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Study Expands Use of Biomarker for Early Diagnosis of Acute Kidney Injury

A biomarker test developed initially to identify early acute kidney injury (AKI) after surgery has been shown to successfully detect AKI in emergency room patients with a variety of urgent health issues.

In a study published online Sept. 5 in the Clinical Journal of the American Society of Nephrology, the findings expand the overall utility and potential medical settings for using the test, according to researchers.

The test measures the protein neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker of early AKI. It was invented by researchers at Cincinnati Children’s Hospital Medical Center to detect AKI earlier than existing methods, and to more promptly begin treatment.

“The majority of our studies on NGAL have been performed in well controlled settings of hospital-acquired AKI, such as cardiac surgery, contrast administration or other critically ill patients,” said Prasad Devarajan, MD, senior author and director of Nephrology and Hypertension at Cincinnati Children’s. “The purpose of this study was to determine the biomarker’s accuracy in a diverse group of patients admitted from the emergency department, where patients with early signs of AKI are often misdiagnosed.”

The study involved patients admitted through the emergency room of Fernando Fonseca Hospital in Portugal, which also closely collaborated on the study. The findings demonstrate the NGAL test, which uses a single drop of blood and provides results within 15 minutes, was able to accurately distinguish AKI from reversible transient kidney dysfunction.

Of 616 patients who participated in the study, individuals who were subsequently diagnosed with true AKI had the highest levels of NGAL detected at the time of hospital admission. The study also identified a cutoff point in NGAL levels above which the risk of acute kidney injury increases tenfold.

Results of a study previously published in 2008 by Devarajan showed that the NGAL test predicted AKI in pediatric heart surgery patients within hours instead of days, allowing treatment that prevented serious damage to kidneys. Prior to the NGAL test, serum creatinine was the only reliable method for detecting kidney damage; however, the long wait for results often resulted in permanent kidney damage.

With a growing number of patients coming to emergency rooms with community-acquired AKI, Devarajan says having a rapid, reliable method of detecting kidney injury is increasingly important.

“This latest study showed that this simple laboratory test provides an accurate prediction of acute kidney injury and its severity in a diverse clinical setting,” said Devarajan. “The identification of biomarkers that differentiate intrinsic AKI from transient reversible forms of renal dysfunction and predict outcomes is a high priority.”

Study: Plasma NGAL for the Diagnosis of AKI in Patients Admitted from the Emergency Department Setting [Clinical Journal of the American Society of Nephrology]

Source: EurekAlert!

Urine Biomarker Test Can Diagnose as well as Predict Rejection of Transplanted Kidneys

A breakthrough non-invasive test can detect whether transplanted kidneys are in the process of being rejected, as well as identify patients at risk for rejection weeks to months before they show symptoms, according to a study published in The New England Journal of Medicine (NEJM).

By measuring just three genetic molecules in a urine sample, the test accurately diagnoses acute rejection of kidney transplants, the most frequent and serious complication of kidney transplants, says the study’s lead author, Dr. Manikkam Suthanthiran, the Stanton Griffis Distinguished Professor of Medicine at Weill Cornell Medical College and chief of transplantation medicine, nephrology and hypertension at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

“It looks to us that we can actually anticipate rejection of a kidney several weeks before rejection begins to damage the transplant,” Dr. Suthanthiran says.

The test may also help physicians fine-tune the amount of powerful immunosuppressive drugs that organ transplant patients must take for the rest of their lives, says Dr. Suthanthiran, whose laboratory developed what he calls the “three-gene signature” of the health of transplanted kidney organs.

“We have, for the first time, the opportunity to manage transplant patients in a more precise, individualized fashion. This is good news since it moves us from the current one-size-fits-all treatment model to a much more personalized plan,” he says, noting that too little immunosuppression leads to organ rejection and too much can lead to infection or even cancer.

Given the promise of the test first developed in the Suthanthiran laboratory at Weill Cornell and previously reported in NEJM, the National Institutes of Health (NIH) sponsored a multicenter clinical trial of nearly 500 kidney transplant patients at five medical centers, including NewYork-Presbyterian/Weill Cornell Medical Center and NewYork-Presbyterian/Columbia University Medical Center. The successful results of that trial are detailed in the July 4 issue of NEJM.

Such a test is sorely needed to help improve the longevity of kidney transplants and the lives of patients who receive these organs, says study co-author Dr. Darshana Dadhania, associate professor of medicine and medicine in surgery at Weill Cornell Medical College and associate attending physician at NewYork-Presbyterian Hospital.

Dr. Dadhania says that the primary blood test now used to help identify rejection — creatinine, which measures kidney function — is much less specific than the three-gene signature.

“Creatinine can go up for many reasons, including simple dehydration in a patient, and when this happens we then need to do a highly invasive needle-stick biopsy to look at the kidney and determine the cause. Our goal is to provide the most effective care possible for our transplant patients, and that means individualizing their post transplant care,” she says. “Using an innovative biomarker test like this will eliminate unnecessary biopsies and provide a yardstick to measure adequate immunosuppression to keep organs — and our patients — healthy.”

Although a number of researchers have tried to develop blood or urine-based tests to measure genes or proteins that signify kidney organ rejection, Dr. Suthanthiran and his research team were the first to create a gene expression profile urine test — an advance that was reported in NEJM in 2001 and, with an update also in NEJM, in 2005.

