Adults with prediabetes were more than twice as likely as those with normal glucose levels to experience a faster decline in kidney function over time, according to new data from a long-term population-based study of more than 1500 individuals.

Chronic kidney disease is one of the fastest growing causes of disability and death worldwide, said lead author Toralf Melsom, MD, of University Hospital of North Norway, Tromsø, Norway.

“Prediabetes affects an estimated 700 million people worldwide and has been associated with early signs of kidney dysfunction, such as hyperfiltration, characterized by an abnormally elevated glomerular filtration rate (GFR),” Melsom told Medscape Medical News. “However, whether prediabetes is a risk factor for loss of kidney function is unknown.”

Study Design

The findings, published in Kidney International, are based on data from the Renal Iohexol Clearance Survey, in which the measured GFR (mGFR) was identified using the single-sample plasma iohexol clearance technique.

The analysis included 1594 middle-aged Europeans (50-62 years) with no history of diabetes, cardiovascular disease, or kidney disease. Approximately half (51%) were female, and 49% had prediabetes at baseline based on the American Diabetes Association (ADA) criteria. Follow-up mGFR was performed after a median of 5.2-6.0 years in 1299 participants and again at 11.0 years in 1151 participants. A total of 1384 individuals had at least one follow-up mGFR assessment.

The primary outcome was accelerated mGFR decline, defined as the 10% steepest decline over the study period. Prediabetes was diagnosed using either World Health Organization (WHO) criteria (fasting glucose, 6.1-6.9 mmol/L) or ADA criteria (fasting glucose, 5.6-6.9 mmol/L; A1c, 5.7%-6.4% [39-47 mmol/mol]).

Key Results

Participants with prediabetes experienced a significantly faster decline in measured kidney function. The odds of accelerated mGFR decline were 2.6 for those meeting WHO prediabetes criteria and 2.0 for those meeting ADA criteria. The mean annual mGFR decline in the total study population was -1.23 mL/min/y. Among participants with prediabetes, mean declines were steeper by 0.30 mL/min/y (WHO) and 0.14 mL/min/y (ADA) than in those without prediabetes.

Similar results were obtained after excluding participants who developed diabetes during follow-up. No significant differences were observed by sex or BMI.

When kidney function was assessed using the standard creatinine- and cystatin C-based estimated GFR (eGFR), the association between prediabetes and kidney function decline was not observed.

“We were surprised by the relatively robust link between prediabetes and a decline in kidney function, as measured by accurate GFR measurements,” Melsom told Medscape Medical News. “Previous studies have relied on inaccurate estimates of GFR, resulting in inconsistent results, but our results suggest that the common method of estimating GFR from creatinine and cystatin C may mask early declines in kidney function.”

Limitations and Implications

The authors noted several limitations to the study, including an observational design that does not provide evidence that treating prediabetes would in fact improve renal outcomes. Furthermore, it included a homogenous population of middle-aged and older White Europeans and a small number of individuals who developed incident chronic kidney disease.

Nonetheless, the results have potential implications for public health, as all definitions of prediabetes were significantly associated with an accelerated decline in kidney function before the onset of diabetes. Melsom noted that this suggests prediabetes offers a “window of opportunity” to prevent chronic kidney disease and subsequent cardiovascular and metabolic complications.

“Lifestyle interventions, such as dietary modifications and regular physical activity, should be recommended to reduce kidney damage in all individuals with prediabetes,” Melsom said.

He added that the results also suggest that effective medications used to prevent GFR loss in diabetes may be tested in certain persons with prediabetes, and a randomized controlled trial of SGLT2 inhibitors in this population may be warranted.

Expert Commentary: The Method Matters

In an accompanying editorial, Phoom Narongkiatikhun, MD, and Petter Bjornstad, MD, both from the University of Washington, Seattle, described the Renal Iohexol Clearance Survey as a significant contribution to population-based kidney research.

They emphasized that mGFR provides a far more accurate assessment of kidney function than eGFR, which has been used in most previous analyses. Although mGFR is influenced by biological variability, “eGFR may underestimate early decline due to non-GFR determinants and limited sensitivity to subtle injury,” they wrote.

The authors noted that accelerated GFR decline was observed even among participants with fasting glucose as low as 5.5 mmol/L (99 mg/dL) compared with those at 4.0 mmol/L (72 mg/dL).

“Over time, this small annual difference could translate into substantial kidney damage,” they noted.

These findings highlight the need for more sensitive and accessible tools to identify early kidney injury, Narongkiatikhun and Bjornstad wrote.

“Millions of individuals with prediabetes may be experiencing silent but progressive kidney damage that goes undetected under current screening practices.”

The Renal Iohexol Clearance Survey studies were supported by the Northern Norway Regional Health Authority. Melsom, Narongkiatikhun, and Bjornstad disclosed having no financial conflicts of interest.