TAG: "Kidney"

Research may lead to cure for deadly kidney disease


Biochemists solve ‘address problem’ in cells that leads to lethal kidney disease.

Carla Koehler, UCLA (Photo by Reed Hutchinson, UCLA)

Research by UCLA biochemists may lead to a new treatment — or even a cure — for PH1, a rare and potentially deadly genetic kidney disease that afflicts children. Their findings also may provide important insights into treatments for Parkinson’s disease, Alzheimer’s disease and other degenerative diseases.

Led by Carla Koehler, a professor of chemistry and biochemistry in the UCLA College, the researchers identified a compound called dequalinium chloride, or DECA, that can prevent a metabolic enzyme from going to the wrong location within a cell. Ensuring that the enzyme — called alanine: glyoxylate aminotransferase, or AGT — goes to the proper “address” in the cell prevents PH1.

The findings were published online in the Proceedings of the National Academy of Sciences and will appear later in the journal’s print edition.

In humans, AGT is supposed to go to an organelle inside the cell called the peroxisome, but for people with a particular genetic mutation, the enzyme mistakenly goes instead to the mitochondria — tiny power generators in cells that burn food and produce most of the cells’ energy — which causes PH1.

Koehler’s team demonstrated that adding small amounts of DECA, which is FDA-approved, to cells in a Petri dish prevents AGT from going to the mitochondria and sends it to its proper destination, the peroxisome.

“In many mutations that cause diseases, the enzyme doesn’t work,” Koehler said. “In PH1 the enzyme does work, but it goes to the wrong part of the cell. We wanted to use DECA in a cell model to block AGT from going to the wrong address and send it back to the right address. DECA blocks the mitochondria ‘mailbox’ and takes it to the peroxisome address instead.”

How often did it work?

“All the time,” said Koehler, a member of UCLA’s Jonsson Comprehensive Cancer Center, Molecular Biology Institute and Brain Research Institute.

For people with the mutation, the correct peroxisome address is present in AGT, but it is ignored because it is accompanied by the address of the mitochondria, which the cell reads first, Koehler said.

Koehler, who also is a member of the scientific and medical advisory board of the United Mitochondrial Disease Foundation, hopes to find out whether a similar “correct address” strategy can slow cancer down. Her laboratory has identified approximately 100 other small molecules, which she calls MitoBloCKs, that she and her colleagues are testing for their ability to combat Parkinson’s, Alzheimer’s and other diseases.

PH1 — short for primary hyperoxaluria 1 — starts at birth and is usually fatal for patients who do not receive both kidney and liver transplants. Approximately half of those with the disease have kidney failure by age 15. Koehler has presented her findings to the Oxalosis and Hyperoxaluria Foundation, which provides support for PH1 patients and their families.

Scientists’ ability to diagnose rare diseases has improved in recent years because technological advances in genomics have made it easier to identify more genetic mutations, Koehler said.

According to Koehler, to treat diseases, scientists must first understand how proteins like AGT move inside the cell. Her research, which encompasses biochemistry, genetics and cell biology, studies how mitochondria are assembled and function, how proteins enter the mitochondria and reach the right location inside cells, and how mitochondria communicate with the rest of the cell.

Her laboratory uses model systems that enable them to study the biochemistry in a way that is not possible with humans. Much of the work is conducted in yeast.

“It’s exciting that our studies in baker’s yeast, a typical laboratory model, might be able to help kids with a complicated disease,” Koehler said.

The lead author of the PNAS research was Non Miyata, a former UCLA postdoctoral fellow in Koehler’s laboratory. Co-authors included Christopher Danpure, emeritus professor at University College London; and Sonia Fargue, a former researcher in Danpure’s laboratory.

Koehler’s research was funded by the National Institutes of Health’s National Institute of General Medical Sciences (grants GM073981 and GM61721).

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CT scan is no better than ultrasound to detect kidney stones


UCSF study leader recommends change in standard practice.

