Kidney function may be an effective predictor of type 2 diabetes risk, researchers reported.
In those with normal estimated glomerular filtration rate (eGFR) levels (≥60 ml/min per 1.73 m2), high levels of blood urea nitrogen (BUN) — >25 mg/dL — was tied to an increased risk for diabetes (hazard ratio 1.27, 95% CI 1.24-1.31), according to Yan Xie, MPH, of the VA Saint Louis Health Care System in Missouri, and colleagues.
The highest risk for incident diabetes was among those with BUN >25 mg/dL paired with an eGFR <15 ml/min per 1.72 m2 (HR 1.68, 95% CI 1.51-1.87), they wrote in Kidney International.
“We have known for a long time that diabetes is a major risk factor for [chronic kidney disease or CKD], but now we have a better understanding that kidney disease, through elevated levels of urea, also raises the risk of diabetes,” said co-author Ziyad Al-Aly, MD, of Washington University in St. Louis, in a press release.
“When urea builds up in the blood because of kidney dysfunction, increased insulin resistance and impaired insulin secretion often result,” he added.
Al-Aly pointed out that “Our results were almost an exact replica of the mouse study. The results showed a clear relationship between urea levels and risk of diabetes.”
The analysis included 1,337,452 individuals from the U.S. Department of Veterans Affairs database, none of whom had diabetes at baseline. Over the median follow-up period of 4.93 years, there were 172,913 (12.93%) incident cases of diabetes. In a weighted analysis, there were 210,873 incident diabetes cases — 23,649 of which occurred in those with a BUN >25 mg/dL (19.85%) versus 18,224 cases in those with a BUN ≤25 (15.32%).
In addition to normal and the highest levels of eGFR, all other groups with elevated BUN levels (>25 mg/dL) also reported an increased incidence for diabetes:
- 60>eGFR≥45 ml/min per 1.73 m2: HR 1.23 (95% CI 1.20-1.27)
- 45>eGFR≥30 ml/min per 1.73 m2: 1.18 (1.15-1.22)
- 30>eGFR≥15 ml/min per 1.73 m2: 1.22 (1.17-1.27)
Younger individuals with high BUN levels in the cohort had a stronger associated diabetes risk compared with those older than the median of age 65 (HR 1.35, 95% CI 1.33-1.37 vs HR 1.20, 1.16-1.24). High BUN levels tied to diabetes risk was also stronger in black individuals compared with other races (HR 1.38, 95% CI 1.34-1.43 vs. HR 1.21, 1.20-1.22).
There was no association with incident diabetes risk across any eGFR groups in individuals with lower BUN levels (≤25 mg/dL).
In an independent assessment of time-updated eGFR levels, those in the lowest two categories of eGFR — 30>eGFR≥ 15 and <15 -- had an increased risk for incident diabetes (HR 1.17, 1.12-1.22; HR 1.64, 1.48-1.82, respectively).
In a two-stage residual inclusion analysis, the research group confirmed an elevated BUN concentration was independently linked with an increased diabetes risk, with every 10 mg/dL increase tied to an increased diabetes risk (HR 1.09, 95% CI 1.08–1.10). However, each 10 ml/min per 1.73 m2 increase in eGFR had no significant impact in diabetes risk (HR 0.99, CI 0.99–1.00).
“Although increased insulin resistance in CKD is now a universally recognized concept, the notion of beta-cell dysfunction (and possibly an insulin secretory defect) in CKD is still not yet widely accepted,” the authors wrote, highlighting how prior study findings paired with their current findings “lends validity and provides epidemiologic evidence in humans of an association between circulating levels of urea and the risk of the development of diabetes in patients with nondiabetic kidney disease.”
“However, our studies cannot attribute the effect seen to decreased insulin secretion (and beta-cell dysfunction) or increased insulin resistance or a combination of both,” they noted. They called for additional research to validate the findings, and to assess potential interventions, such as pharmacology, manipulation of the microbiome, or through other methods.
Click here for the American Association of Clinical Endocrinologists’ type 2 diabetes management algorithm and resource center for the management of diabetes comorbidities including CKD.
The study was funded by a grant from the U.S. Department of Veterans Affairs.
Xie and co-authors disclosed no relevant relationships with industry.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner