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Increased solutes led to ESRD in type 2 diabetes
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High concentrations of metabolites or uremic solutes and low concentrations of certain amino acids and their derivatives were found to increase the risk for end-stage renal disease in a nested case-control study of patients with type 2 diabetes.
“Alterations of metabolism in general are key to diabetes, and studies like this may have huge potential for unraveling new pathways which will lead to developing new drugs and new diagnostic tests,” Monika Niewczas, MD, PhD, of Harvard Medical School and research associate in the laboratory of Joslin Diabetes Center’s section of genetics and epidemiology, said in a press release.
The substudy of the Joslin Kidney Study examined 40 patients who progressed to ESRD during 8 to 12 years of follow-up and 40 control participants who did not develop the disease.
Monika Niewczas
Data indicate that 262 named metabolites were detected in at least 80% of the patients, making them “common,” and 119 (45%) of those common metabolites were consistent over time and defined as “stable.” Of those, 18 were identified as uremic solutes, researchers wrote. Myo-inositol was the polyol-derived uremic solute most strongly associated with progression to ESRD, with an OR of 3.2 (95% CI, 1.7-5.9), whereas pseudouridine was the nucleotide-derived uremic solute most associated with progression to ESRD, with an OR of 7.8 (95% CI, 3.1-19).
Looking beyond uremic solutes, 39 metabolites were amino acids or their derivatives and were common and stable over time. Of those, 14 (29%) were associated with the risk of progression to ESRD.
After analysis for shared underlying biology, researchers found the following significant ORs for C-glycosyltryptophan, carnitine derivatives urate and urea, and hydroxyl derivatives, respectively: erythritol, 2.1 (95% CI, 1-4.5); glutaroyl carnitine, 2.6 (95% CI, 1.3-5.4); and 2-hydroxyisovalerate, 0.4 (95% CI, 0.2-0.9).
The addition of pseudouridine or C-glycosyltryptophan, which were the most significantly different metabolites between progressors and non-progressors, to the logistic model forced other metabolites to “borderline or nonsignificant,” according to researchers.
“This is the first demonstration that abnormal plasma concentrations of certain metabolites are associated with risk of progression to ESRD at a very early stage of diabetic nephropathy,” they wrote.
“Metabolomics is an exciting new field, and this exploratory study is rich in very robust findings,” Niewczas said. “Until now, researchers generally were focusing their studies on uremic solutes just at the single-metabolite level, but here we used a very robust, high-throughput platform that screened a few thousand metabolites instead.”
Disclosure: Three of the researchers report financial ties with Metabolon.
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Niewczas MA. Kidney Int. 2014;doi:10.1038/ki.2013.497.
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