Abstract
Background and Aims
The immune checkpoint inhibitors (ICIs) became a vital part of cancer treatment. The ICIs seem to be safer than chemotherapy for kidneys in clinical trials. However, recent observational studies from high-resource settings pointed out the possible underreporting of renal adverse events like acute kidney injury (AKI) in the clinical trials due to focusing only to the renal immune-related adverse events. Additionally, clinical trials generally enroll a fitter population with lesser comorbidities and include mostly treatment-naive patients making studies in real-life cohorts imperative for evaluating the AKI rates during ICI treatment. From these points, we aimed to evaluate the AKI rates and predisposing factors in ICI-treated patients.
Method
This retrospective study has evaluated the data of adult metastatic cancer patients treated with ICIs in Hacettepe University Cancer Center from 01.2014 to 12.2019. All patients other than the ones treated within the context of clinical trials or followed in other institutions after the first dose of ICIs were included. Baseline demographics, cancer types, patient weight and heights, ICI type and the number of cycles, serum creatinine and the estimated GFR values under treatment, regular medications, and comorbidities were recorded. AKI was defined by Kidney Disease Improving Global Outcomes criteria. The predisposing factors to AKI development were evaluated with the univariate and multivariate analyses.
Results
A total of 147 patients were included in the analyses. Median age was 61 [interquartile range (IQR) 51-67], and 69.4% of the patients were male. Patients were given a median of 8 (IQR 5-17) ICI cycles. Patients with melanoma (24.5%), non-small cell lung cancer (15%), and renal cell carcinoma (25.9%) comprised almost 2/3 of the cohort and 72.8% of the patients were treated with nivolumab. Hypertension was the most common comorbidity (38.1%), followed by chronic kidney disease (21.2%) and type 2 diabetes (19.7%). Median Charlson Comorbidity Index (CCI) was 8 (7-9).
Median follow-up was 10.3 (IQR 6.3-19.4) months, and patients had median 9 (IQR 5-18) serum creatinine measurements. During the follow-up, 28 patients (19%) had at least one AKI episode with multiple AKI episodes in 3 patients (10.7%). The median time to AKI development was 2.53 (IQR 1.39-6.19) months. Almost all AKI events were mild (grade 1 or 2 in 27/28) and reversible (25/28). In univariate analyses, coronary artery disease (CAD) (p=<0.001), chronic kidney disease (CKD) (p=0.002), previous nephrectomy (p=0.015), iodinated contrast exposure in the week before immunotherapy (p=0.035), the use of renin-angiotensin-aldosterone system inhibitors (p=0.046) or proton pump inhibitors (PPI) (p=0.041) was associated with an increased AKI risk. The association between diabetes (p=0.067), higher CCI (9 vs. ≥9, p=0.107), baseline lactate dehydrogenase levels (p=0.177), and performance status (ECOG 0 vs. ≥1, p=0.235) and AKI risk did not reach statistical significance. In multivariate analyses, patients with CKD (OR: 3.719, 95% CI: 1.375- 10.057, p=0.010) or CAD (OR: 4.774, 95% CI: 1.803- 12.641, p=0.002) had increased AKI risk. Additionally, regular PPI use (OR: 2.734, 95% CI: .991- 7.542, p=0.052) had borderline statistical significance for AKI development. The development of AKI was not associated with decreased survival (HR: 0.726, 95% CI: 0.409-1.291, p=0.276).
Conclusion
In this study, we observed AKI development under ICIs in almost one in five cancer patients. The increased AKI rates in patients with CAD, CKD, or regular PPI use pointed out the need for better onco-nephrology collaboration in all ICI-treated patients, with a particular emphasis in these high-risk patients.
Novel immune checkpoints beyond PD-1 in advanced melanoma