Skeptics Retreat

Cells replace organ function

David Humes, M.D., has put up with a lot of skepticism over the years from people who didn’t believe that ordinary cells — even a few million of them — could replace the function of an entire complex organ like the human kidney.

Now, after a decade of work, Humes’ persistence is paying off. What was once just a vague concept of a “bioartificial kidney” is now a reality that is saving lives of critically ill patients. A biotechnology company, Nephrion, is funding the clinical trials required for FDA approval to make Humes’ renal tubule assist device, or RAD, commercially available. The company also is tackling the challenge of how to mass-produce, store and ship a device made of living cells.

“We have proved the concept that organ replacement therapy may be achievable in acute and chronic organ failure,” says Humes, a professor of internal medicine. “These are just the first glimpses of how we may be able to impact the natural history of disease in a substantial way.”

Each year, nearly 200,000 people in the United States develop acute renal failure — also called acute kidney injury. This complex, life-threatening disorder occurs when injured kidneys shut down. Although some patients can recover, the mortality rate for AKI has remained between 50 percent and 70 percent for the past four decades.

Shock, dehydration, infection, certain medications and trauma can destroy the kidney’s renal proximal tubule cells and trigger acute kidney injury. The body can repair renal proximal tubule cells and grow new ones, but the process takes 10-14 days. During this time, patients are vulnerable to a vicious spiral of events that can lead to multiple organ failure and death.

Conventional treatment for AKI has been dialysis — an extracorporeal (outside-the-body) process that filters impurities and waste products from the blood. But filtering blood isn’t what renal proximal tubule cells do. They reabsorb vital nutrients and fluids lost during filtration, and they have important metabolic, endocrine and anti-inflammatory functions that can’t be duplicated by an inanimate membrane in a kidney dialysis machine.

The renal tubule assist device is a 10-inch-long cylinder containing thousands of hollow fibers lined with millions of live human proximal tubule cells. The cells are grown from progenitor cells harvested from kidneys donated for transplant, but unable to be used. Inside the RAD, the cells seem to carry out the same functions they would in a living kidney.

“The idea behind it was simple,” Humes says. “If the primary problem in AKI is damaged renal proximal tubule cells and you can replace the function of those cells, you can change the patient’s poor prognosis.”

In a recent phase II clinical trial involving 58 critically ill patients with acute kidney injury at 12 medical centers nationwide, the 28-day mortality rate for patients treated with conventional dialysis was 66 percent. Patients treated with the RAD, in addition to dialysis, had a 33 percent mortality rate. Within the first 180 days following therapy, the mortality rate for patients receiving the combination therapy was reduced by about 50 percent.

Humes says his next goal is to miniaturize the RAD and make a portable device which can be worn by people with chronic kidney disease, a condition that affects nearly 17 percent of Americans. Humes already has developed a prototype — about the size of a personal digital assistant — that contains 10 times more RPT cells and can be frozen and stored.

Humes also is exploring how cell therapy technology could be adapted for other types of organ failure. —Kimberlee Roth and Sally Pobojewski

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Disparities Not All Black and White

Sometimes a research study raises more questions than it answers. Arden Morris, M.D., an assistant professor of surgery and chief of general surgery at the VA Ann Arbor Healthcare System, was surprised by the results of her recent research on racial disparities in survival from rectal cancer.

Morris knew that long-term survival rates for black patients following rectal cancer surgery were 14 percent to 20 percent lower than they were for white patients. Several possible reasons for the difference, including less access to specialists, had been suggested by other researchers, but no one knew for sure.

To find the answer, Morris and her collaborators pulled data from a cancer registry maintained by the National Cancer Institute. They analyzed information on 2,582 whites and 134 blacks ages 66 and older who had been diagnosed and treated surgically for stage II or stage III rectal cancer.

The research team found no significant difference between the percentages of black and white patients who consulted a medical oncologist or radiologist after rectal cancer surgery. But there were big differences in what happened after patients left the physician’s office.

While 70 percent of white patients in the study went on to receive chemotherapy, only 54 percent of black patients did so. Only 74 percent of blacks were treated with radiation therapy, as opposed to 83 percent of whites. Adjuvant chemotherapy and radiation increase survival rates by about 20 percent in patients with rectal cancer, so the fact that fewer black patients receive these therapies is cause for concern.

