Urinary proteomics predict onset of microalbuminuria in normoalbuminuric type 2 diabetic patients, a sub-study of the DIRECT-Protect 2 study

TY - JOUR

T1 - Urinary proteomics predict onset of microalbuminuria in normoalbuminuric type 2 diabetic patients, a sub-study of the DIRECT-Protect 2 study

AU - Lindhardt, Morten

AU - Persson, Frederik

AU - Zürbig, Petra

AU - Stalmach, Angelique

AU - Mischak, Harald

AU - de Zeeuw, Dick

AU - Lambers Heerspink, Hiddo

AU - Klein, Ronald

AU - Orchard, Trevor

AU - Porta, Massimo

AU - Fuller, John

AU - Bilous, Rudolf

AU - Chaturvedi, Nish

AU - Parving, Hans-Henrik

AU - Rossing, Peter

N1 - © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Background Early prevention of diabetic nephropathy is not successful as early interventions have shown conflicting results, partly because of a lack of early and precise indicators of disease development. Urinary proteomics has shown promise in this regard and could identify those at high risk who might benefit from treatment. In this study we investigate its utility in a large type 2 diabetic cohort with normoalbuminuria. Methods We performed a post hoc analysis in the Diabetic Retinopathy Candesartan Trials (DIRECT-Protect 2 study), a multi centric randomized clinical controlled trial. Patients were allocated to candesartan or placebo, with the aim of slowing the progression of retinopathy. The secondary endpoint was development of persistent microalbuminuria (three of four samples). We used a previously defined chronic kidney disease risk score based on proteomic measurement of 273 urinary peptides (CKD273-classifier). A Cox regression model for the progression of albuminuria was developed and evaluated with integrated discrimination improvement (IDI), continuous net reclassification index (cNRI) and receiver operating characteristic curve statistics. Results Seven hundred and thirty-seven patients were analysed and 89 developed persistent microalbuminuria (12%) with a mean follow-up of 4.1 years. At baseline the CKD273-classifier predicted development of microalbuminuria during follow-up, independent of treatment (candesartan/placebo), age, gender, systolic blood pressure, urine albumin excretion rate, estimated glomerular filtration rate, HbA1c and diabetes duration, with hazard ratio 2.5 [95% confidence interval (CI) 1.4-4.3; P = 0.002] and area under the curve 0.79 (95% CI 0.75-0.84; P < 0.0001). The CKD273-classifier improved the risk prediction (relative IDI 14%, P = 0.002; cNRI 0.10, P = 0.043). Conclusions In this cohort of patients with type 2 diabetes and normoalbuminuria from a large intervention study, the CKD273-classifier was an independent predictor of microalbuminuria. This may help identify high-risk normoalbuminuric patients for preventive strategies for diabetic nephropathy.

AB - Background Early prevention of diabetic nephropathy is not successful as early interventions have shown conflicting results, partly because of a lack of early and precise indicators of disease development. Urinary proteomics has shown promise in this regard and could identify those at high risk who might benefit from treatment. In this study we investigate its utility in a large type 2 diabetic cohort with normoalbuminuria. Methods We performed a post hoc analysis in the Diabetic Retinopathy Candesartan Trials (DIRECT-Protect 2 study), a multi centric randomized clinical controlled trial. Patients were allocated to candesartan or placebo, with the aim of slowing the progression of retinopathy. The secondary endpoint was development of persistent microalbuminuria (three of four samples). We used a previously defined chronic kidney disease risk score based on proteomic measurement of 273 urinary peptides (CKD273-classifier). A Cox regression model for the progression of albuminuria was developed and evaluated with integrated discrimination improvement (IDI), continuous net reclassification index (cNRI) and receiver operating characteristic curve statistics. Results Seven hundred and thirty-seven patients were analysed and 89 developed persistent microalbuminuria (12%) with a mean follow-up of 4.1 years. At baseline the CKD273-classifier predicted development of microalbuminuria during follow-up, independent of treatment (candesartan/placebo), age, gender, systolic blood pressure, urine albumin excretion rate, estimated glomerular filtration rate, HbA1c and diabetes duration, with hazard ratio 2.5 [95% confidence interval (CI) 1.4-4.3; P = 0.002] and area under the curve 0.79 (95% CI 0.75-0.84; P < 0.0001). The CKD273-classifier improved the risk prediction (relative IDI 14%, P = 0.002; cNRI 0.10, P = 0.043). Conclusions In this cohort of patients with type 2 diabetes and normoalbuminuria from a large intervention study, the CKD273-classifier was an independent predictor of microalbuminuria. This may help identify high-risk normoalbuminuric patients for preventive strategies for diabetic nephropathy.

U2 - 10.1093/ndt/gfw292

DO - 10.1093/ndt/gfw292

M3 - Journal article

C2 - 27507891

SN - 0931-0509

JO - Nephrology, Dialysis, Transplantation

JF - Nephrology, Dialysis, Transplantation

ER -