Background: Microalbuminuria is an early sign of kidney disease in diabetes and indicates cardiovascular risk. We tested if a prespecified urinary proteomic risk classifier (CKD273) was associated with development of microalbuminuria and if progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone. Methods: Prospective multicentre study in people with type 2 diabetes, normal urinary albumin excretion and preserved renal function in 15 European specialist centres. High-risk individuals determined by CKD273 were randomised 1:1 (interactive web response system) in a double-blind randomised controlled trial comparing spironolactone 25 mg o.d. to placebo. Primary endpoint was development of confirmed microalbuminuria in all individuals with available data. Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone and association between CKD273 and impaired renal function defined as a glomerular filtration rate < 60 ml/min per 1•73 m 2. This study is registered with ClinicalTrials.gov: NCT02040441 and is completed. Findings: From March 25, 2014 to September 30, 2018 we followed 1775 participants, 12% (n=216) had high-risk urinary proteomic pattern of which 209 were included in the trial and assigned spironolactone (n=102) or placebo (n=107). Median follow-up time was 2•51 years (IQR 2•0-3•0). Progression to microalbuminuria was seen in 28•2% of high-risk and 8•9% of low-risk people (P< 0•001) (hazard ratio (HR), 2•48; 95% confidence interval [CI], 1•80 to 3•42 P<0•001, independent of baseline clinical characteristics). A 30% decline in eGFR from baseline was seen in 42 (19•4 %) high-risk participants compared to 62 (3•9 %) low-risk participants, HR 5•15; 95 % CI (3•41 to 7•76; p<0.0001). Development of microalbuminuria was seen in 35 (33%) randomised to placebo and 26 (25%) randomised to spironolactone treatment (HR 0•81, 95% CI, 0•49 to 1•34, P=0•41). Harms: hyperkalaemia was seen in 13 versus 4, and gynaecomastia in 3 versus 0 subjects on spironolactone and placebo, respectively. Interpretation: In people with type 2 diabetes and normoalbuminuria, the urinary proteomic classifier CKD273 was associated with a 2•5 times increased risk for progression to microalbuminuria over a median of 2•5 years, independent of clinical characteristics. Spironolactone did not prevent progression to microalbuminuria in high-risk subjects.

In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012-000452-34 and Clinicaltrials.gov: NCT02040441).

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Background Diabetic retinopathy (DR) is a microvascular complication of diabetes highly associated to cardiovascular disease and diabetic kidney disease. However, these associations are not thoroughly investigated at an early type 2 diabetes disease stage. This study therefore evaluated the association between baseline DR status and development of cardiovascular events (CVEs), microalbuminuria, and kidney function decline and in persons with type 2 diabetes and normal urinary albumin excretion. Methods Post-hoc analysis of the PRIORITY study including 1758 persons with type 2 diabetes and normoalbuminuria followed for a median of 2.5 (IQR: 2.0–3.0) years. The study was originally designed to investigate a urinary proteomic risk classifier predictor of microalbuminuria development. DR at baseline was defined as non-proliferative and proliferative abnormalities, macular oedema, or history of laser treatment. Cox models were fitted to investigate the association of DR status with development of 1) a CVE composite defined as non-fatal myocardial infarction, stroke, coronary artery bypass graft, percutaneous coronary intervention, hospitalization for heart failure, or all-cause mortality; 2) persistent microalbuminuria (urinary albumin-creatinine ratio > 30mg/g); and 3) chronic kidney disease (CKD) G3 (eGFR < 60 mL/min/1.73m2). Models were adjusted for relevant risk factors. Results At baseline, 304 (17.3%) had DR. Compared to persons without DR, they were older (mean ± SD: 62.7 ± 7.7 vs 61.4 ± 8.3 years, p = 0.019), had longer diabetes duration (17.9 ± 8.4 vs. 10.6 ± 7.0 years, p < 0.001), and higher HbA1c (62 ± 13 vs. 56 ± 12 mmol/mol, p < 0.001). The adjusted hazard ratios of DR at baseline for development of CVE (n = 64), microalbuminuria (n = 197), and CKD (n = 166) were: 2.61 (95%CI: 1.44, 4.72), 1.50 (95%CI: 1.07, 2.11), and 0.87 (95%CI: 0.56, 1.34), and, compared to without DR. Baseline levels of the urinary proteomics classifier did not influence the results. Conclusions Presence of DR in normoalbuminuric type 2 diabetes was associated with an increased risk of developing CVE and microalbuminuria, but not with kidney function decline.