Research Expanding into Diabetic Kidney Disease

San Francisco—Diabetic kidney disease is 1 of the more common long-term complications of diabetes, and diabetes is subsequently the main cause of end-stage renal disease and is associated with a high mortality rate. During a symposium at the ADA meeting, researchers examined the success and limitations of current diagnostic, prognostic, and clinical efforts of diabetic kidney disease with a look toward future therapeutic options.

“Having diabetes and kidney disease is a risk for dying,” said Katherine R. Tuttle, MD, FACP, FASN, clinical professor of medicine, University of Washington School of Medicine. The risk factors for diabetic kidney disease are well-recognized. She attributed older age, male sex, poor glycemic control, high blood pressure, more albumin in the urine, and lower glomerular filtration rate (GFR) as risk factors that suggest a poor prognosis. She added that it is difficult to determine risk based solely on these traditional markers.

There are many areas of research for new biomarkers, explained Dr. Tuttle; however, she said lifestyle considerations may help clinicians to prevent and manage the risk of diabetic kidney disease. Independent of diabetes, she said that overweight and obesity are major contributors to the development of chronic kidney disease. Dr. Tuttle highlighted a study by Wang et al published in Kidney International in 2008 that found obesity was second only to proteinuria for increasing the risk of end-stage renal disease in a 25-year cohort study. She mentioned that diet, smoking, prenatal environments, and periodontal disease are also linked with diabetic kidney disease.

“Perhaps the best thing to do is to prevent diabetes to avoid diabetic kidney disease,” said Dr. Tuttle. “But in those who get it, modifying environmental factors, particularly diet, but also smoking, chronic infection, and avoiding nephrotoxins, is helpful as well.”

Clinicians recognize that loss of GFR indicates worsening of kidney disease, but they may not recognize that the trajectory of loss can help estimate risk. Albuminuria and GFR are the only validated markers currently available but neither is without limitations. Because there may be dissociation with changes in albuminuria and changes in GFR, practice guidelines recommend using both measures.

M. Luiza Caramori, MD, MSc, PhD, assistant professor, endocrinology and diabetes, University of Minnesota, said, “Assessment of both [albuminuria and GFR] allows for improved prognostication of renal and cardiovascular events in the general population and in diabetes.”

However, she focused her presentation on the limitations of using albuminuria and GFR in type 1 and type 2 diabetes. She noted that studies of normoalbuminuria in patients with type 1 diabetes with reduced GFR have shown more advanced renal lesions. Furthermore, normoalbuminuria in patients with type 1 diabetes with more serious underlying renal injury are at increased risk for diabetic nephropathy progression. Among normoalbuminuria in patients with type 2 diabetes with reduced GFR, research has shown that this patient population may have atypical diabetic nephropathy as well as other kidney diseases.

“Current recommended screening tests [albuminuria and GFR] do not identify all patients with diabetic kidney disease, since serious diabetic glomerular lesions can be present in normoalbuminuria patients with normal GFR,” concluded Dr. Caramori.

Meanwhile, researchers are developing markers using proteomics and other omic techniques to discover and validate biomarkers. Peter Rossing, MD, DMSc, head of research, Steno Diabetes Center, Gentofte, Denmark, continued the presentation by discussing new biomarkers under development. “New markers should not only be able to predict outcome,” he said, “they should perform better on top of what we already have in our toolbox.”

Dr. Rossing’s group is working with a novel biomarker from Mosaiques Diagnostics in Hannover, Germany. The biomarker is based on a urinary proteomic assay that appears to identify high-risk patients with a high degree of specificity and sensitivity. A clinical trial is currently underway using spironolactone. “If this is successful, we have demonstrated that the marker really works and also that we have a treatment to add on top of the standard of care,” he explained.

Dr. Rossing’s trial is 1 of several studies underway or currently recruiting. Rajiv Agarwal, MD, professor of medicine, Indiana University School of Medicine, concluded the presentation with a discussion of promising new therapies for diabetic kidney disease. He noted that there have been a number of failed and abandoned trials in the past decade, but there are promising therapies in the pipeline.

He mentioned 3 trials currently recruiting: (1) CARMELINA [Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with type 2 Diabetes Mellitus at High Vascular Risk]; (2) CREDENCE [Canagliflozin and Renal Events in Diabetes Established Nephropathy Clinical Evaluation]; and (3) PERL [Preventing Early Renal Function Loss in Diabetes], which is assessing allopurinol.

Dr. Agarwal said the various trials with multiple targets raises cautious optimism that important therapies will be developed in this area. “Hopefully some of the abandoned therapies will be resurrected in the hopes of slowing the relentless march of diabetic nephropathy to dialysis or death,” he said.—Eileen Koutnik-Fotopoulos