FDA clears test to help patients with kidney transplants

The U.S. Food and Drug Administration today announced that it has cleared a test to help manage potential organ rejection in kidney transplant patients. The test, called QMS Everolimus Immunoassay, monitors the blood level of everolimus, a drug that helps prevent rejection in kidney transplants.

Everolimus, marketed under the trade name Zortress, was approved by FDA in April 2010 for use in adult kidney transplant patients who are at low-to-moderate immunologic risk.

Transplant patients are routinely given drugs that suppress the immune system (immunosuppressants) such as a regimen containing everolimus, cyclosporine, basiliximab, and corticosteroids. These drugs help prevent organ rejection, which occurs when the body’s immune system attacks and destroys a transplanted organ.

Some immunosuppressants are associated with toxic side effects that can injure transplanted kidneys. Balancing the levels of immunosuppressants is critical since transplant patients must take these drugs for the rest of their lives.

“QMS Everolimus is the first FDA-cleared test physicians can use to maintain appropriate levels of the immunosuppressant everolimus,” said Jeffrey Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health.

QMS Everolimus is one of a number of FDA-cleared or -approved tests physicians can use to monitor and manage immunosuppressant levels, including tests for cyclosporine, tacrolimus, and sirolimus. These tests, along with careful monitoring of clinical signs and symptoms of organ rejection, tissue biopsies, and other lab tests, may increase the chance of having a successful transplant and possibly extend the survival of a transplanted kidney.

In addition to other evaluations, Thermofisher, the manufacturer of QMS Everolimus, demonstrated the performance of the test by comparing results from the new test to the results from everolimus reference tests used in the clinical trial of everolimus. When the clinical trial blood samples were tested with QMS Everolimus, the results, on average, were similar to those of the clinical trial reference test.

More than 87,000 patients are awaiting a kidney transplant in the United States, according to the Health Resources and Services Administration’s Organ Procurement and Transplantation Network.

QMS Everolimus is manufactured by Waltham, Mass.-based Thermofisher. Zortress is marketed by East Hanover, N.J.-based Novartis.

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Natural system for eliminating salt may point to new antihypertensives

A study of the body system that deals with Americans’ love affair with salt may yield more insight into why so many end up hypertensive and how to better treat them.

A team of scientists from the Medical College of Georgia, the University of Utah and the University of Texas at San Antonio is looking at how the kidneys know you’ve eaten too much salt and what they do to eliminate it. The work is funded by a $11.2 million National Institutes of Health Program Project grant.

Their focus, endothelin, ironically has a bad rep as a “death peptide” because of its shared ancestry with the Israeli burrowing asp that can shut down coronary arteries with one bite.

But the powerful protein produced by the kidney takes direction – good or bad – from its receptors, according to Dr. David Pollock, renal physiologist at MCG’s Vascular Biology Center and director of the program project.

“It’s like politics: all things are local,” said Pollock.  In this case the upright guy tends to be the B receptor, which aids sodium excretion while its roguish sibling A receptor – the same one that shuts down the coronary arteries of asp victims – blocks it. When all goes well, the balancing act regulates the sodium level with the kidneys producing more endothelin and B receptors to eliminate the excess.

However in hypertension models, the B receptor doesn’t work so well, although exactly why is still unclear. “It’s this balance between A’s and B’s that is critical,” Pollock said. “If your balance becomes unbalanced you will have salt-sensitive hypertension.”  That’s why he is looking at the pathways that become activated on a high-salt diet and just what the A receptor is up to.

He and his colleagues are studying rats deficient in B receptors; they are a slightly hypertensive on a regular diet and very hypertensive on a high-salt diet.  More circuitously, the researchers also infused angiotensin, a powerful blood vessel constrictor, into rats causing similar dysfunction of the B receptors.

“We also think without the B receptor function, your A’s go a little bit crazy,” Pollock said. Not only do the A’s constrict, they promote inflammation, which can further damage blood vessels. In fact, a high-salt diet can cause even B receptors to behave badly, said Dr. Jennifer Pollock, MCG biochemist and a project leader.

Across the country, Dr. Donald Kohan, nephrologist and physiologist at the University of Utah, wants to figure out what prompts the kidneys to make more endothelin in the face of a high-salt diet. He is studying kidney cells to examine how endothelin production changes and ideally learn why. The goal, again, is drug therapies to inspire this natural phenomenon.

The results when A receptors go unchecked include stiff, tortuous blood vessels; a thick boggy pumping chamber in the heart; and other major organ damage that includes the kidney.

