New Ways to Diagnose and Treat Diabetic Nephropathy Is Topic of Joint Symposium

With “disturbing news about diabetic nephropathy” as a backdrop, Lori M. Laffel, MD, MPH, co-chaired the first joint symposium of ASN and the American Diabetes Association (ADA) on June 27 as part of ADA’s 71st annual meeting in San Diego. “Despite an increase in the use of pharmacological therapies, the prevalence of diabetic nephropathy (DN) has not decreased,” said Laffel, of the Joslin Diabetes Center.

Laffel was referring to findings published in the June Journal of the American Medical Association (JAMA), “Temporal Trends in the Prevalence of Diabetic Kidney Disease in the United States,” based on data from the National Health and Nutrition Examination Survey.

The proportion of diabetic patients taking glucose-lowering medications climbed from 56.2 percent in 1988–1994 to 74.2 percent in 2005–2008, according to the JAMA article, and the use of renin-angiotensin-aldosterone system inhibitors soared from 11.2 percent to 40.6 percent during those same time periods. However, during these two periods, the prevalence of impaired GFR increased from 14.9 percent to 17.7 percent. Although impaired albuminuria declined from 27.3 percent to 23.7 percent, this decrease was not statistically significant, according to the authors of the JAMA article.

Titled “New Concepts in Diagnosing and Treating Diabetic Nephropathy,” the first joint symposium was targeted to endocrinologists and other ADA conference attendees. The second joint symposium is slated to occur at ASN’s Kidney Week 2011, Nov. 8–13, in Philadelphia.

“We [nephrologists] spend a lot of time taking care of patients with diabetes, since it is the leading cause of chronic kidney disease and end stage kidney disease,” said symposium co-chair and ASN past president Sharon Anderson, MD. “So it behooves us as nephrologists to stay current on diabetes treatments.”

ASN president Joseph V. Bonventre, MD, PhD, spoke about the role of renal proximal tubule injury and dysfunction in the pathophysiology of DN. Bonventre, of Harvard Medical School, was one of the four symposium speakers.

“Specific proximal tubular injury leads to interstitial fibrosis and glomerulosclerosis,” he said. “It may be that the kidney tubules are the primary place where diabetes has its earliest actions.”

A potential sensitive and specific biomarker for early tubular injury is the transmembrane glycoprotein kidney injury molecule-1 (KIM-1), which Bonventre’s laboratory cloned and characterized. Expressed only by proximal tubule cells, KIM-1 is undetectable in normal kidneys. With acute kidney injury, the mRNA and the protein are markedly upregulated.

In mice models, long-term expression of KIM-1 leads to kidney failure, and replacement of normal KIM-1 with a mutated form results in a molecule that fails to uptake oxidized lipids and glycation end products, said Bonventre. Citing unpublished research from his laboratory, he noted that high ambient glucose enhances KIM-1 expression in renal epithelial cells.

In a February 2011 Kidney International article, Bonventre and colleagues reported that low urinary levels of KIM-1 and the lysosomal enzyme N-acetyl-beta-D-glucosaminidase (NAG) are associated with regression of microalbuminuria (MA) in patients with type 1 diabetes (T1D) who were monitored for two years. MA regression occurred independently of glycemic control, blood pressure, or treatment with angiotensin converting enzyme inhibitors.

Bonventre and colleagues also reported that significantly elevated urinary levels of KIM-1 and NAG characterized patients with T1D and MA in comparison with diabetic patients with normoalbuminuria and with healthy control individuals without diabetes. These and other studies suggest that KIM-1 may serve not only as a therapeutic target for drug development but also as the basis of an early diagnosis test for DN.

Symposium speaker Bruce A. Perkins, MD, MPH, addressed predictive biomarkers of early DN beyond MA.

“Recent studies have shown us that microalbuminuria on its own is not the perfect predictor of who will develop advanced kidney disease, and we need to get beyond the idea of relying so much on microalbuminuria,” he said.

In the recent studies, elevated urinary albumin excretion regressed to normoalbuminuria in a majority of T1D patients. In only a minority of T1D patients did MA lead to proteinuria, said Perkins, of the University of Toronto.

“What we and others have learned is that the old notion that people don’t start to lose renal function until they have proteinuria appears to have been false,” he pointed out. In about one third of T1D patients, GFR loss can begin at the onset of microalbuminuria, well before proteinuria appears. “End stage renal loss can occur before proteinuria,” Perkins noted, referring to the Joslin Diabetes Center’s findings of renal function decline in T1D patients with normal albumin excretion.

As a potential biomarker for early GFR loss, Bruce proposed serial measurement of serum cystatin C, a cysteine protease inhibitor that is freely filtered by the renal glomeruli and metabolized by the proximal tubule.

In an April 2011 issue of JAMA, researchers reported that combining creatinine-based estimated GFR and urine albumin-to-creatinine ratio with cystatin C was associated with improved prediction of end stage kidney disease and all-cause death. Cystatin C and albuminuria were both strongly and independently associated with all-cause death among patients with or without chronic kidney disease (CKD) defined by creatinine-based estimated GFR. The risk of future end stage renal disease (ESRD) was concentrated within the patient subset with CKD defined by all three markers. The second highest risk group for ESRD was missed by creatinine but was detected by cystatin C and albumin/creatinine ratio.

“If we screen people with new onset microalbuminuria, we now know that about a third of them will lose substantial GFR in subsequent years, so we could measure serum cystatin C levels over time to estimate the rate of decline and identify those people at highest risk of reaching advanced kidney disease,” Perkins said.

As another potential biomarker for early GFR loss, Perkins cited tumor necrosis factor-α (TNFα/TNF), a key mediator of inflammation that also plays a role in apoptosis. Joslin researchers have shown that soluble TNF receptors are strong predictors of early GFR loss in T1D. Perkins referred to Joslin scientists’ ADA poster reporting that plasma levels of TNF receptors did not increase with renal function loss in T1D patients. The Joslin researchers concluded that because elevation of TNF receptors preceded kidney dysfunction, they could be both predictors of, and risk factors for, early GFR loss in T1D.

Kumar Sharma, MD, spoke about novel treatments for DN, including the investigational antifibrotic and antiinflammatory drug pirfenidone. Sharma, of UC San Diego, headed a randomized, double-blind, placebo-controlled clinical study that evaluated pirfenidone in 77 DN patients with elevated albuminuria and reduced GFR.

“Pirfenidone not only halted decline but actually improved kidney function in these patients,” said Sharma, who with his collaborators reported the study findings in an article published in the April 2011 issue of the Journal of the American Society of Nephrology.

Sharma also spoke about bardoxolone methyl, first in a new class of antioxidant inflammation modulators. In the June 24, 2011, issue of the New England Journal of Medicine, investigators reported the results of a phase 2, double-blind, randomized, placebo-controlled trial in 227 CKD patients. “Bardoxolone improved eGFR as early as four weeks after initiation of treatment,” Sharma said. Improved GFR characterized patients at both 24 and 52 weeks.

Marie Pavlakis, MD, of Beth Israel Medical Center, reviewed data supporting the use of preemptive kidney transplantation before the start of dialysis. “The treatment of choice for these diabetics would be a live donor kidney transplant before dialysis treatment,” she said. “We have evidence that people who get kidney transplants preemptively live longer and do better, and the kidney lasts longer than in people who get a transplant when they are already on dialysis.”

“Research shows the highest mortality risk for type 1 diabetics is for those on dialysis,” she added. “We need to get the message out to the endocrinology community on the remarkable mortality benefit that predialysis kidney transplantation offers for type 1 diabetics.”

September 2011 (Vol. 3, Number 9)