Thursday, March 31, 2005
A researcher at Cincinnati Children's Hospital Medical Center has identified a protein that allows for earlier and quicker diagnosis of kidney failure -- a diagnosis that now often occurs too late to treat kidney failure effectively.
The research, which is published in the current issue of The Lancet, sites evidence in favor of using the protein neutrophil gelatinase-associated lipocalin, or NGAL, as a new biomarker for diagnosing kidney failure (also called acute renal failure) in patients.
"Despite major achievements in treating children and adults with kidney failure, little has changed in the last four decades to diagnose kidney failure early enough before it progresses into a chronic or deadly condition," according to Prasad Devarajan, MD, director of the Division of Nephrology and Hypertension at Cincinnati Children's and principal investigator of the study.
"We set out to identify genes and biomarkers that could help us make the diagnosis well before it is too late. We identified a candidate protein for the early and rapid diagnosis of acute renal injury that occurs in a common clinical condition, namely after cardiac surgery," he said.
While many conditions and diseases can lead to kidney failure, it is more often the result of decreased blood flow to the kidneys from major surgery or injury, stroke, sepsis, dehydration, or adverse reactions to medications. The kidneys will stop working over a period of hours, days, or in some cases, weeks.
Five percent of all patients admitted to the hospital and 30-50 percent of those in intensive care units will have kidney failure. In these cases, 50-80 percent of people will die.
The current gold standard in diagnosing kidney failure (serum creatinine measurement) leads to a diagnosis one to three days after the initial injury, but by testing for high concentrations of NGAL, Dr. Devarajan and colleagues at Cincinnati Children's found they could get definitive test results within hours. (These results were independently confirmed by collaborators at Columbia University in New York -- Jonathan Barasch, MD, PhD, and Kiyoshi Mori, MD, PhD).
"In current clinical practice, when kidney failure occurs, the diagnosis is unacceptably delayed. Ironically, even tragically, effective preventive and therapeutic measures are widely available, but rarely administered in a timely manner due to the lack of early biomarkers of kidney failure," Dr. Devarajan said.
The Lancet study used as its model children undergoing cardiopulmonary bypass surgery, 10-40 percent of these children will experience kidney failure.
Earlier studies in animal models by Dr. Devarajan and colleagues found evidence confirming the NGAL gene and protein are directly correlated to kidney failure. The gene and its biomarkers were present in higher concentrations during acute renal injury, he said. These studies have paved the way for designing new treatments for humans.
"The NGAL gene was one of the most upregulated in animal models with acute renal disease. The protein product of this gene showed up in urine samples very early after kidney failure," Dr. Devarajan said.
The research team at Cincinnati Children's took a drop of blood and urine samples from 71 patients. They adapted a diagnostic test, called ELISA, that would easily and accurately detect NGAL in urine and blood samples. The test results revealed high concentrations of the protein NGAL, which indicated the high possibility of kidney failure. Of the 71 patients, 20 (28 percent) developed kidney failure one to three days after surgery. In these same patients, NGAL was easily detectable in urine and blood within two hours of the operation. The NGAL in patients' urine increased by about 15 fold two hours after surgery. NGAL in blood samples increased about six fold two hours after surgery.
"Statistically, this is an outstanding biomarker, which led us to believe that urine and blood-based NGAL are novel, sensitive, specific, highly predictive early biomarker for acute renal injury and in this case, at least in cardiac surgery patients," he said.
The new diagnostic test could also benefit patients of abdominal surgery, stroke, trauma, sepsis, kidney transplantation and those undergoing treatment with several nephrotoxic drugs, such as aminoglycoside antibiotics, chemotherapeutic agents and radiocontrast agents.
Treating patients who suffer from complications of acute kidney failure is expensive. In the United States, approximately $10 billion is spent annually to treat adults with acute kidney failure. Kidney failure occurs in up to 40 percent of adults after cardiac surgery with one to five percent needing dialysis, of which 80 percent may die. Dr. Devarajan said that diagnosing kidney failure before it progresses will most likely result in a significant health care cost savings.
This study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health, American Heart Association Ohio Valley Affiliate, the March of Dimes Foundation, and the Translational Research Initiative from Cincinnati Children's.
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Cincinnati Children's is a 423-bed institution devoted to bringing the world the joy of healthier kids. Cincinnati Children's is dedicated to transforming the way health care is delivered by providing care that is timely, efficient, effective, family-centered, equitable and safe. It ranks third nationally among all pediatric centers in research grants from the National Institutes of Health. The Cincinnati Children's vision is to be the leader in improving child health.