg/kg) were prescribed.…”

“…A recent retrospective observational study showed that, in the first year after initiation of CPIs, 8% encountered a sustained AKI episode. After careful record evaluation, 3% (one in three to four sustained AKI episodes) was judged as an IRAE; however, no structural pathology data was available to validate this (6). Therefore, patients with cancer and kidney injury should undergo a careful evaluation for potential causes to make the correct diagnosis to guide appropriate management.…”

Kidney Biopsy Should Be Performed to Document the Cause of Immune Checkpoint Inhibitor–Associated Acute Kidney Injury: CON

“…Immune checkpoint inhibitors (ICPis) have revolutionized the treatment of cancers by engaging the patient's own immune system against the tumor (1)(2)(3). Checkpoint pathways are innate mechanisms to put the brakes on immune activation.…”

“…Checkpoint pathways are innate mechanisms to put the brakes on immune activation. Approved agents target checkpoint pathways mediated by cytotoxic T lymphocyteassociated antigen 4 (CTLA4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PDL-1) (1,(4)(5)(6)(7). Releasing the breaks on the immune system enhances destruction of tumor cells, but can lead to immune-related adverse effects (8,9), including renal toxicity (1,2,(10)(11)(12)(13).…”