“The consequences are measurable targets,” said Dr. Edward Inscho, MCG physiologist and a project leader, noting that treatments are available but “preventing it from occurring is something we are not very good at yet.”

To help put the pieces together, Inscho is focusing on how blood vessels that feed directly into kidney filters react to a high-salt diet. Blood, containing salt, continuously flows through the kidneys. The researchers have seen that excess salt increases B receptor expression, which should help the kidneys filter more sodium then get rid of it.

“If you filter more, you have more salt available for excretion,” Inscho said. He wants to know what’s happening with A and B receptors inside the tiny vasculature of the kidneys. He’s using B-deficient rats and drugs that block either receptor to get a better idea about both. The idea is to figure out not just how they normally work but how the system becomes dysfunctional in hypertension.  “I think we are beginning to understand how the B receptor may factor into some other regulatory systems the kidney may use to control filtration,” he said.

Noted Jennifer Pollock, “Your kidneys in theory should be able to lower your blood pressure but because people do remain hypertensive, that means there must a problem with your kidneys as well.” She suspects that endothelin activates production of nitric oxide when it hits the B receptor. Nitric oxide, which dilates blood vessels, prompts the sodium channels in kidney tubules to fold inward.

“The salt can’t get in and so it gets excreted,” Jennifer Pollock said. “We are connecting the dots now.” If they are correct, they have found a new mechanism for controlling salt excretion that is a natural drug target. Since it’s difficult to enhance nitric oxide, it likely will be necessary to find another cue to prompt sodium channels to fold up their tents. She developed a mouse lacking nitric oxide synthase, which prompts nitric oxide production, to help pursue the theory.

Co-investigator Dr. James Stockand in Texas is investigating mechanisms for how endothelin affects transport of sodium in and out of the cell, focusing on proteins known as ion channels. Dr. Jennifer Sullivan, pharmacologist/physiologist at MCG’s Vascular Biology Center, is providing support and expertise with the numerous animal models needed for the grant.

“The future of pharmaceutical therapies is going to be the right balance of different drugs,” said David Pollock.  “Most people with high blood pressure are also taking cholesterol medicine and possibly other drugs. So the future has to be what is the right formula for you and your situation.”

The scientists hope their studies will point the way to these new, targeted options.

By Toni Baker
Medical College of GA

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Emory, Georgia Tech, Children's Healthcare of Atlanta Team Up on Kidney Replacement Devices for Kids

When children need kidney dialysis because of disease or congenital defects, doctors are forced to adapt adult-size dialysis equipment. No FDA-approved kidney replacement devices exist that are specifically designed for children.

To address this problem, physicians and researchers from Emory University, Children’s Healthcare of Atlanta and the Georgia Institute of Technology have teamed up to develop a kidney replacement device capable of treating children.

Over the past five years, the three institutions have further solidified a cohesive relationship aimed at medical discovery, quality-care improvement and health care innovation.

The team has been awarded a Challenge grant of $1 million from the National Institutes of Health (NIH) to refine a prototype device. The grant is part of the American Recovery and Reinvestment Act (ARRA) funding. Challenge grants are part of a new NIH program to stimulate rapid advances in focused disease areas.

Matthew Paden, MD, assistant professor of pediatrics (critical care) at Emory University School of Medicine and a physician at Children’s Healthcare of Atlanta, is the grant’s principal investigator. Ajit P. Yoganathan, PhD, Regents’ Professor of biomedical engineering in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, is the grant’s co-investigator.

“The adaptations doctors are forced to perform make adult kidney replacement devices inaccurate and potentially dangerous when used with kids,” Paden says. “We have invented a new continuous renal replacement therapy device that is designed specifically with kids in mind. It can be used accurately on a six-pound child, all the way up to a football linebacker.”

In the United States, it is estimated that at least 5,000 children per year, or 1 percent of the 500,000 children admitted to intensive care units, require some form of renal replacement therapy. Children may need kidney replacement therapy because of severe infections that lead to the kidney-damaging inflammatory condition called sepsis, or because of congenital defects, which can only be permanently remedied by a kidney transplant.

Paden says adult dialysis equipment can have a tendency to withdraw too much fluid from a pediatric patient, leading to dehydration and loss of blood pressure. Other possible problems resulting from inaccurate dialysis equipment include clotting or internal bleeding. Part of the problem is that the volume of blood required to fill up the tubes leading to and from the apparatus is too large, Paden says. As the child gets smaller, the proportion of blood outside the body gets larger.

