Gene for devastating kidney disease discovered

December 21, 2009

Researchers from Children's Hospital Boston and Brigham and Women's Hospital have identified an important genetic cause of a devastating kidney disease that is the second leading cause of kidney failure in children, according to The NephCure Foundation.

The study, published online December 20 by Nature Genetics, may provide clues to developing treatments for the disease, focal segmental glomerulosclerosis (FSGS), which currently forces children and young adults onto dialysis and often requires a kidney transplant. No effective treatments are known, and years of research have failed to uncover the underlying disease mechanism.

FSGS attacks the kidney's filtering system, causing proteins to be lost into the urine and reducing the kidney's ability to filter wastes from the blood. According to NephCure, which helped fund the study, 26 million Americans suffer from chronic kidney disease, of which FSGS is one of the most common forms.

Patients with FSGS are often treated with steroids, which are only partially effective and have very harsh side effects. In addition, they often face several trips a week to the hospital for dialysis, and many require a kidney transplant, along with lifelong treatment with powerful immunosuppressants to prevent organ rejection.

The research team, led by Elizabeth Brown, MD of Children's Division of Nephrology, working in the laboratory of Martin Pollak, MD of the Renal Division at Brigham and Women's Hospital, identified the gene by performing a genetic linkage analysis in two large families with FSGS. Linkage analysis is a gene-finding technique that compares affected with unaffected family members, looking for a piece of DNA whose location is already known, and that is inherited only by affected members. Using that piece of DNA as a "signpost," researchers can then look nearby to find the disease gene.

Using this technique, Brown and colleagues homed in on a region of chromosome 14q. By sequencing multiple genes in this region, they detected nine different mutations, all of them in a gene called INF2. They then sequenced INF2 in 91 additional families. In all, they found INF2 mutations in 11 of 93 families.

There have been a few descriptions of other genes that result in FSGS, but Brown and colleagues think INF2 is an important find. Mutations on this gene seem to affect larger numbers of families than those on previously discovered genes, and may be more relevant in understanding how the disease originates physiologically.

"The discovery that multiple families have mutations in INF2 is exciting and not only furthers our understanding of FSGS, but also tells us that INF2 and the pathways in which it is involved are important for normal kidney function," says Brown. "FSGS is a frustrating disease for clinicians, as we have little understanding of the biology and poor treatment options. We hope that further scientific work on INF2 will lead to better options."

INF2 encodes a protein that regulates actin, a protein vital to creating and maintaining the architecture of the cell. Both actin and INF2 are abundant in podocytes, the kidney cells that are crucial to filtering toxins. These cells are structurally complex, with extensions that interlock with those of other cells. Based on their findings, the researchers believe that disruption of INF2 in podocytes compromises their structure and, hence, their function.

In 2007 alone, 1,117 kidney transplants were performed on FSGS patients, according to NephCure. "To make matters worse, many patients have recurrence of the disease soon after transplant," says William Harmon, MD, chief of Children's Division of Nephrology. "First it ruins your native kidney, then it can return instantly in the transplant and ruin that also."

"It truly is heart-breaking to have to look a child in the eye and know there's currently little that can be done to cure them of this disease," says Henry Brehm, executive director of The NephCure Foundation, which has dedicated over $6 million towards research of FSGS and Nephrotic Syndrome in recent years. "This study shows that the answers are there to be found."
-end-
The study abstract can be accessed online at http://www.nature.com/ng/journal/vaop/ncurrent/abs/ng.505.html. Coauthors were Johannes Schlöndorff and Daniel Becker of HMS and Brigham and Women's Renal Division, Hiroyasu Tsukaguchi, Andrea Uscinski of Brigham and Women's Renal Division, Henry Higgs of Dartmouth Medical School, and Joel Henderson of Brigham and Women's Department of Pathology.

For more information on FSGS, visit The NephCure Foundation's website (www.nephcure.org).

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the Clinical Investigator Training Program: Beth Israel Deaconess Medical Center Harvard and Massachusetts Institute of Technology Health Sciences and Technology, Pfizer Inc., Merck and Co., The NephCure Foundation, and the Cole Pasqualucci Nephrotic Syndrome and FSGS Research fund.

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 13 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 396-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.

Brigham and Women's Hospital (BWH) is a 777-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery network. In July of 2008, the hospital opened the Carl J. and Ruth Shapiro Cardiovascular Center, the most advanced center of its kind. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. The BWH medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in quality improvement and patient safety initiatives and its dedication to educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 900 physician-investigators and renowned biomedical scientists and faculty supported by more than $485 M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative. For more information about BWH, please visit www.brighamandwomens.org.

Boston Children's Hospital

Related Kidney Transplant Articles from Brightsurf:

The effects of social determinants of health on kidney transplant candidates
Social determinants of health are associated with patient-reported outcomes in adults who are eligible to undergo kidney transplantation evaluations.

Tailored education system to benefit kidney transplant patients
Researchers find their computer-tailored education system, 'Your Path to Transplant' increases knowledge and readiness to pursue kidney transplant.

Kidney transplant, the cost of accounting for patients' preferences
Taking into account patients' preferences can help speed up the organ allocation process and improve the life quality of the recipients, as shown by a joint study conducted by Ca' Foscari University and the University of Padua

New hope for kidney revival for transplant
Cell therapy delivered directly to the kidney can revive a 'marginal' organ, improving function and could offer new hope for providing more kidneys for transplant.

Are kidney transplant patients at higher risk? The European experience
The risk of death is relatively high in kidney transplant patients admitted to hospital with COVID-19.

The economic burden of kidney transplant failure in the United States
A recent analysis published in the American Journal of Transplantation estimates that for the average US patient who has undergone kidney transplantation, failure of the transplanted organ (graft failure) will impose additional medical costs of $78,079 and a loss of 1.66 quality-adjusted life years.

Mixed chimerism improves long-term kidney transplant outlook
Mixed chimerism - the continued mixing of donor and recipient blood cells following a transplant of blood progenitor cells - could improve outcomes for kidney transplant recipients, according to a new clinical study in about 50 patients.

Kidney paired donation is an excellent option for transplant candidates
An analysis compared transplant recipients who received kidneys through national kidney paired donation and those who received kidneys from other living donors (such as relatives, friends or other paired exchange mechanisms).

Mediterranean diet may help preserve the kidney health of transplant recipients
In a study of kidney transplant recipients, those with higher adherence to the Mediterranean diet were less likely to experience kidney function loss.

New blood test can detect rejection by antibodies after kidney transplant
A group of European scientists led by KU Leuven has found a biomarker that can identify patients with symptoms of kidney rejection symptoms after a transplant as a result of antibodies.

Read More: Kidney Transplant News and Kidney Transplant Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.