The research team measured the levels of messenger RNA (mRNA) molecules produced as genes are being expressed, or activated, to make proteins. To do this, they developed a number of sophisticated tools to measure this genetic material. “We were told we would never be able to isolate good quality mRNA from urine,” he says. “Never say never.”

He and his colleagues found that increased expression of three mRNAs can determine if an organ will be, or is being, rejected. The mRNAs (18S ribosomal (rRNA)–normalized CD3ε mRNA, 18S rRNA–normalized interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA) indicate that killer T immune cells are being recruited to the kidney in order to destroy what the body has come to recognize as alien tissue.

The signature test consists of adding levels of the three mRNAs in urine into a composite score. Tracked over time, a rising score can indicate heightened immune system activity against a transplanted kidney, Dr. Suthanthiran says. A score that stays the same suggests that the patient is not at risk for rejection.

“We were always looking for the most parsimonious model for an organ rejection biomarker test,” Dr. Suthanthiran says. “Minimizing the number of genes that we test for is just more practical and helps to give us a clearer path towards diagnosis and use in the clinic.”

Physicians can tailor a patient’s use of multiple immunosuppressive drugs by lowering the doses steadily, and monitoring the patient’s composite score over time. Any increase would suggest a somewhat higher dose of therapy is needed to keep the organ safe.

“This is akin to monitoring blood glucose in a patient with diabetes,” Dr. Suthanthiran says. “Because different people have different sensitivity to the two-to-four immunosuppressive drugs they have to take, this test offers us a very personalized approach to managing transplantations.”

Predicting rejection weeks before it happens

The clinical trial began in 2006 with participation from five medical centers — NewYork-Presbyterian/Columbia University Medical Center, the University of Pennsylvania’s Perelman School of Medicine, the Northwestern University Feinberg School of Medicine, the University of Wisconsin School of Medicine and Public Health and NewYork-Presbyterian/Weill Cornell Medical Center, which contributed 122 of the total 485 kidney transplant patients.

The gene-expression studies were led by Dr. Suthanthiran with his laboratory serving as the Gene Expression Monitoring (GEM) core and the clinical trial was led by Dr. Abraham Shaked, director of the PENN Transplant Institute at the Perelman School, on behalf of the Clinical Trials in Organ Transplants 04 (CTOT-04) Study Investigators. The GEM core was blinded to the clinical status of the patients including their biopsy results and the data collection and analysis were performed by an independent statistical center sponsored by NIH.

Researchers collected 4,300 urine specimens during the first year of transplantation, starting at day three post-transplantation. The urine samples were shipped to the GEM core at Weill Cornell Medical College, where analysis of the urine revealed that the three gene-based biomarkers signature could distinguish kidney recipients with biopsy confirmed rejection from those whose biopsies did not show signs of rejection or who did not undergo a biopsy because there was no clinical sign of rejection.

The researchers used the signature to derive a composite score and identify a threshold value indicative of rejection. This score accurately detected transplant rejection with a low occurrence of false-positive and false-negative results. “It is about 85 percent accurate, which is much higher than the creatinine test used today,” Dr. Suthanthiran says. Investigators then validated the diagnostic signature by obtaining similar results when they tested a set of urine samples collected in a separate CTOT clinical trial.

Dr. Suthanthiran anticipates conducting another NIH-funded clinical trial to test whether the signature test can be used to personalize individual immunosuppressive therapy. He says that NIH is also interested in submitting the test to the federal Food and Drug Administration for approval.

These studies have provided enough information that many medical centers can test their own kidney transplant patients for rejection using the publicly-available formula for the biomarker test. Dr. Suthanthiran also is working to develop a way for patients to submit samples via mail for biomarker testing, and avoid an office visit. The study was supported by NIH grants UO1AI63589 and R37AI051652, the Qatar National Research Foundation (NPRP 08-503-3-111) and by a Clinical and Translational Science Center Award (UL1TR000457, to Weill Cornell Medical College).

Study: Urinary-Cell mRNA Profile and Acute Cellular Rejection in Kidney Allografts

Source: Weill Cornell Medical College

TGen Method Isolates Biospecimens for Treatment of Kidney Disease

Researchers at the Translational Genomics Research Institute (TGen) have developed a method of isolating biospecimens that could lead to a less costly, less invasive and more accurate way of diagnosing chronic kidney disease, or CKD.

Biomarkers: New Tools of Modern Medicine

Over the last few decades there has been an explosion in the discovery of biomarkers for diagnosis, disease monitoring, and prognostic evaluation. In the April issue of Translational Research, entitled “Biomarkers: New Tools of Modern Medicine,” an international group of medical experts explores the promise and challenges of biomarker discovery and highlights the latest advances in the use of biomarkers in various diseases.

Quest Diagnostics Launches First Molecular Test for Kidney Organ Transplant Rejection

Quest Diagnostics (NYSE: DGX), the world’s leading provider of diagnostic testing, information and services, today announced the availability of the industry’s first molecular blood test for identifying renal (kidney) organ-transplant rejection. The Renal Transplant Monitoring laboratory-developed test is designed to help physicians detect kidney failure weeks before conventional tests or clinical symptoms signify damage. The test may potentially improve patient care for kidney transplant patients while helping to lower sizeable healthcare costs associated with renal transplant failure.