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Monday, February 27, 2012

Genetic, Physiological, and Pharmacological Amelioration of Ischemic Injury Susa, D. 2010-11-03 Doctoral Thesis


Organ transplantation is the treatment of choice for end stage organ failure, and in recent decades one year results have greatly improved. Two major problems facing the transplant community remain; long-term survival of organ grafts has still not reached its full potential, and the shortage of suitable donor organs is still increasing. Long-term graft survival is significantly hampered by chronic transplant dysfunction (CTD). This still poorly defined process of untreatable functional deterioration of an organ following transplantation accounts for approximately 30 percent of graft loss in the first 5 years after transplantation. In the kidney CTD, also known as chronic allograft nephropathy (CAN), is clinically characterized by progressive renal dysfunction, associated with hypertension and proteinuria. Renal biopsies show characteristic but nonspecific histopathological changes in the vascular, glomerular and tubulointerstitial compartments of the kidney, which overlap with the histology of normally aging kidneys. Although the term CAN has been recently replaced by “interstitial fibrosis and tubular atrophy without evidence of any specific etiology” [3], we continue to use CAN in this thesis, as this is the terminology used in the majority of the literature available to date. Increasing evidence suggests that the development of CAN is multifactorial in origin, with alloantigen dependent and allo-antigen independent factors contributing to the decline of renal graft function. Of the allo-antigen independent factors, donor age and cold ischemia time seem to be the major correlate to transplant survival. Clinical observations suggest an inverse relationship between both donor age and ischemia time and long-term graft survival. The mechanisms by which donor age or ischemia lead to reduced functional life span are currently unknown.

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