Discovery of Novel Proteomic Biomarkers for the Prediction of Kidney Recovery from Dialysis-Dependent AKI Patients

Abstract

Background: Acute kidney injury requiring dialysis (AKI-D) is associated with prolonged hospitalization, mortality, and progressive chronic kidney disease (CKD) among survivors. Previous studies have examined only select urine or serum biomarkers for predicting kidney recovery from AKI. Methods: Serum samples collected on day 8 of randomized renal replacement therapy from 72 patients enrolled in the Veteran s Affairs/National Institutes of Health Acute Renal Failure Trial Network study were analyzed by the SOMAscan proteomic platform to profile 1305 proteins in each sample. Of these patients, 38 recovered kidney function and dialysis was discontinued, while another 34 patients remained on dialysis by day 28. Results: Differential serum levels of 119 proteins, with 53 higher and 66 lower, were detected in samples from patients who discontinued dialysis compared to patients who remained on dialysis by day 28. Patients were classified into tertiles based on SOMAscan protein measurements for the 25 proteins most differentially expressed. The association of serum levels of each protein with kidney recovery was further evaluated using logistic regression analysis. Higher serum levels of CXCL11, CXCL2/CXCL3, CD86, Wnt-7a, BTK, c-Myc, TIMP-3, CCL5, ghrelin, PDGF-C, survivin, CA2, IL-9, EGF, and neuregulin-1, and lower levels of soluble CXCL16, IL1RL1, stanniocalcin-1, IL-6, and FGF23 when classified in tertiles, were significantly associated with better kidney recovery. This significant association persisted for each of these proteins after adjusting for potential confounding risk factors including age, gender, cardiovascular SOFA score, congestive heart failure, diabetes, modality of intensive dialysis treatment, cause of AKI, baseline serum creatinine, day-8 urine volume, and estimated 60-day mortality risk. Conclusions: These results suggest concerted changes between survival-related proteins and immune-regulatory chemokines in regulating angiogenesis, endothelial and epithelial remodeling, and kidney cell regeneration, illustrating potential mechanisms of kidney recovery. Thus, this study identifies potential novel predictive biomarkers of kidney recovery in AKI-D patients.