“Now we know that the initial visit with an oncologist is not the barrier to treatment,” says Morris. “Our next step is to try to understand the human factors that contribute to this discrepancy.” —SP

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One-Two Punch for Heart Health

Communication is the key to a stress-free discharge, according to a team of caregivers and administrators who work on unit 5B in University Hospital. When it comes to lowering blood pressure and the associated risk of heart attack, stroke and other cardiovascular events, it appears that two drugs are definitely better than one. So much better, in fact, that a clinical trial comparing the effectiveness of two-drug regimens in 10,700 patients was stopped ahead of schedule.

The study’s clear winner was a two-drug combination tablet containing an ACE inhibitor and a calcium channel blocker, or CCB. Patients with hypertension who took this combination had 20 percent fewer cardiovascular-related events than volunteers who took an ACE inhibitor combined with a diuretic. Both drug combinations lowered blood pressure to recommended levels in 80 percent of study participants.

“These results demonstrate the superiority of the ACE/CCB combination treatment for reducing cardiovascular morbidity and mortality,” says Kenneth Jamerson, M.D., a professor of internal medicine in the Cardiovascular Center.

Current clinical care guidelines recommend starting hypertension patients on just one drug, usually a diuretic, and adding other drugs only as needed. According to Jamerson, the study results indicate it’s time to change those guidelines. —SP

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Cornea Count Increases

Many parts of the human body deteriorate in old age, but the cornea is not one of them. A nationwide study of patients who received corneal transplants found that corneas from older donors worked just as well as those from younger donors.

The cornea is a piece of clear, dome-shaped tissue that covers the front of the eye to protect it and help focus light. In the United States, more than 39,000 donated corneas are transplanted every year.

Kellogg Eye Center was one of 80 sites that participated in the Cornea Donor Study. For five years, researchers followed 1,101 people who received corneal transplants to monitor how long their new corneas continued to function and remain clear.

The transplant success rate was 86 percent. The success rate was the same for corneas from donors ages 12 to 65 as it was for corneas from donors ages 66 to 75, says Alan Sugar, M.D., a professor of ophthalmology and visual sciences at the Kellogg Eye Center.

Based on the study results, the National Eye Institute now recommends that eye banks expand the cornea donor pool to include donors up to 75 years old. Current guidelines limit the pool to people 65 and younger. Opening the donor pool to older people could increase the potential supply of corneas available for transplant by 20 percent to 35 percent, according to the NEI. —SP

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Health Briefs

Survival rates for children with acute lymphoblastic leukemia, the most common type of childhood cancer, have never been higher. Thanks to more effective therapies, 87 percent of five-year survivors now live to adulthood. But survival comes with a price: At least half the survivors still struggle with chronic medical conditions — a result of chemotherapy or radiation used to treat the disease. U-M researchers say leukemia survivors, especially those who received radiation or survived a relapse, should have long-term follow-up. —SP

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The Association for the Accreditation of Human Research Protection Programs recently granted full accreditation to the University of Michigan. AAHRPP accreditation indicates that the University meets or exceeds all state and federal regulations for safe and ethical conduct of research with human subjects. U-M currently has nearly 5,000 active research projects involving human participants. —SP

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Clogged carotid arteries in the neck increase the risk of a stroke. But is it safer to remove the built-up plaque with surgery or insert a mesh tube called a stent to open the blocked artery? In a study of high-risk patients, U-M researchers found there’s no difference. Patients treated with surgery were just as likely to have a heart attack, stroke or die within three years as a matched group of patients treated with stents. —SP

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More high school and college students are popping pills and downing energy drinks to stay alert and handle the stress of final exams. Studies have reported the use of stimulant drugs in up to 35 percent of college students and as many as 10 percent of high school students. U-M researchers warn that abuse of stimulants and energy drinks can have serious medical consequences — including anxiety, depression, irritability, high blood pressure and stroke. —SP

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Robert Kelch (M.D. 1967, Residency 1970), U-M executive vice president for medical affairs and CEO of the Health System, and his wife, Jeri, listen as bells in Burton Tower toll for six minutes to honor the six Survival Flight and transplant team members killed in an airplane crash on June 4, 2007. The ceremony was one of several campus events held on June 4 to commemorate the one-year anniversary of the tragedy. “Virtually every day since that horrific moment, I think about our lost team,” Kelch said. “I think about what they stood for, what they achieved and what they sacrificed.”