Rebecca Smith-Bindman, UC San Francisco

To diagnose painful kidney stones in hospital emergency rooms, CT scans are no better than less-often-used ultrasound exams, according to a clinical study conducted at 15 medical centers and published in the Sept. 18 issue of the New England Journal of Medicine.

Unlike ultrasound, CT exposes patients to significant amounts of radiation. Although CT scans are favored by emergency-room physicians for kidney stone diagnosis, ultrasound should be used as the first step, according to senior study author Rebecca Smith-Bindman, M.D., a professor in the departments of radiology; epidemiology and biostatistics; and obstetrics, gynecology and reproductive medicine at UC San Francisco.

“Ultrasound is the right place to start,” Smith-Bindman said. “Radiation exposure is avoided, without any increase in any category of adverse events, and with no increase in cost.” Patients in the study who were first examined with ultrasound sometimes received a follow-up CT exam at the physician’s discretion.

“Our results do not suggest that patients should undergo only ultrasound imaging, but rather that ultrasonography should be used as the initial diagnostic imaging test, with further imaging studies performed at the discretion of the physician on the basis of clinical judgment,” the study authors said.

Kidney stone rates are increasing, and in a 2010 National Health and Nutrition Examination Survey, one in 11 people reported having had at least one kidney stone. The use of CT to diagnose kidney stones has risen 10-fold in the last 15 years. CT exams generally are conducted by radiologists, while ultrasound exams may be conducted by emergency room physicians as well as radiologists.

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Improving long-term health of kidney transplant recipients


UCSF is lead institution on $17M multicenter study to improve long-term survival.

Flavio Vicenti, UC San Francisco

UC San Francisco is the lead institution on a new seven-year, $17 million multicenter study funded by the National Institutes of Health to determine if certain immune system cells and/or a drug now used for treating rheumatoid arthritis can be effective in improving and maintaining the long-term health of kidney transplant recipients.

The goal of this study is to reduce or eliminate inflammation in kidney transplants and prevent the associated decline in function, thereby maximizing long-term organ survival. It will involve two clinical trials and research in parallel by biologists and by researchers for the mechanistic cores.

Despite advances in transplantation – reducing early acute rejection rates to less than 15 percent and improving one-year graft survival to more than 90 percent – long-term graft success rates have remained unchanged at 4 percent loss annually. A major contributor is progression of interstitial fibrosis and tubular atrophy in the kidney.

The cells that the researchers are focused on are regulatory T cells (Tregs), which are a small population of lymphocytes that suppress the activity of other immune cells. They maintain normal immune system homeostasis and safeguard against autoimmune diseases, and their immunosuppressive properties also can be harnessed to control transplant rejection.

Tregs have the potential to induce long-term donor-specific tolerance without impeding desired immune responses to pathogens and tumors in transplant patients.

The principal investigator of the study is Flavio Vincenti, M.D., UCSF professor of medicine and a kidney and pancreas transplant specialist at UCSF Medical Center. Other participating institutions are the University of Alabama at Birmingham, Emory University and Cedars-Sinai Medical Center.

“This grant allows us to work toward achieving two important advances in the transplant field,” said Vincenti. “We can introduce personalized medicine by treating patients based on molecular profiling of their kidney. We also can allow control of the response to the transplant by the patients’ own immune systems by regulatory T cells, either through infusions or pharmacologically.”

Researchers believe inflammation can be controlled in kidney transplant recipients by increasing the number or activity of Tregs, either by infusing them into the body or by blocking interleukin 6 (IL6) with the drug tocilizumab.

To do so, they will conduct two clinical trials – TASK (Treg Adaptive therapy in Subclinical inflammation in Kidney transplantation) and TRAIL (Therapy to Reduce Allograft Inflammation with IL6 inhibition).

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First-of-its-kind program seeks to encourage kidney donors


UCSF joins with Walgreens in blood pressure testing program for living kidney donors, potential donors.

While recipients of living donor kidney transplants receive steady follow-up care, the living donors themselves also need to be monitored. To make follow-up care more accessible, UC San Francisco and Walgreens are collaborating to launch the first program in the country that provides blood pressure testing at no charge to living kidney donors.

