Incidence and Clinical Features of Immune-Related Acute Kidney Injury in Patients Receiving Programmed Cell Death Ligand-1 Inhibitors

Abstract

Background: Programmed cell death receptor ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) with a side effect profile that may differ from other classes of ICIs such as those directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 receptor (PD-1). Being the more recently approved class of checkpoint inhibitors, there are no studies investigating the frequency, etiology and predictors of acute kidney injury (AKI) in patients receiving PD-L1 inhibitors.

Methods: This was a retrospective cohort study of patients who received PD-L1 inhibitors during 2017 to 2018 in our healthcare system. AKI was defined by a ≥1.5-fold rise in serum creatinine from baseline. The etiology of all cases of sustained AKI (lasting >48 hours) and clinical course were determined by review of electronic health records.

Results: The final analysis included 599 patients. Within 12 months of ICI initiation, 104 patients (17%) experienced AKI, and 36 (6%) experienced sustained AKI; however, only 5 (<1%) experienced suspected PD-L1-related AKI. The PD-L1-related AKI occurred a median of 99 days after starting therapy. All patients concurrently received another medication known to cause acute interstitial nephritis (proton pump inhibitors, nonsteroidal anti-inflammatory drugs, or antibiotics) at the time of the suspected PDL1-related AKI.

Conclusion: Although AKI is common in patients receiving PD-L1 therapy, the incidence of suspected PD-L1-related AKI is low (<1%) and may be less common when compared to other classes of ICIs. This cohort provides further validation that other drugs associated with acute interstitial nephritis may be involved in the pathogenesis of ICI-related AKI.

Keywords: PD-L1 inhibitors; acute interstitial nephritis; acute kidney injury; immune checkpoint inhibitor; immune-related adverse events.

Graphical abstract

Figure 1

Patient flow and acute kidney injury (AKI) outcomes among patients treated with programmed death ligand-1 (PD-L1) inhibitors. Overall, 17% of the included cohort developed AKI. ∗Among patients with transient AKI (lasting <48 hours), 36 (53%) occurred in outpatients; the majority did not have creatinine measurements immediately repeated, but it normalized by the following clinic visit (mean: 14 days, SD: 9 days until next check). Among those with AKI that was confirmed to have been sustained AKI, lasting for >48 hours, the etiology and Kidney Disease: Improving Global Outcomes (KDIGO) severity stage are shown. ∗∗Of the 9 patients with KDIGO grade 3 AKI, 4 patients had progressive kidney failure and died during the hospital stay, and none underwent renal replacement therapy. ATN, acute tubular necrosis; SCr, serum creatinine.

Figure 2

Overall incidence of all acute kidney injury (AKI), sustained AKI, and programmed death ligand-1 (PD-L1)–related AKI in patients receiving atezolizumab, durvalumab, and avelumab. Among the 347 patients who received atezolizumab, 64 patients (18%) experienced any AKI, 25 (7%) had sustained AKI, and 4 (1%) had PD-L1–related AKI. Among the 153 patients who received durvalumab, 21 (14%) experienced any AKI, 5 (3%) had sustained AKI, and 1 (1%) experienced PD-L1–related AKI. Among the 99 patients who received avelumab, 19 (19%) experienced any AKI, 6 (6%) had sustained AKI, and none had PD-L1–related AKI.

Figure 3

Incidence of programmed death ligand-1 (PD-L1)–related acute kidney injury (AKI) compared to historical estimates of cytotoxic T-lymphocyte−associated protein 4 (CTLA-4), programmed cell death 1 receptor (PD-1), and CTLA-4/PD-1 combination therapy–related AKI. The incidence of immune checkpoint inhibitor (ICI)–related AKI from clinical trial data was gathered in 2 meta-analyses (Cortazar et al. [2016] and Manohar et al. [2019]) and 1 observational real-world study (Seethapathy et al. [2019]). The incidence of CTLA-4–related AKI was 2% in Cortazar et al. and 4.8% in Seethapathy et al. The incidence of PD-1 related AKI was 1.9% in Cortazar et al., 2.2% in Manohar et al., and 2.3% in Seethapathy et al. The incidence of ICI-AKI with combination CTLA-4 and PD-1 therapy was 4.9% from Cortazar et al. In comparison, the incidence of PD-L1–related AKI was 0.8% in our study.