185-OR: Longitudinal Changes in KidneyIntelX and Association with Progressive Decline in Kidney Function in the CANVAS Trial

Abstract

KidneyIntelX is a composite risk score incorporating biomarkers and clinical variables for predicting progression of prevalent diabetic kidney disease (DKD). The change of this score over time in response to SGLT2 inhibitors and how these changes associate with future kidney outcomes is unknown. We measured soluble Tumor Necrosis Factor Receptor 1 (sTNFR-1), soluble Tumor Necrosis Factor Receptor 2 (sTNFR-2), and Kidney Injury Molecule (KIM-1) on banked samples from CANVAS trial participants with baseline DKD (eGFR <60 ml/min/1.73 m2 or UACR ≥30 mg/mg) and determined the KidneyIntelX risk score at baseline and year 1. We assessed the effect of canagliflozin (CANA) on KidneyIntelX scores and how changes from baseline to year 1 were associated with subsequent DKD progression (composite outcome of eGFR decline of ≥5 ml/min/year [using 6-week eGFR as baseline in the CANA group], ≥40% sustained decline in eGFR, or kidney failure). There were 1016 participants with prevalent DKD who had baseline and year 1 plasma samples. Median age was 64 years, 30% were female, median eGFR was 66 ml/min and median UACR was 55 mg/g. After year 1, 68 (6.7%) participants experienced the composite outcome over a median of 4.9 years. CANA reduced KidneyIntelX risk by 5.1% (95% CI -6.6 to -3.6) at year 1 vs. increasing by 5.8% (95% CI 3.4 to 8.1) in placebo (p <0.001). Each percent reduction in KidneyIntelX score at year 1 was associated with a 2% lower risk of the composite outcome (OR per unit 0.98, 95% CI 0.97 to 0.99; p <0.001) after adjusting for baseline score and treatment arm. The associations between the change in KidneyIntelX and outcome were consistent in the treatment arm and placebo arm (pinteraction=0.63). In conclusion, CANA treatment reduced KidneyIntelX risk scores. Changes in the KidneyIntelX score from baseline to 1 year predict future risk of DKD progression whether they resulted from kidney protection afforded by SGLT2i therapy, or decline in kidney function caused by disease progression. Disclosure D. W. Lam: None. G. N. Nadkarni: Advisory Panel; Self; Renalytix AI plc., Consultant; Self; AstraZeneca, Renalytix AI plc., Variant Bio, Research Support; Self; Renalytix AI plc., Stock/Shareholder; Self; Renalytix AI plc. B. Neal: Advisory Panel; Self; Abbott, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Roche Pharma, Servier Laboratories, Research Support; Self; Janssen Pharmaceuticals, Inc., Merck Schering Plough, Roche Pharma, Servier Laboratories. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, St. Jude Medical. N. Rosenthal: Employee; Self; Janssen Research & Development, LLC. M. K. Hansen: Employee; Self; Janssen Pharmaceuticals, Inc. H. L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Mitsubishi Corporation Life Sciences Limited, Mundipharma International, Novo Nordisk, Retrophin, Inc., Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC. S. Coca: Advisory Panel; Self; Akebia Therapeutics, Inc., Bayer AG, Boehringer Ingelheim International GmbH, Consultant; Self; CHF Solutions, Relypsa Inc., Renalytix AI plc., Takeda Pharmaceutical Co., Research Support; Self; inRegen, XORTX Therapeutics Inc., Stock/Shareholder; Self; Renalytix AI plc.