UCSF will provide vouchers for blood pressure tests redeemable at more than 4,500 Walgreens pharmacies and Healthcare Clinic at select Walgreens locations nationwide. Vouchers also are available to potential kidney donors, as blood pressure testing is a part of the initial screening process.

Tests are available daily during pharmacy and clinic hours with no appointment necessary and administered by health care professionals at Walgreens pharmacies and Healthcare Clinic at select Walgreens.

“The use of living donors has revolutionized kidney transplants, and this new program provides the opportunity to monitor their long-term health in a convenient, efficient way,” said John Roberts, M.D., professor of surgery and chief of UCSF Transplant Service and former president of the United Network for Organ Sharing (UNOS). “UCSF performs the most kidney transplant procedures in the United States, and we are pleased to be first to join with Walgreens in this effort that we hope encourages people to donate as there is a critical need.”

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Robot-assisted technique improves surgeons’ ability to remove kidney tumors


UCLA-led study finds the approach may shorten surgeries, could reduce risk of complications.

Schematic showing the robotic device's proper position during surgery. (Image by Eric Treat, UCLA)

Roughly 50,000 Americans are diagnosed with kidney cancer each year. Most of them have small tumors that doctors discover while screening for other health problems.

The surgeries to remove renal tumors can be difficult, particularly if the cancer is on the posterior side of the kidney and if patients have had previous abdominal surgery, because scar tissue from previous operations usually makes it hard for surgeons to distinguish the normal parts of the body from one another.

Now, a study led by Dr. Jim Hu and researchers at UCLA’s Jonsson Comprehensive Cancer Center has shown that a newer surgical technique called robot-assisted retroperitoneoscopic partial nephrectomy is more effective than other current techniques to remove kidney tumors when the masses are located on the back of the kidney or when a patient has had previous abdominal surgery. RARPN is a minimally invasive laparoscopic procedure in which surgeons use precise robotic arms and magnified, high-definition 3-D cameras.

The study, published online in European Urology, was the largest multicenter study to date on this technique. The five-year project reviewed surgeries for 227 patients whose average age was 60, with most between ages 52 and 66.

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Siblings discover relationship in time for kidney donation


Life-saving procedure performed at UCLA.

Guadalupe Villanueva and Frank Ybarra

Two people whose lives intersected at times over the last couple of decades discovered only a few months ago that they are actually brother and sister. The sister said it was nothing less than divine intervention — because it gave her the opportunity to donate a kidney to her newfound brother in a life-saving procedure that took place June 24 at the Ronald Reagan UCLA Medical Center.

“I don’t know what to say,” Frank Ybarra said to Guadalupe Villanueva as they embraced shortly before the surgery.

“You don’t have to say anything,” Villanueva said. “This is our destiny, from here on.”

“This is a step; it’s a start,” said Ybarra, who had been on dialysis due to kidney failure since September 2012.

“Yep, it’s a beginning,” she replied.

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UC Irvine receives NIH grant to study kidney disease


Grant also will track treatment methods.

Kamyar Kalantar-Zadeh, UC Irvine

UC Irvine Health will use a $3.4 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health to examine the “Transition of Care in Chronic Kidney Disease (CKD).”

The award is one of three U.S. Renal Data System five-year contracts bestowed by the NIH upon academic centers to examine chronic kidney disease and its risk factors and consequences, including treatment modalities and outcomes of patients with CKD. The UC Irvine Health Division of Nephrology & Hypertension won a national competition to bring this prestigious grant to the UC Irvine campus.

“Our studies over the next half a decade will examine the nature and outcomes of the transition to dialysis treatment or kidney transplantation that happens in more than 100,000 Americans with advanced chronic kidney disease each year,” said Dr. Kamyar Kalantar-Zadeh, principal investigator and chief of the UC Irvine Health Division of Nephrology & Hypertension.

The award will establish the UC Irvine Medical Center in Orange as a U.S. Renal Data System Special study center for five years. The data system is a national clearinghouse for information about chronic and end-stage kidney disease and treatment modalities for these patients. It collaborates with the federal Centers for Medicare & Medicaid Services, the United Network for Organ Sharing and 18 ESRD networks across the nation.

