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.

Patients with type 1 diabetes (T1D) have a higher risk of developing chronic kidney disease, cardiovascular events (CVEs), and mortality than the general population. We hypothesized that two previously published biomarkers, namely PRO-C6, a biomarker of collagen type VI formation, and C3M, a biomarker of collagen type III degradation, may be associated with impaired renal function and have prognostic value for adverse renal, CVE, and mortality in patients with T1D. RESEARCH DESIGN AND METHODSPRO-C6 and C3M in serum (sPRO-C6, sC3M) and urine (uPRO-C6, uC3M) were measured by ELISA in 663 patients with T1D ranging from normoalbuminuric to macroalbuminuric. Association of the biomarkers with mortality, CVEs, heart failure, decline in estimated glomerular filtration rate (eGFR) ‡30%, and end-stage renal disease (ESRD) were tested in Cox proportional hazards models after log 2 transformation and adjusted for relevant clinical characteristics. Hazard ratios (HRs) were reported per doubling of biomarker levels. RESULTSHigh levels of sPRO-C6 were independently associated with a higher risk of all-cause mortality (HR 2.26 [95% CI 1.31-3.87], P < 0.0031). There was an association with higher risk of CVEs (n = 94) and heart failure (n = 28) but not after adjustment (P ‡ 0.58). In relation to renal outcomes, adjusted sPRO-C6 was associated with a higher risk of eGFR decline ‡30% in T1D, with eGFR >45 and >30 mL/min/1.73 m 2 , and with a higher risk of ESRD (all P £ 0.03). Higher uPRO-C6 was associated with a lower risk of decline in eGFR. CONCLUSIONSIn patients with T1D, higher sPRO-C6 was an independent predictor of both decline in eGFR and development of ESRD and of all-cause mortality. Higher uPRO-C6 was also associated with a lower risk of decline in eGFR.Despite improvements in the medical care of patients with type 1 diabetes (T1D), the risk of developing chronic kidney disease (CKD) and cardiovascular events (CVEs) and of premature death remains higher in these patients compared with the general population (1-4). There is growing evidence that dysregulation of extracellular matrix (ECM) turnover is associated with accelerated systemic and renal fibrosis and

Previous studies have provided inconclusive results on the role of uric acid (UA) in risk prediction. Here we aimed to improve the power and precision of the predictive value of UA for the risk of decline in kidney function, cardiovascular events (CVEs), and mortality in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODSPlasma UA was measured in 670 patients with T1D and various degrees of albuminuria, ranging from normoalbuminuria to macroalbuminuria. Associations of UA with an estimated glomerular filtration rate (eGFR) decline of ‡30%, CVEs, and mortality were analyzed. The median follow-up time was 5.3 years [interquartile range (IQR) 2.7-6.2 years] for a decline in eGFR of ‡30%, 5.8 years (2.5-6.4 years) for progression in albuminuria status, 5.1 years (4.7-5.6 years) for CVE, and 6.2 years (5.8-6.7 years) for mortality. Both univariable and multivariable associations of UA with relevant outcomes and variables were reported. Hazard ratios (HRs) were calculated per doubling of the UA level. RESULTSA doubling in UA level was associated with a higher risk of decline in eGFR of ‡30% (n = 89) (HR 3.18 [IQR 1.71-5.93]; P < 0.001), CVE (n = 94) ; P = 0.011), and mortality (n = 58) (HR 2.58 [IQR 1.12-5.90]; P = 0.025) in adjusted analyses. Adding UA to the adjusted model including conventional risk factors improved the relative integrated discrimination index by 12.6% for a decline in eGFR of ‡30% (P < 0.001), 6.5% for CVE (P = 0.010), and 11.8% (P = 0.003) for mortality. A doubling in UA level was also associated with a steeper decline in eGFR (P < 0.0026) and a steeper increase in urine albumin-to-creatinine ratio (P < 0.0027) in adjusted analysis. CONCLUSIONSIn individuals with T1D, a higher UA level is associated with a higher risk of decline in kidney function, CVE, and mortality, independently of other risk factors. Our results suggest that UA has a promising role in risk stratification among individuals with T1D.

In type 1 diabetes patients, higher UA was associated with lower kidney function and other diabetic complications. The association between higher UA and lower eGFR and lower diastolic BP was independent of traditional risk factors.

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