New explanation for the mechanism behind chronic allograft nephropathy Rudolf Pichlmayr Prize for Heidelberg scientist and pediatrician
If donor kidneys gradually deteriorate in the years following transplant, rejection by the immune system is rarely the cause. A more likely reason is accelerated senescence of the renal transplant, leading to progressive functional impairment.
Privatdozentin Dr. Dr. Anette Melk of the Heidelberg University Children's Hospital has detected the significance of this aging process for donor kidney failure. In recognition of her work on this issue the German Transplant Society (DTG) has awarded her the Rudolf Pichlmayr Prize 2006. Endowed with 10,000 euros and named after the pioneer of German transplant medicine, the Prize is awarded for outstanding achievement in this field and was presented to Dr. Melk at the Annual Conference of the DTG in Munich in October 2006.
The University of Heidelberg Children's Hospital (medical director Professor Dr. Georg Hoffmann) has the largest children's kidney centre in Germany (headed by Professor Dr. Franz Schaefer). Over 430 kidney transplants have been performed here since 1970, an average of about 15 per year.
Every year over 2,500 people in Germany, including about 100 children, are given a kidney transplant. In about half of these cases the transplant ceases to function within a period of ten years. If this failure takes place gradually, medical scientists refer to the phenomenon as chronic allograft nephropathy (CAN). In adults, CAN is the second most frequent cause of long-term transplant failure, in children it is the most frequent cause of all. Today, medication can effectively prevent the immune system from attacking the alien organ. But up to now, the causes of premature loss of kidney function were unknown.
Increased production of aging marker in transplant failure
Dr. Melk adduces two arguments for her new hypothesis. "Cells in kidneys with CAN have commonalities with the cells of older healthy kidneys," says the scientist from the Pediatric Nephrology department of the University Children's Hospital. In addition, kidneys from older donors in which the cells already display signs of aging increase the risk of CAN. "So our assumption was that after transplantation the kidney cells age more quickly, thus causing the transplant to gradually forfeit its function," Dr. Merk explains.
Anette Melk compared tissue from damaged kidneys with samples taken from the same organ at the time of transplantation. She found that in cells from CAN kidneys large amounts of the cell-cycle inhibitor p16 were identifiable. This inhibitor plays a role in kidney senescence. In fact, the production of this protein exceeded the amount detectible in healthy kidney cells during the aging process. By contrast, the p16 count in renal transplants without CAN was normal.
This discovery paves the way for improved therapy. "As we are now familiar with this mechanism, it is conceivable for us to be able to block early aging in the donor kidney and thus delay or possibly even prevent chronic allograft nephropathy," says Dr. Melk. One encouraging sign is that renal transplants from mice unable to produce p16 survived considerably longer than those from mice with p16.
Melk A, Schmidt BM, Vongwiwatana A, Rayner DC, Halloran PF. Increased expression of senescence-associated cell cycle inhibitor p16INK4a in deteriorating renal transplants and diseased native kidney. Am J Transplant. 2005 Jun;5(6):1375-82.
Melk A. Senescence of renal cells: molecular basis and clinical implications. Nephrol Dial Transplant. 2003 Dec;18(12):2474-8.
Privatdozentin Dr. Dr. Anette Melk
University of Heidelberg Children's Hospital
Pediatric Nephrology Section
Department of Pediatrics I
phone: 06221/562302 (secretary's office)
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