The project will be conducted at the UC Irvine Medical Center and the Veterans Affairs Medical Center in Long Beach. The study population will consist of veterans treated at VA medical centers across the nation and members of Kaiser Permanente Southern California who are transitioning to renal replacement therapy.

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Kidney transplant recipients meet donors for first time


Paired exchange renews the lives of four people with chronic kidney disease.

Kidney transplant donors and recipients who participated in the four-way exchange were (from left) Chris Ewing, Darrel Ellis, Steve Saunders, Olga Belozertseva, Tatiana Belozertseva, Mike Navarec, Michelle Roley and Eric Soik.

In a rare and touching moment at UC Davis Medical Center, four kidney transplant patients met the four people — strangers to them before today — who one month ago gave them the gift of life.

The transplants were the result of a process known as paired exchange, which typically occurs when a donor wants to give a kidney to a friend or family member with end-stage kidney disease but can’t due to mismatched blood types or antibodies. The donor agrees to give a kidney to a different recipient, whose unmatched donor does the same.

“Sometimes paired exchanges are completed with two pairs, and sometimes they are more complex,” said Sharon Stencel, a nurse and coordinator of the Living Kidney Donor Program at UC Davis. “In this case, someone stepped up to donate a kidney who didn’t have a particular recipient in mind. That triggered a chain of exchanges that resulted in four people — including someone on the waiting list — getting new organs and new lives.”

Given the shortage of deceased donor kidneys, paired exchange of living donors has become an increasingly important way to speed the transition from the transplant wait list to the operating room. It also can lead to better outcomes for recipients. Newer organ retrieval procedures have made the process easier for donors as well.

“While we have excellent outcomes with deceased organ donations, kidneys from living donors are viable up to twice as long — an average of 17 years versus 10,” said Christoph Troppmann, a surgeon with the UC Davis Transplant Center. “We also use less-invasive techniques for removing kidneys so scarring is minimal and recovery time is much quicker than it was a decade ago.”

One month after her surgery, donor Michelle Roley of Lockeford is “feeling wonderful” and happy that she helped restore her father’s health.

“I knew we weren’t the same blood type, but I went into the donation process hoping to be part of a paired exchange because it was the best way to help my dad,” she said.

Before the surgery, Roley’s father, Mike Navarec of Stockton, had chronic kidney disease that kept him at home for hours tethered to a dialysis machine and “worried about whether or not I would wake up in the morning,” he said. “Now, I look forward to planning a trip to the Holy Land.”

Roley’s kidney was donated to Eric Soik of Camino, who was on the transplant wait list. Navarec received a kidney from Tatiana Belozertseva of Russia. Chris Ewing of El Dorado Hills — the nondirected donor who initiated the exchange — gave a kidney to Darrel Ellis of Sparks, Nev. Steve Saunders of Reno, Nev., gave a kidney to Olga Belozertseva of Brentwood.

The UC Davis Transplant Center, which has the only kidney transplant program in inland, Northern California, has provided specialized care to kidney transplant recipients and living kidney donors since 1985. In collaboration with hospitals and transplant registries nationwide, the center has coordinated 25 paired kidney exchanges, including two four-way exchanges. Currently, there are nearly 1,200 people on a waiting list for donor kidneys at UC Davis, where more than 300 kidney transplants are performed each year.

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UC Davis Transplant Center opens Fresno location


Clinic will expand access to kidney, pancreas transplant care in Central California.

Luke Preczewski, UC Davis

Luke Preczewski, UC Davis

The UC Davis Transplant Center — one of the nation’s premier transplant programs — has opened a new clinic in Fresno to expand access to kidney and pancreas transplant care in Central California.

The clinic provides pre- and post-transplant medical evaluations for recipients and kidney donors. Transplant surgery will still be provided at the center’s main location at UC Davis Medical Center in Sacramento.

