Effects of Neprilysin Inhibition on Urine Tubular Biomarkers in CKD: Findings from the UK HARP III Trial

Background: Sacubitril/valsartan has shown benefits in heart failure and may have renoprotective effects. Its impact on kidney tubular health in CKD remains unclear. Several urine biomarkers have been developed to understand the role of kidney tubules in kidney disease progression. Methods: The effects of sacubitril/valsartan 200mg twice daily vs irbesartan 300mg once daily on creatinine-indexed urine biomarkers were assessed using spot samples in 411 participants from UK HARP III at baseline, 3 months, and 6 months. Urine biomarkers included markers of proximal tubular function (alpha-1 microglobulin [α1M]); functional reserve (epidermal growth factor and uromodulin); tubular stress and fibrosis (dickkopf-3, monocyte chemoattractant protein-1, and human cartilage glycoprotein-39) and; inflammation and injury (interleukin-18 [IL-18], kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin [NGAL]). A mixed model repeated measures approach was used to quantify the study average effect of treatment on urine tubular biomarkers. Results: At baseline, the most abundant creatinine-indexed urine biomarker was α1M, a surrogate for proximal tubular reabsorption dysfunction, with a median [Q1,Q3] value 39124 mcg/g [21289, 61846]. The least abundant urine biomarker was cytokine IL-18 (98 ng/g [41, 191]). Compared to allocation to irbesartan, allocation to sacubitril/valsartan reduced NGAL, a lipocalin secreted in the distal tubules after ischemia and reperfusion, by 18% (95% CI: -32 to -1, Fig 1). These changes were evident at 3 months and persisted at 6 months. No significant changes were observed for the other biomarkers, and there was no evidence of effect modification by key baseline characteristics across all biomarkers studied. Conclusion: Sacubitril/valsartan had no significant effect on urine biomarkers of tubular function, reserve, injury, and fibrosis compared to irbesartan. Its effect on NGAL suggests neprilysin inhibition may have distal tubular effects in CKD. Funding: Commercial Support - Funding support from Novartis granted to the trial sponsor University of OxfordValues show study average biomarker levels.