Existing dialysis equipment for adults takes up space comparable to a refrigerator, while Paden says the team’s goal is to have a pediatric device the size of a shoebox.

The inventors:

Lakshmi Prasad Dasi, PhD, former research engineer at Georgia Tech, now assistant professor of mechanical engineering at Colorado State University.
James Fortenberry, MD, pediatrician in chief and medical director of critical care for Children’s Healthcare of Atlanta, and clinical associate professor of pediatrics (critical care) at Emory School of Medicine
Matthew Paden
Ajit Yoganathan

The team’s plan is to test their prototype in the laboratory and prepare for live experiments over the next two years, with the goal of being ready for clinical trials in five years.

“This is a project where we are taking technology from the laboratory bench to the basinet,” Yoganathan says. “First, we have to build a machine capable of reliably performing these tasks without damaging blood cells in the process.”

The team’s prototype device is also designed to work in tandem with equipment that replaces the function of the heart and lungs for severely ill patients. Extracorporeal membrane oxygenation (ECMO) equipment is commonly used in neonatal intensive care units for newborns whose lungs can’t work properly. Children requiring ECMO often have fluid overload and swelling. The demand for ECMO has been rising because of H1N1 influenza, which in severe cases leads to respiratory failure.

Emory, Georgia Tech and Children’s Healthcare of Atlanta are in the process of patenting the kidney replacement device. As the technology is developed further, it could be licensed to an existing company or a new start-up company.

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FDA: Byetta Label Revised to Include Safety Information on Possible Kidney Problems

The U.S. Food and Drug Administration today acted on new safety information about possible kidney function problems, including kidney failure, in patients taking Byetta (exenatide), a drug used to treat Type 2 diabetes.

From April 2005 through October 2008, the FDA received 78 reports of problems with kidney function in patients using Byetta. Some cases occurred in patients with pre-existing kidney disease or in patients with one or more risk factors for developing kidney problems.

Nearly 7 million prescriptions for Byetta were dispensed between April 2005 and September 2008. The 78 cases represent a small percentage of the total number of patients using the drug to control blood sugar (glucose) levels.

The most common side effects associated with Byetta include nausea, vomiting, and diarrhea. These side effects may have contributed to the development of altered kidney function. Kidney malfunction can result in a build-up of waste products in the blood, leading to serious illness or life-threatening conditions.

“Health care professionals and patients taking Byetta should pay close attention to any signs or symptoms of kidney problems,” said Amy Egan, M.D. M.P.H., of the Division of Metabolism and Endocrinology Products at the FDA’s Center for Drug Evaluation and Research. “Patients also should be aware that problems with kidney function could lead to changes in urine color, frequency of urination or the amount of urine, unexplained swelling of the hands or feet, fatigue, changes in appetite or digestion, or dull ache in mid to lower back.”

Patients who experience any of these symptoms should immediately discuss them with their health care professional.

To help health care professionals and patients better weigh the known risks and benefits of Byetta, the FDA worked with the manufacturer to update the drug’s prescribing information (label). A description of these label changes can be found online.

Byetta is manufactured by San Diego-based Amylin Pharmaceuticals Inc.

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FDA Approves New Treatment for Advanced Form of Kidney Cancer

The U.S. Food and Drug Administration today approved Votrient (pazopanib), the sixth drug to be approved for kidney cancer since 2005.

Votrient is an oral medication that interferes with angiogenesis, the growth of new blood vessels needed for solid tumors to grow and survive.

Votrient is intended for people with advanced renal cell carcinoma, a type of kidney cancer in which the cancerous cells are found in the lining of very small tubes (tubules) in the kidney. In 2009, approximately 49,000 people were diagnosed with renal cell carcinoma and 11,000 people died from the disease.

“The last five years have seen dramatic improvements in treatment options for patients with kidney cancer. Before 2005, the options available offered only limited effectiveness,” said Richard Pazdur, M.D., director, Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research.

The five other drugs approved for kidney cancer and their approval dates are: Sorafenib (December 2005), Sunitinib (January 2006), Temsirolimus (May 2007), Everolimus (March 2009), and Bevacizumab (July 2009).

The safety and effectiveness of Votrient was evaluated in a 435-patient study that examined a patient’s progression-free survival – the length of time, following enrollment in the study, before the tumor began growing again or before the patient died. Progression-free survival averaged 9.2 months for patients receiving Votrient compared to 4.2 months for patients who did not receive the drug.

