Novel and non-invasive markers of immune checkpoint inhibitor-associated acute kidney injury
OA Version
Citation
Abstract
INTRODUCTION: The introduction of immune checkpoint inhibitors (ICIs), a class of immunotherapy drugs, into the field of hematology/oncology has revolutionized the treatment of many malignancies. The benefits of these medications are enormous, but their use comes with some risks. Through systemic activation of the immune system, ICIs may cause immune-related adverse events (irAEs). One such irAE is acute kidney injury (AKI) directly attributed to the ICI, referred to as ICI-AKI. The consequences of such a diagnosis include temporary or permanent discontinuation of ICI therapy and irreversible loss of kidney function. ICI-AKI is notoriously challenging to diagnose, and the gold standard diagnostic test is a kidney biopsy, which is often contraindicated or difficult to obtain. The incidence of any AKI while on ICIs is 15-20%, though true ICI-AKI is closer to 2-5%. As the breadth of immunotherapy becomes more comprehensive, the need for markers to differentiate true ICI-AKI from other AKI causes becomes more urgent.
OBJECTIVES: There were two goals for this thesis. Objective 1 was to examine the efficacy of positron emission tomography-computed tomography scan (PET-CT) in diagnosing ICI-AKI, specifically acute tubulointerstitial nephritis (ATIN). Objective 2 was to explore using cell-free RNA (cfRNA) as a biomarker for AKI.
METHODS: For Objective 1, clinical and radiological data were collected from eight patients with AKI directly attributed to their ICI therapy. These patients had a baseline PET-CT scan performed within 90 days before initiation of ICI therapy and a follow-up PET-CT scan within 14 days before or after ICI-AKI diagnosis. A nuclear radiologist interpreted the scans and provided quantitative data on radiotracer uptake in the renal cortex, referred to as the mean standardized uptake value (SUVmean). We compared baseline and follow-up SUVmean using a two-tailed Wilcoxon signed-rank test with a significance level of 0.05. For Objective 2, a cfRNA analysis of the plasma samples from patients on immunotherapy who develop AKI was conducted. Forty-six samples were taken at the time of AKI (timepoint 1 (TP1)), and 32 had a matched sample 60 days (+/-30) following AKI (timepoint 2 (TP2)).
RESULTS: For Objective 1, an increase in SUVmean was observed in all eight patients during ICI-AKI. The rise in raw SUVmean values was statistically significant (p-value <0.00001). After calculating the average percent change in SUVmean for each patient, the median change was 38.6 (IQR 8.0-58.6). For Objective 2, sixty-one differentially expressed genes (DEGs) were identified at TP1 versus TP2. Two mitochondrial transcripts (MT-ND4 and MT-ATP8) were found whose expression depended on the etiology of AKI (ATIN versus obstruction). Three genes (BNIP3L, HBA1, and FAM210B) were noted to have overlapping differential expression patterns in both AKI severity and timepoint comparisons.
CONCLUSIONS: While the results for both objectives are preliminary, they are promising for future research on novel and noninvasive indicators of ICI-AKI and the eventual clinical correlations of that research. This analysis indicates that PET-CT imaging can aid in diagnosing ICI-AKI, as radiotracer uptake rises at the time of injury. The DEGs identified in the cfRNA analysis can be further investigated to create a machine model to predict AKI, which later could be expanded into a clinically relevant “liquid biopsy” to diagnose AKI in a non-invasive manner.
Description
2024