Protecting Renal Function in Diabetes
Diabetic nephropathy (DN) is a long-standing complication of diabetes caused by accumulating injury to the glomerular microvasculature of the kidneys. DN is frequently asymptomatic, particularly in early stages, but can be detected using annual kidney-function and albuminuria tests. Estimated glomerular filtration rate (eGFR) is a blood test of kidney function that can detect DN; in a heathy kidney eGFR normally ranges from 90 to 120 mL/min per 1.73 m2.
Over time, diabetes may mediate an accumulation of glomerular tissue injury and scarring, leading to a decline in the ability to filter the blood, contributing to elevations in urine albumin concentration.1-3 DN can eventually cause leg swelling, changes in appetite, nausea, fatigue, and end-stage renal disease (ESRD), leading to dialysis or kidney transplantation.1-5 DN is estimated to underlie more than 40% of ESRD cases. It is also a risk factor for cardiovascular complications, including coronary artery disease, peripheral arterial disease, and stroke.1
The molecular pathways involved in the onset and progression of DN are complex, and are currently understood to include kidney fibrosis, and abnormalities in sugar metabolism and neurohormonal regulation. 1 Genetic and environmental factors are thought to modify the rate of progression of DN toward ESRD.2
Standard DN treatment targets the renin-angiotensin-aldosterone system (RAAS) neuroendocrine pathway with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). 1 Comprehensive management of DN includes RAAS inhibition plus lipid control, reduced dietary salt intake, smoking cessation, physical exercise and weight loss.2 RAAS inhibition-based therapy slows—but does not always prevent—DN progression.1,3 Despite RAAS-inhibition treatment, about 30% of patients still develop DN-related complications.1,3
“Unfortunately, several recent renal protection trials have failed, demonstrated harm or reported effects that are far below expectations based on data from experimental models,” Yuliya Lytvyn and coauthors from the Department of University of Toronto in Ontario, Canada, noted in a recent review of new and old agents for DN management.1 “For example, trials with early RAAS blockade in patients with type 1 diabetes were neutral and in type 2 diabetes studies using dual RAAS blockade, protein kinase C-β inhibition, endothelin receptor antagonists or the antioxidant bardoxolone have reported disappointing results.”