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 - Funding Information:
F.P. reports having received research grants from Astra Zeneca and lecture fees from Astra Zeneca, MSD, Janssen, Lily, Boehringer Ingelheim, Novo Nordisk A/S, Novartis, and being consultant/advisory board member for Astra Zeneca. P.Z. is an employee of Mosaiques Diagnostics. H.M. is the cofounder and co-owner of Mosaiques Diagnostics. M.P. received travel grants and consultancy fees for attending committee meetings from Abbott, AstraZeneca, Sanofi, Novartis and Takeda. H.-H.P. received travel grants and consultancy fee for attending committee meetings from AstraZeneca and Takeda. P.R. received lecture fees from Novartis and Boehringer Ingelheim and research grant from Novartis, has served as a consultant for Merck and has equity interest in Novo Nordisk. M.L., F.P. and P.R. are employed at Steno Diabetes Center, Gentofte, Denmark. Steno Diabetes Center is an independent academic institution owned by Novo Nordisk A/S and The Novo Nordisk Foundation.
Funding Information:
This work was supported in part by EU Funding through SysKID (HEALTH-F2-2009-241544).
Publisher Copyright:
© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
Copyright:
Copyright 2018 Elsevier B.V., 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.
KW - albuminuria
KW - clinical trial
KW - diabetes mellitus
KW - diabetic nephropathy
KW - proteomics
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U2 - 10.1093/ndt/gfw292
DO - 10.1093/ndt/gfw292
M3 - Article
C2 - 27507891
AN - SCOPUS:85034817320
SN - 0931-0509
VL - 32
SP - 1866
EP - 1873
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 11
ER -