The Fresno clinic is located at 1189 E. Herndon Ave. and will be open one day per month. The number of clinic days will increase based on patient need. To arrange for a referral or schedule an evaluation, call toll free (800) 821-9912.

Fresno is the largest city in California without a transplant center within 25 miles, yet about 17 percent of California’s kidney transplant patients are in the Fresno region. One of the closest centers is at UC Davis Medical Center, which is about 170 miles away.

“We wanted to reduce that travel time as much as possible for patients and their families,” said Luke Preczewski, executive director of the transplant program.

UC Davis performed 339 kidney transplants in 2013, making it by volume the second-largest program in the nation. According to 2012 data from the Scientific Registry of Transplant Recipients, UC Davis offers the shortest average adult kidney transplant wait time (37.2 months) of any California hospital.

For information about the UC Davis Transplant Center, visit www.ucdmc.ucdavis.edu/transplant.

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New link found between obesity, early decline in kidney function


Body mass index “in and of itself” increases risk of developing chronic kidney disease.

Vanessa Grubbs, UC San Francisco

Vanessa Grubbs, UC San Francisco

A new UC San Francisco-led study of nearly 3,000 individuals links obesity to the development of kidney disease. The work also shows that, when properly measured, declines in kidney function are detectable long before the emergence of other obesity-related diseases such as diabetes and high blood pressure.

Healthy kidneys are vital to the proper functioning of the heart and brain, as well as the skeletal and immune systems, and the research adds additional urgency to the call for doctors to intervene early in life with obese patients, the researchers said.

“We’re getting larger and larger at younger and younger ages, so the problems we will see that are directly related to obesity are going to become more common and they’re going to start earlier in life,” said Vanessa Grubbs, M.D., UCSF assistant adjunct professor of medicine and first author of the new study. “Even before the level at which we can diagnose illnesses, decline in kidney function is happening. Is it reversible? We’re not sure. Preventable? It stands to reason that it would be.”

In the new study, published online in The American Journal of Kidney Diseases on Dec. 2, Grubbs and senior author Kirsten Bibbins-Domingo, Ph.D., M.D., professor of medicine, led a team that analyzed 10 years’ worth of health data from CARDIA (Coronary Artery Risk Development in Young Adults), a national multicenter research project that has tracked the health of thousands of black and white young adults since its beginnings in 1985.

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A miracle baby


Dialysis couldn’t stop one woman’s dream of motherhood.

Growing up, Elizabeth Hill had her entire life planned. She would be her family’s first college graduate, a successful professional and, above all, a mother. “I always knew I was born to be a mom,” she says.

At 17, however, she was diagnosed with lupus, a disease that can attack almost any part of the body. “At first I fell into a deep depression,” the Yorba Linda resident explains. “But then I decided I was going to live a normal life.”

She did just that, earning her degree and later working as a human resources manager — a job she loved.

Hill was still living with lupus, though. By 2008, her kidneys were irreparably damaged by the disease. She received a kidney transplant, but it failed after just two years.

Seriously ill, Hill began dialysis treatments to cleanse her blood of the impurities normally eliminated by the kidneys. The treatments were lifesaving, but being on dialysis meant she would probably never have children.

“Dialysis patients rarely become pregnant,” says Dr. Carol Major, a UC Irvine Health maternal-fetal medicine specialist. And if they do, they usually miscarry.

This is because “a developing fetus is extremely vulnerable to metabolic changes that take place during dialysis,” explains Dr. Kamyar Kalantar-Zadeh, chief of the UC Irvine School of Medicine’s Division of Nephrology & Hypertension.

Then — against the odds — Hill learned she was pregnant. “I had a million emotions,” she says. “I’d been told this would never happen, but now it had.”

The 34-year-old Hill was immediately referred to UC Irvine Health, one of the nation’s leading centers for treating kidney disease and managing high-risk pregnancies. UC Irvine Health kidney and obstetric-gynecologic specialty services both have been ranked among the best in the country by U.S. News & World Report.

Hill’s treatment team included nephrologists as well as obstetricians with expertise in managing complex, high-risk pregnancies. “We coordinated her treatment across all specialties on a daily basis,” says Major, who cared for Elizabeth throughout her pregnancy.

