Kidney Disease Research Updates
Fall 2008

NIDDK Workshop Pursues Better Ways to Assess Kidney Function and Disease

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) tapped the expertise of academic, Government, and industry scientists during a June workshop to explore ways of assessing kidney function and damage, including the development of new biomarkers and imaging techniques and clinical trials to test them.

The workshop was in part a response to the growing problem of chronic kidney disease (CKD), estimated to affect 26 million Americans. Early CKD has few symptoms and often progresses untreated.

“Chronic kidney disease and end-stage renal disease together consume about 27 percent of the Medicare budget,” said Robert A. Star, M.D., director of the NIDDK’s Division of Kidney, Urologic, and Hematologic Diseases. “We need new biomarkers, outcome measures, assessment tools, and imaging methods.”

Quest for Biomarkers

Finding an alternative to measuring serum creatinine, a normal waste product in the blood and the most frequently used biomarker for assessing kidney function, was a central theme of the workshop. Doctors use creatinine levels to estimate the glomerular filtration rate (GFR), an indirect measure of the kidneys’ filtering capacity. However, creatinine’s natural tendency to vary based on a person’s age, sex, muscle mass, diet, ethnicity, and physical activity limits its practical usefulness in guiding patient care. And, according to Star, designing clinical trials around creatinine is quite difficult.

“The ideal biomarker for chronic kidney disease would be something that is noninvasive, reliable, and a simple tool that can be used for diagnosing and determining the severity of disease, risk for progression, the most appropriate therapy, and the response and toxicity of a particular therapy,” said Catherine Stehman-Breen, M.D., M.S., vice president of global development at the biotechnology company Amgen. But “we are not likely to find a biomarker that can do all of these things.”

Assessment panels comprising multiple biomarkers may be required to accurately assess kidney function. Biomarkers can be simple—such as blood pressure or an x ray—or complex, such as genes or substances in the blood, urine, or tissue.

Cystatin C is a leading candidate for inclusion in a kidney function assessment panel geared toward detecting early kidney disease. Unlike creatinine, serum levels of cystatin C are believed to be relatively independent of age, sex, and muscle mass, said Michael Shlipak, M.D., chief of the general internal medicine division at the San Francisco Veterans Administration Medical Center. “Cystatin C captures early preclinical impairment of GFR that is not detected by creatinine-based estimates of GFR.”

Other potential biomarkers for kidney function or injury assessment discussed at the workshop include

• kidney injury molecule-1 (KIM-1)
• neutrophil gelatinase-associated lipocalin (NGAL)
• interleukin-18 (IL-18)
• interleukin-6 (IL-6)
• N-acetyl-β-D-glucosaminidase (NAG)
• L-type fatty acid binding protein (L-FABP)
• albumin
• B2-microalbumin
• glutathione S-transferase-a (GST-a) and glutathione S-transferase-p (GST-p)
• alkaline phosphatase
• gamma-glutamyl transpeptidase (GGT)

Imaging Methods

Workshop attendees also discussed a range of conventional and emerging imaging techniques. Magnetic resonance imaging, ultrasound, novel contrast studies, and plasma clearance techniques can measure GFR but are underused, according to Bruce Molitoris, M.D., director of both nephrology and the Center for Biological Microscopy at Indiana University. “Nephrology personnel do not understand radiology; radiologists do not understand the kidney,” he said, citing the need for an interdisciplinary approach to assessing kidney function.

Participating scientists identified solutions, such as direct funding for interdisciplinary training programs, to close the gap among the nephrology, radiology, and engineering research communities. Such programs would encourage interaction and “synergize development of the field,” said Molitoris.

The workshop also tagged methods ripe for clinical development, including studies for monitoring kidney size, oxygenation, inflammation, and regional perfusion. Perturbed kidney blood flow and renal reserve are also important areas that need further investigation.

Surrogate Endpoints

To expand and accelerate clinical trials, the workshop focused on identifying surrogate endpoints that can predict and substitute for real clinical endpoints. “We may need different surrogates for early versus later-stage disease and for early versus later-stage drug development,” reported Glenn Chertow, M.D., chief of nephrology at Stanford University, who chaired a breakout session about designing clinical trials. U.S. Food and Drug Administration officials were on hand to outline the pilot process for qualifying surrogate endpoints and biomarkers.

“We are really at the bottom of the pile when it comes to the number of clinical trials conducted in chronic kidney disease,” said Stehman-Breen, “and one of the reasons is the very long lag time between diagnosis and the ultimate, hard clinical endpoint of end-stage renal disease or death.”

Candidate surrogate endpoints for acute kidney injury identified at the workshop include

• death
• dialysis or dramatic change in serum creatinine
• acidosis
• blood levels of potassium, phosphorus, and hemoglobin
• urine output
• doubling of cystatin C

Endpoints identified for CKD were

• slope in the estimated GFR/measured GFR
• doubling of serum creatinine
• proteinuria
• cyst enlargement in polycystic kidney disease
• mesangial expansion in type 1 diabetes
• GFR reserve
• fibrosis by biopsy
• impaired erythropoiesis
• hyperphosphatemia

The workshop stimulated interest in discovering and validating new biomarkers to improve the early diagnosis, staging, and prognosis of kidney disease and for use as intermediate or surrogate outcome measures that will ultimately improve the treatment of kidney disease.

The NIDDK is releasing a Request for Application for a chronic kidney disease discovery and validation consortium (RFA–DK–08–015) in December 2008.

For more information about kidney disease, visit www.kidney.niddk.nih.gov.

NIH Publication No. 09–4531
December 2008

[Top]