Urinary biomarker pattern may predict progression of CKD in type 2 diabetes
Click Here to Manage Email Alerts
Researchers using a urinary proteomics-based signature were able to successfully predict progression to microalbuminuria and chronic kidney disease among a cohort of adults with type 2 diabetes and preserved renal function at baseline, according to findings published in The Lancet Diabetes & Endocrinology.
“We have proven, for the first time in a prospective study, that the urinary proteomic-based analysis CKD273 works as a predictor for future risk for progression in kidney disease, both for increase in albuminuria as well as for loss of renal function,” Peter Rossing, MD, head of diabetes complications research at the Steno Diabetes Center in Gentofte, Denmark, told Healio. “Secondly, we tried to see if we could mitigate this risk with spironolactone. That was not possible to show, maybe because the study was smaller than initially planned or maybe because it just does not work. However, as we begin to see renal benefits in studies with SGLT2 inhibitors and GLP-1 receptor agonists, it would be obvious to test some of these compounds in future studies, and we are trying to set that up.”
In an observational study with an embedded randomized controlled trial, Rossing and colleagues analyzed data from 1,775 adults with type 2 diabetes, normal urinary albumin excretion and preserved renal function from 15 specialist centers in 10 European countries between March 2014 and September 2018 (mean age, 62 years; 62% men). All participants were tested with the CKD273 classifier at screening and were classified as high risk (CKD273 classifier score > 0.154; n = 216; mean age, 63 years) or low risk (score 0.154; n = 1,559; mean age, 61 years). High-risk participants were entered into the randomized controlled trial (n = 209) and randomly assigned 25 mg spironolactone once daily (n = 102) or placebo (n = 107). Mean follow-up time was 2.51 years.
“The components of CKD273 include collagen fragments, which are assumed to relate to early fibrosis in the kidney,” Rossing and colleagues wrote. “Therefore, spironolactone, which is considered to be a antifibrotic via blockade of aldosterone, could be a potentially useful intervention in the context of CKD273-predicted early diabetic kidney disease.”
Primary endpoint was development of confirmed microalbuminuria; secondary endpoints were reduction in incidence of microalbuminuria with spironolactone among participants in the intention-to-treat population, and the association between CKD273 risk score and measures of impaired renal function, based on estimated glomerular filtration rate.
Predicting progression
Within the observational cohort, 61 of the high-risk participants (28%) and 139 of the low-risk participants (9%) progressed to microalbuminuria, for an adjusted HR of 2.48 (95% CI, 1.8-3.42), and 48 of high-risk participants (26%) and 119 of low-risk participants (8%) developed impaired renal function, defined as an eGFR of less than 60 mL/min/1.73 m2, for an adjusted HR of 3.5 (95% CI, 2.5-4.9).
After adjustment for baseline eGFR and urinary albumin to creatinine ratio, researchers observed a 30% decrease in eGFR from baseline among 42 high-risk participants (19%) and 62 low-risk participants (4%) for an HR of 5.15 (95% CI, 3.41-7.76).
Among the trial cohort, 25% of participants assigned spironolactone and 33% of participants assigned placebo developed microalbuminuria during follow-up, for an HR of 0.81 (95% CI, 0.49-1.34).
“We had anticipated a 40% reduction in albuminuria progression, which cannot be excluded because it is within the 95% CI,” the researchers wrote.
Those assigned spironolactone were more likely to experience events of plasma potassium concentrations of more than 5.5 mmol/L (13% vs. 4%).
One participant died in the placebo group due to a cardiac event; and one participant died in the spironolactone group due to cancer, deemed unrelated to study drug, according to researchers.
Promise, challenges of proteomics
“The clinical implication could be a new test to improve prediction, to pinpoint the people with diabetes who need particular care in terms of treating the known risk factors for kidney disease,” Rossing said. “The challenge is currently the price, and although we refer to a health economic analysis demonstrating it would be cost-efficient, it may be a challenge still.”
In commentary accompanying the study, Susanne B. Nicholas, MD, PhD, an associate professor of medicine in the division of nephrology at UCLA, wrote that although the study did not achieve its primary endpoint, the study was successful in several aspects.
“Indeed, the authors did show that CKD273 could predict progression to microalbuminuria long term, independent of clinical characteristics, and a 30% decrease in eGFR from baseline in participants at high risk of microalbuminuria,” Nicholas wrote. “However, the study also had challenges that might be encountered in designing studies that use proteomics. An important aspect is the use of an appropriate comparator, as is necessary for validation of any biomarker. The use of microalbuminuria, instead of gold standard kidney biopsies, remains a hindrance in validating and advancing novel biomarkers.”
Rossing suggested that new studies with other agents such as SGLT2 inhibitors, GLP-1 receptor agonists or new aldosterone antagonists used for people positive for CKD273 would be useful, as well as similar studies conducted in people with type 1 diabetes and kidney disease and people without diabetes with kidney disease.
“As the same urinary proteomic analysis can provide risk scores that may indicate risk for heart failure or atherosclerotic cardiovascular disease, future studies should address if these complications could also be reduced in high-risk individuals,” Rossing said. – by Regina Schaffer
For more information:
Peter Rossing, MD, can be reached at the Steno Diabetes Center Copenhagen, 2820 Gentofte, Denmark; email: peter.rossing@regionh.dk.
Disclosures: Rossing reports he has received lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Merck and Novo Nordisk, and consultant fees from AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Mundipharma and Novo Nordisk, with all fees given to Steno Diabetes Center, and reports having an equity interest in Novo Nordisk. Please see the study for all other authors’ relevant financial disclosures. Nicholas reports no relevant financial disclosures.
Read more about
Click Here to Manage Email Alerts