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Urinary tubular biomarkers as predictors of kidney function decline, cardiovascular events and mortality in microalbuminuric type 2 diabetic patients

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Abstract

Aims

Urinary levels of kidney injury molecule 1 (u-KIM-1) and neutrophil gelatinase-associated lipocalin (u-NGAL) reflect proximal tubular pathophysiology and have been proposed as risk markers for development of complications in patients with type 2 diabetes (T2D). We clarify the predictive value of u-KIM-1 and u-NGAL for decline in eGFR, cardiovascular events (CVE) and all-cause mortality in patients with T2D and persistent microalbuminuria without clinical cardiovascular disease.

Methods

This is a prospective study that included 200 patients. u-KIM-1 and u-NGAL were measured at baseline and were available in 192 patients. Endpoints comprised: decline in eGFR > 30%, a composite of fatal and nonfatal CVE consisting of: cardiovascular mortality, myocardial infarction, stroke, ischemic heart disease and heart failure based on national hospital discharge registries, and all-cause mortality. Adjusted Cox models included traditional risk factors, including eGFR. Hazard ratios (HR) are provided per 1 standard deviation (SD) increment of log2-transformed values. Relative integrated discrimination improvement (rIDI) was calculated.

Results

During the 6.1 years’ follow-up, higher u-KIM-1 was a predictor of eGFR decline (n = 29), CVE (n = 34) and all-cause mortality (n = 29) in adjusted models: HR (95% CI) 1.68 (1.04–2.71), p = 0.034; 2.26 (1.24–4.15), p = 0.008; and 1.52 (1.00–2.31), p = 0.049. u-KIM-1 contributed significantly to risk prediction for all-cause mortality evaluated by rIDI (63.1%, p = 0.001). u-NGAL was not a predictor of any of the outcomes after adjustment.

Conclusions

In patients with T2D and persistent microalbuminuria, u-KIM-1, but not u-NGAL, was an independent risk factor for decline in eGFR, CVE and all-cause mortality, and contributed significant discrimination for all-cause mortality, beyond traditional risk factors.

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Acknowledgements

We thank all participants and acknowledge the work of study nurse Lone Jelstrup and lab technicians Anne G. Lundgaard, Berit R. Jensen, Tina R. Juhl, and Jessie A. Hermann, employees at Steno Diabetes Center, Copenhagen.

Funding

European Foundation for the Study of Diabetes (EFSD), clinical research grant in Type 2 Diabetes. Internal funding was provided by Steno Diabetes Center Copenhagen, Gentofte, Denmark.

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Authors and Affiliations

  1. Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820, Gentofte, Denmark

    Viktor Rotbain Curovic, Tine W. Hansen, Mie K. Eickhoff, Bernt Johan von Scholten, Henrik Reinhard, Frederik Persson & Peter Rossing

  2. Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Peter Karl Jacobsen

  3. Department of Endocrinology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Hans-Henrik Parving

  4. University of Copenhagen, Copenhagen, Denmark

    Peter Rossing

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  1. Viktor Rotbain Curovic
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Contributions

VRC, TWH, MKE, BJvS, HR, PJ, FP, H-HP, and PR conceived and designed the research; VRC, TWH, MKE, BJvS, FP and PR analyzed and interpreted the data; TWH performed the statistical analysis; VRC, wrote the manuscript; TWH, MKE, BJvS, HR, PJ, FP, H-HP, and PR critically revised the manuscript for key intellectual content; PR obtained funding and supervised the study. All authors approved the final version of the manuscript. VRC is responsible for the integrity of the work as a whole.

Corresponding author

Correspondence to Viktor Rotbain Curovic.

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Conflict of interest

F. P. reports having received research Grants from Astra Zeneca, lecture fees from Astra Zeneca, MSD, Janssen, Lily, Boehringer Ingelheim, Novo Nordisk, Novartis and being consultant/advisory board member for Astra Zeneca, Bayer, Amgen and MSD. P. R. received lecture fees from Bayer and Boehringer Ingelheim, and research Grant from Novartis, Astra Zeneca, Novo Nordisk and has served as a consultant for Bayer, Astra Zeneca, Astellas, Boehringer Ingelheim, AbbVie, Novo Nordisk (all honoraria to his institution) and having equity interest in Novo Nordisk. The results presented in this paper have not been published previously in whole or part, except in abstract format.

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All procedures have been in accordance to ethical standards and ethical law, were applied, including the 1964 Declaration of Helsinki and the guidelines for Good Clinical Practice.

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All subjects in the study gave their informed and signed consent prior to inclusion.

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Rotbain Curovic, V., Hansen, T.W., Eickhoff, M.K. et al. Urinary tubular biomarkers as predictors of kidney function decline, cardiovascular events and mortality in microalbuminuric type 2 diabetic patients. Acta Diabetol 55, 1143–1150 (2018). https://doi.org/10.1007/s00592-018-1205-0

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