POS-223 Clinical Utility of KidneyIntelX in Patients with Early Stages of Diabetic Kidney Disease in CANVAS Participants

Abstract

Prediction of progression during early stages of diabetic kidney disease (DKD) and determination of those most likely to derive benefits from therapies a priori is challenging. KidneyIntelX is a new test that incorporates clinical data and three plasma biomarkers using machine learning into a composite risk score for DKD progression that has yet to be applied to a clinical trial cohort. We performed a post-hoc analysis of CANVAS Study participants with diabetes and prevalent DKD (defined by estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 or UACR > 30 mg/g at enrollment). Three circulating biomarkers in plasma, soluble Tumor Necrosis Factor Receptor 1 (sTNFR-1), soluble Tumor Necrosis Factor Receptor 2 (sTNFR-2), and Kidney Injury Molecule (KIM)-1, were measured with proprietary multiplex assays. We calculated chronic eGFR slope from 6 weeks in the canagliflozin arm and from baseline in the placebo arm and compared the proportion of individuals experiencing the composite kidney outcome of estimated glomerular filtration rate (eGFR) decline of ≥5 ml/min/year, ≥40% sustained decline in eGFR, or kidney failure within 5 years in CANVAS participants stratified by KidneyIntelX risk categories based on the existing model vs. the KDIGO risk strata. We also assessed clinical response to canagliflozin vs. placebo within KidneyIntelX and KDIGO risk strata. We included 1325 (31% of original cohort of 4330) CANVAS participants with prevalent DKD and available baseline plasma samples (mean age 64 years, 32% female, mean eGFR 65 mL/min/1.73 m2, median uACR 56 mg/g). During a mean follow-up of 5.6 years, 131 (9.9%) of this subgroup with baseline DKD experienced the composite kidney outcome. KDIGO categorization based on eGFR and uACR stratified 69%, 23% and 8% of the DKD population into “moderately increased risk,” “high risk,” and “very high risk,” with event rates of 7%, 17%, and 18% (relative risk [RR] of 2.3, 95% CI 1.3-4.2 for the “very high risk” vs. “moderately high risk” in the treatment arm and RR of 3.4, 95% CI 1.5-7.5 in the placebo arm). Using risk cutoffs from prior validation studies, KidneyIntelX stratified patients to low (40%), intermediate (45%), and high risk (15%) strata with event rates of 3%, 10%, and 26% (RR of 6.0 , 95% CI 3.2-11.3 for the high vs. low risk groups in the treatment arm and RR 15.2, 95% CI 4.8-37.8 in the placebo arm) (Figure). The treatment effects of canagliflozin vs. placebo varied by baseline strata of KidneyIntelX. In the low risk stratum, the RR was 1.65 (95% CI 0.54-5.08), in the intermediate stratum the RR was 0.59 (95% CI 0.36-0.98), and in the high-risk stratum the RR was 0.67 (95% CI 0.38-1.18). In the high-risk stratum, the absolute risk reduction (ARR) for canagliflozin vs. placebo for the composite kidney outcome was 8% vs. an ARR of 2.6% in the overall DKD population. KidneyIntelX successfully risk-stratified a large multi-national external cohort for risk of progression of DKD, with larger differences in observed events across KidneyIntelX risk strata compared to KDIGO risk strata. Moreover, individuals scored as high risk by KidneyIntelX have the potential to achieve greater absolute risk reductions for the outcome with canagliflozin treatment compared to non-stratified DKD participants.