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Study Identifies Biomarkers That Could Lead to Improved Organ Selection and Outcomes in Patients Receiving Transplanted Organs from Brain-Dead Donors

University of Pittsburgh School of Medicine study finds inflammatory biomarker is associated with decreased long-term survival

PITTSBURGH, June 25, 2008 — Higher levels of the immune protein interleukin-6 (IL-6), a biomarker for inflammation, are associated with decreased survival in patients receiving organs for transplant from brain-dead donors, University of Pittsburgh School of Medicine researchers report in the June issue of Critical Care Medicine, the official journal of the Society of Critical Care Medicine. The results suggest that biomarkers such as IL-6 might be used to help identify organs that are more suitable for transplant, improving survival and health outcomes for recipients, the researchers note.

Despite efforts to increase awareness of the need for organ donation, there remains a critical shortage of organs, with a significant number coming from patients left brain-dead following traumatic injury or illness. And while it is known that brain death induces a massive inflammatory response, the influence of this immune response on organ procurement, transplantation and long-term survival for recipients has been less clear. The Pitt study is “the first time that a marker of inflammation in an organ donor has been shown to predict outcome in the transplant recipient,” the authors write.

Led by investigators in Pitt’s Clinical Research, Investigation and Systems Modeling of Acute Illness (CRISMA) Laboratory, researchers evaluated data from 30 brain-dead organ donors at the University of Pittsburgh Medical Center (UPMC) and the University of Texas Health Science Center in Houston who gave 91 organs for transplant to 78 recipients between April and November 2004. Bloodstream levels of immune system proteins IL-6, IL-10 and tumor necrosis factor, all cytokines associated with inflammation, were measured in organ donors hourly for four hours following declaration of brain death, and again immediately prior to organ procurement. For study purposes, recipients, whose transplants took place at many hospitals around the country in addition to Houston and Pittsburgh, were followed through May 2005.

“We found that lower concentrations of IL-6 in the bloodstream of donors prior to organ procurement were significantly associated with improved survival,” said John A. Kellum, M.D., senior author of the study and professor, Department of Critical Care Medicine, University of Pittsburgh School of Medicine. “Patients who received organs from donors with lower IL-6 levels were substantially less likely to have complications following transplant requiring hospitalization and were more likely to have longer survival after hospital discharge.”

All organ donors experienced increases in bloodstream concentrations of the three cytokines measured following brain death, but increases in IL-6 were linked most closely with decreased survival. “These data strongly suggest that the ‘cytokine storm’ seen immediately following brain death negatively affects organ function,” said Raghavan Murugan, M.D., study first author and assistant professor, Department of Critical Care Medicine, University of Pittsburgh School of Medicine.

The Pittsburgh team suggests that it is premature to recommend routine screening of IL-6 levels in potential organ donors, but that the study findings open a distinct avenue of future scientific inquiry related to minimizing the inflammatory response in organ donors. “This is one relatively small study, but if the findings are confirmed, I think there is promise to possibly use this technique to ultimately improve organ selection and patient outcomes,” said Dr. Kellum.

Currently, the potent anti-inflammatory steroid drug solumedrol is used to treat inflammation in organ donors as standard practice at many hospitals, including UPMC. While the present study, which enrolled donors in 2004 and 2005, could not demonstrate that solumedrol improves outcomes (perhaps because only a few donors received the drug), it does appear that the steroid reduced inflammation as measured by decreased levels of IL-6. This effect was most pronounced just before organ procurement, which also is when IL-6 levels were most predictive, the authors write.

In addition to Drs. Kellum and Murugan, study authors include Ramesh Venkataraman, M.D., Michele Elder, R.N., Melinda Carter, B.S., Nicholas J. Madden, B.S., all of the CRISMA Laboratory, Department of Critical Care Medicine, University of Pittsburgh; Abdus S. Wahed, Ph.D., Department of Biostatistics, University of Pittsburgh; and Georgene Hergenroeder, R.N., and David Powner, M.D., University of Texas Health Science Center.

The study was supported by funding from the Health Resources and Services Administration, U.S. Department of Health and Human Services.

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