“To better maintain the delicate balance so critical for mother and baby,” says Kalantar, “Elizabeth underwent dialysis six times a week instead of the usual three.”

During dialysis, the fluid removed had to be carefully measured and analyzed to ensure that the developing fetus was still receiving enough fluid volume. And after each dialysis session, Hill underwent fetal heart rate monitoring for more than an hour to make sure the baby was doing well. On Sundays — the one day Hill didn’t make the trek to UC Irvine Medical Center — she and Major texted each other.

“Dr. Major and I have this amazing bond,” Hill explains. “She’s so incredibly wonderful and caring. I’ve never met a doctor like her.”

Even with the unprecedented care she received, Hill’s pregnancy was extremely difficult — jeopardized by anemia and a liver condition that caused intolerable itching.

“When Elizabeth developed liver problems, we called in our liver disease experts,” Kalantar says. “We tailored treatment to her unique needs, using all our expertise and resources to deal with each setback.”

Hill braved all the complications, risks and discomfort, having faith that her baby would be healthy. Her determination paid off.

Baby Audrey was born in November 2012, just four weeks short of full-term. “It was the most unbelievable feeling in the world,” recalls Hill. “Dr. Major kept telling me, ‘We did it. She’s perfect.’”

Hill is back on dialysis three days a week, and mom and baby are thriving, thanks to Hill’s extraordinary strength and determination, her faith, her husband, Sean, and her UC Irvine Health doctors.

“Elizabeth is an amazing woman and mother,” says Major. “She was told she would never get pregnant, yet she got the proper care and had a completely successful pregnancy. Her story is a source of hope for other women who are facing the same challenges.”

To learn more about kidney disease and dialysis services, visit ucirvinehealth.org/dialysis. For more information about high-risk pregnancy care, visit ucirvinehealth.org/high-risk or call (714) 456-2911.

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Scientists halt deadly organ tissue scarring in its tracks


UCSF-led study uses drug to target fibrosis of lungs, liver and kidney.

Dean Sheppard, UC San Francisco

Dean Sheppard, UC San Francisco

UC San Francisco scientists report that they were able to arrest, and even reverse, tissue scarring of the liver, kidneys and lungs in mice.

The scarring, also known as fibrosis, is a major factor in nearly half of all deaths in developed countries.

“Scarring is a critical component of organ dysfunction in most chronic diseases – kidney failure, liver failure, lung failure, heart failure,” said Dean Sheppard, M.D., UCSF professor of medicine and senior author of the new study. “But there’s no effective therapy for tissue scarring that’s approved by the FDA [Food and Drug Administration]. Although scarring contributes to the progression of all these diseases, we currently have no way to treat it.”

The scientists accomplished the work by targeting a family of proteins on the surface of certain cells.

In the study, first author Neil C. Henderson, M.D., Ph.D., a former postdoctoral associate in Sheppard’s laboratory and now at the University of Edinburgh, and an international team of scientists first devised a genetic technique to selectively knock out a five-member family of receptors known as alpha V integrins (“INT-uh-grins”) in the collagen-producing fibroblast cells of mice. These cells drive the excessive scarring seen in fibrosis.

The genetic deletion had a strong protective effect: Methods that reliably induce liver scarring in normal mice had little effect on mice lacking alpha V integrins. Knocking out alpha V integrins also protected the mice from fibrosis of the lungs and kidney.

On the other hand, the scientists did not observe any protective effect when they knocked out individual members of the alpha V integrin family, suggesting that fibrosis may be best treated by targeting the family as a whole.

The study was reported online on Nov. 10 Nature Medicine.

Based on these findings, members of the team based at St. Louis University in Missouri designed a drug that specifically blocks the action of all five alpha V integrins, and the compound prevented fibrosis as effectively as the genetic deletion of these integrins. Moreover, the drug, known as CWHM 12, was able to prevent the progression of established fibrosis in the liver and lungs, and even to reverse some of the damage caused to those organs by fibrotic disease.

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