• Prevention & Screening
• Renal Disease
• Diabetes Mellitus

Nephropathy is a major complication of diabetes, and its incidence has been increasing despite improvements in renal protection and glycemic control. Thus, it is crucial to identify patients who are at risk for early diabetic nephropathy and to develop preventive interventions. Since the 1980s, microalbuminuria has been an early marker of progressive kidney disease in diabetes, and although this marker is a “great example of predictive validity, [it] is no longer predictive on its own,” said Bruce Perkins, MD, MPH, University Health Network, Toronto, Ontario, Canada. Instead, he said, early progressive glomerular filtration rate (GFR) loss should be the focus, and new biomarkers must be identified.

Dr. Perkins noted that several studies have indicated that microalbuminuria is a functional abnormality in diabetes and remits to normoalbuminuria over time in most patients. Although it was once thought that renal function decline was a late-occurring event that was associated with proteinuria, later studies have indicated that the initiation of renal function decline occurs soon after the onset of microalbuminuria and is not conditional on progression to proteinuria.

Early GFR loss begins at the onset of microalbuminuria in about 30% of patients with type 1 diabetes, said Dr. Perkins, and “represents a committed step—a point of no return,” with the constant loss of renal function leading to advanced stages of chronic kidney disease. However, early GFR loss does not have very good agreement with the degree of microalbuminuria or its subsequent course.

In contrast, serial measurements of serum cystatin C can accurately assess GFR changes over time. Cystatin C is a nonglycosylated basic protease inhibitor that is produced by all nucleated cells, and it has estimated GFR well, even in patients with normal or elevated renal function [Cherney DZ et al. Diabet Med 2010]. Dr. Perkins said that taking serial measurements of cystatin C over time is one improved strategy for predicting the risk of diabetic nephropathy.

Another strategy for predicting the risk of renal disease is to find an accurate and reliable single measure, and Dr. Perkins noted that several urinary and systemic factors have been associated with subsequent early GFR loss. For example, early GFR loss has been associated with urinary excretion of some advanced glycation end products and chemokines, urinary proteomics, and tubular markers.

With regard to systemic factors, in patients with type I diabetes, high levels of soluble tumor necrosis factor receptors are strongly associated with decreased renal function, and serum uric acid concentrations at the high end of the normal range have been associated with impaired renal function in patients, with effects that are independent of those of microalbuminuria [Niewczas MA et al. Clin J Am Soc Nephrol 2008; Rosolowski ET et al. Clin J Am Soc Nephrol 2008]. Dr. Perkins said that these findings suggest that it may be possible to slow renal function loss in patients with early diabetic renal failure through the use of anti-TNF drugs and therapies that reduce serum uric acid.

Dr. Perkins emphasized the need for research to identify biomarkers for early GFR loss. Research must move beyond the reporting of associations between factors and renal failure to determine biomarker thresholds through diagnostic study methodology. Studies should also be conducted to determine the mechanisms of early GFR loss and to discover therapies that slow this loss.

• © 2011 MD Conference Express