Adverse reactions included diarrhea, high blood pressure, hair color changes, nausea, loss of appetite, vomiting, fatigue, weakness, abdominal pain and headache. Votrient can also cause severe and fatal liver toxicity. Health care professionals should order blood tests to monitor liver function before and during treatment with the drug. Since Votrient can harm a fetus, it should not be used during pregnancy.

The drug has also been associated with heart rhythm irregularities. Patients receiving Votrient should be monitored with periodic electrocardiograms, which measure heart rhythm, and blood tests to monitor electrolytes since an electrolyte imbalance can lead to an irregular heart rhythm.

Votrient is manufactured by London-based GlaxoSmithKline.

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FDA Requires Labeling Change for Some Drugs Used to Prevent Rejection of Kidney Transplants

The U.S. Food and Drug Administration today said that it will require manufacturers of some immunosuppressant drugs used in kidney (renal) transplantation to update their labeling to reflect an increased risk of infections.

The required label changes affect the following immunosuppressant drugs used to help prevent rejection of transplanted organs:

* Rapamune (sirolimus)
* Sandimmune (cyclosporine) and cyclosporine generics
* Neoral (cyclosporine modified), and generics
* Cellcept (mycophenolate mofetil) and generics
* Myfortic (mycophenolic acid)

The FDA is requiring the labeling changes based on its review of reported adverse events. The labeling changes must reflect the reported increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus-associated nephropathy, which can mainly affect kidney transplant patients. Such infections may lead to serious outcomes, including kidney graft loss.

Information about the increased risk for opportunistic infections already is included in the labeling of the immunosuppressive drug Prograf (tacrolimus).

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Transplantation of Kidneys from Black Cardiac-Death Donors Provide Black Recipients with the Best Long-Term Survival

Contrary to prevailing assumptions, Johns Hopkins researchers have shown that kidneys recovered from black donors who died from cardiac death offer the best survival rate for black recipients of a deceased-donor kidney.

This discovery, released online this week and appearing in the October 2008 issue of the Journal of the American Society of Nephrology, challenges the long-held belief that kidneys from white brain-death donors offers the best deceased-donor transplant survival rate for either black or white recipients.

“Our findings indicate that increased use of kidneys from cardiac-death donors could help reduce the organ shortage and improve outcomes for black kidney transplant recipients,” says lead author Jayme Locke, M.D., M.P.H., of the Department of Surgery at Johns Hopkins.

Locke and a team of Johns Hopkins researchers examined the outcomes of more than 25,000 black adults who received a deceased-donor kidney transplant between 1993 and 2006.

Results showed that black recipients who received a kidney from a black cardiac-death donor had a 70 percent reduction in the risk of kidney loss and a 59 percent reduction in risk for death when compared to black recipients who received a kidney from a white brain-death donor.

“Our data is consistent with the previous observation that black recipients seem to do better with kidneys from white brain-death donors than they do with kidneys from black brain-death donors or white cardiac-death donors, however, the fact that black recipients have the best outcomes with kidneys from black cardiac-death donors is significant,” says co-lead author Daniel Warren, Ph.D., of the Department of Surgery at Johns Hopkins.

He says that the exact mechanisms responsible for racial differences in outcomes after kidney transplantation are not known, however, the results suggest that the genetic background of the donor and recipient likely have a significant impact on long-term outcomes.

“We believe that an improved understanding of the molecular consequences of cardiac and brain death is critical to improving outcomes for all kidney transplant recipients and warrants further investigation,” he added.

There are currently more than 70,000 Americans waiting for kidney transplants. Only about 600 deceased-donor kidneys donated after cardiac death are currently used for transplantation versus 7,000 donated after brain death.

This discrepancy is due in part to the belief that kidneys that are exposed to cardiac death generally suffer more damage than kidneys that are exposed to brain death.

“Our results show this is not always true, and that is significant news for all patients waiting for a kidney,” says Locke.

Other researchers who worked on this study from Johns Hopkins include Robert Montgomery, M.D., Ph.D.; Andrew Cameron, M.D.; Joseph Melancon, M.D.; Dorry Segev, M.D.; Andrew Singer, M.D., Ph.D.; Christopher Simpkins, M.D., M.P.H.; Andrea Zachary, Ph.D.; Francesca Dominici, Ph.D.; Mary Leffell, Ph.D.; and Deborah McRann, B.S.N.