INTRODUCTION: Sacubitril/valsartan shows benefits in heart failure and may have kidney protective effects. Its impact on kidney tubular health in chronic kidney disease (CKD) remains unclear. We evaluated the effects of sacubitril/valsartan on urinary markers of tubular dysfunction and injury in UK Heart and Renal Protection-III (HARP III, ISRCTN:11958993). METHODS: Urine tubular biomarkers were measured at baseline, 3 and 6 months using first morning void or spot urine samples among 411 participants from UK HARP III. A mixed model repeated measures approach was used to quantify the study average effect of treatment on the urine biomarkers. RESULTS: Compared to allocation to irbesartan, allocation to sacubitril/valsartan reduced neutrophil-gelatinase associated lipocalin (NGAL), a marker secreted in the distal tubules after ischemia and reperfusion, by 18% (95% CI: -32% to -1%). 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. DISCUSSION: In UK HARP-III, sacubitril/valsartan reduced urinary NGAL compared with irbesartan but did not affect other tubular biomarkers of injury, ischemia and fibrosis, suggesting limited tubular benefits, consistent with no observed effect on kidney function.