PRIORITY: Urine Test Spots Future Kidney Disease in Diabetes

Marlene Busko

October 03, 2019

BARCELONA, Spain — Using the proteomic classifier CDK273 urine test, researchers identified patients with type 2 diabetes and normal urinary albumin who were at high risk of developing microalbuminuria (early kidney disease) in a European study.

However, therapy with the renin-angiotensin-aldosterone system (RAAS) blocker spironolactone was not better than placebo in preventing progression to kidney disease in these high-risk patients, Peter Rossing, MD, DMSc, Steno Diabetes Center, Copenhagen, Denmark, reported.  

He presented the findings from PRIORITY (Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention of Early Diabetic Nephropathy in Type 2 Diabetic Patients with Normoalbuminuria study) here at the European Association for the Study of Diabetes (EASD) 2019 Annual Meeting.

In close to 2000 patients with type 2 diabetes and normal urine albumin, the proteomic test identified 1 in 10 patients as high risk, he said. And after adjusting for commonly measured baseline risk factors, the high-risk patients had a 2.5-fold greater risk of progressing to microalbuminuria.  

Session chair Christian Delles, MD, University of Glasgow, UK, who was a principal investigator, told Medscape Medical News that the test identifies kidney disease "at very early stages...before a patient has detectable microalbuminuria, at which point damage to the kidneys has already occurred."

Early detection would allow "targeted and early preventative approaches," Delles said.

And although spironolactone therapy did not halt the progression to early kidney disease in the high-risk patients in the study, future research might identify new or existing drugs that could, he noted.

Indeed, said Rossing: "I think there are many other good choices that we could apply in future studies. Just this year we had the first positive study in patients with established kidney disease with the SGLT2 inhibitors."

And Delles added that screening potential clinical trial participants with the CKD273 test could spare patients who are unlikely to develop kidney disease from needless exposure to a study drug. 

Identifying Renal Disease Risk vs Preventing Disease Progression 

Rossing told delegates at EASD that diabetic kidney disease has a large impact on a person's wellbeing and mortality and on healthcare costs.

However, current treatments "use albuminuria as a marker at a time when there is already [kidney] damage and then try to delay the onset of organ failure and the need for dialysis."

The PRIORITY study aimed to identify high-risk patients at an earlier stage, and then to see if spironolactone — a diuretic with well-known antihypertensive benefits — might reduce the risk of progression to diabetic kidney disease.

Researchers enrolled 1775 adults (age 18-75 years) with type 2 diabetes and a normal urine albumin to creatinine ratio (UACR, < 30 mg/g) at 15 sites in 10 European countries and measured the patients' CKD273 proteomic pattern using the biomarker test developed by Mosaiques Diagnostics.

The CKD273 test uses capillary electrophoresis coupled to mass spectrometry (CE-MS) to detect 273 peptides in the urine — mainly alpha-1-antitrypsin and fibrinogen protein fragments — that are markers of kidney fibrosis and inflammation. In 2016, the company received a letter of support from the US FDA to encourage further development of the test.

In the current study, the test identified 216 patients at high risk of developing microalbuminuria and 1559 at low risk.

During an average of 4.5-years of follow-up, high-risk patients were three times more likely to develop microalbuminuria than low-risk patients (28% vs 9%).

After even adjusting for "all the conventional risk factors that we already measure in the clinic including GFR and albuminuria," as well as age, gender, A1c, systolic blood pressure, retinopathy, and UACR, "there was a 2.5 fold higher event rate in those with a high-risk proteomic pattern" (hazard ratio [HR], 2.48; P < .0001), Rossing said.

The risk of developing CKD stage 3 or worse (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m2) was also significantly higher in the patients with a high-risk CKD273 pattern (P < .0001)

Of the high-risk patients, 209 consented to the intervention and were then randomized to receive spironolactone (102 patients) or placebo (107 patients) for 2.5 years.

The rate of new kidney disease was similar in the treated and placebo groups (26% and 35%, respectively; HR, 0.81; P = .41).

Other Renoprotective Drugs?

Perhaps there was no renoprotection with spironolactone, Rossing speculated, because the drug only reduces albuminuria at more advanced stages of kidney disease, or because the study was too short and/or too small.

However, Delles noted, "there are new drugs that specifically target inflammation and fibrosis in the kidney currently under development or in clinical trials."

And "of the drugs that are currently in clinical use," he continued, "some of the novel antidiabetic drugs, such as SGLT2 inhibitors, could be very promising for the prevention of microalbuminuria and ultimately [diabetic kidney disease]."

"Maybe some of these agents could be applied in high-risk individuals," Rossing suggested, "or maybe it's simply sufficient to optimize our treatment strategy with the current means — improvement of glycemic control, targeting blood pressure more intensively, and so on."

"We Really Need Biomarkers Linked to the Treatment Itself"

Asked to comment, Ian H. de Boer, MD, University of Washington, Seattle, who was not involved in PRIORITY, said: "The strong association of the proteomics classifier with risk of microalbuminuria and reduced eGFR demonstrates that 'omics' platforms have great potential to identify new pathways and risk markers of kidney disease."  

But the "more important lesson," he told Medscape Medical News in an email, "is that using biomarkers to select trial participants based on high risk of a study outcome isn't necessarily enough to advance new therapies."

"What we really need are biomarkers that are linked to the treatment itself," so that it's possible to identify a propensity to respond to that treatment, said de Boer.

"That is the essence of precision medicine. Omics strategies can help us toward that goal moving forward," he noted.

PRIORITY was funded under the Framework Programme 7 of the European Commission Directorate General for Research and Innovation.

EASD 2019 Annual Meeting. Presented September 19, 2019.

For more diabetes and endocrinology news, follow us on Twitter and Facebook.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....