Prevention of acute renal allograft failure - part 2

The specific aim of the proposed RCT is to elucidate whether conditioning of deceased organ donors with 1 g of methylprednisolone or placebo will ameliorate inflammation in the donor kidney and subsequently lead to reduced rates of postischemic acute renal transplant failure (ARTF). ARTF is the main risk factor for shortened allograft survival. The proposal is based on the data we obtained over the past three years in the FWF project entitled "Prevention of postischemic ARTF". With the financial support from the FWF we determined the genome-wide gene expression pattern of human donor kidneys before transplantation and found that a unique molecular signature of transcripts responsible for inflammation and immune response was present only in kidneys that subsequently developed ARTF. Transcription factor analysis suggested coregulation of these molecular pathways. Phylogenetic footprinting was used to corroborate the in silico findings. In the present application we will investigate whether the autonomous storm of cytokines and inflammation caused by the brain death syndrome can be diminished by a single shot high dose corticosteroid given hours before the organs are being harvested. This intervention should shut down inflammation in- and reduce immune response to- the donor organ. The efficacy of this conditioning will be evaluated by genome-wide gene expression analysis of transplant kidney wedge biopsies obtained before engraftment. The ultimate clinical study end point is the incidence and duration of ARTF in the transplant recipients. Since the calculated sample size to show a reduction of ARTF from 40 to 20% is roughly 100 donors, a multicenter approach is proposed. The participating transplant centers are Innsbruck, Vienna and Budapest. Based on the numbers transplanted in these three institutions in 2003, sample collection should be completed within one year. The experimental analysis of the gene expression profiles will be completed at the end of the second study year. Bioinformatics work up and transcription factor analysis of the experimentally obtained data will be finalized in the mid third year. This study is designed to ultimately answer the clinically important question of whether incidence and duration of ARTF can modified. The applicant has set up an infrastructure over the last three years that provides an unique opportunity for the successful management of this research application.

The specific aim of the proposed RCT is to elucidate whether conditioning of deceased organ donors with 1 g of methylprednisolone or placebo will ameliorate inflammation in the donor kidney and subsequently lead to reduced rates of postischemic acute renal transplant failure (ARTF). ARTF is the main risk factor for shortened allograft survival. The proposal is based on the data we obtained over the past three years in the FWF project entitled "Prevention of postischemic ARTF". With the financial support from the FWF we determined the genome-wide gene expression pattern of human donor kidneys before transplantation and found that a unique molecular signature of transcripts responsible for inflammation and immune response was present only in kidneys that subsequently developed ARTF. Transcription factor analysis suggested coregulation of these molecular pathways. Phylogenetic footprinting was used to corroborate the in silico findings. In the present application we will investigate whether the autonomous storm of cytokines and inflammation caused by the brain death syndrome can be diminished by a single shot high dose corticosteroid given hours before the organs are being harvested. This intervention should shut down inflammation in- and reduce immune response to- the donor organ. The efficacy of this conditioning will be evaluated by genome-wide gene expression analysis of transplant kidney wedge biopsies obtained before engraftment. The ultimate clinical study end point is the incidence and duration of ARTF in the transplant recipients. Since the calculated sample size to show a reduction of ARTF from 40 to 20% is roughly 100 donors, a multicenter approach is proposed. The participating transplant centers are Innsbruck, Vienna and Budapest. Based on the numbers transplanted in these three institutions in 2003, sample collection should be completed within one year. The experimental analysis of the gene expression profiles will be completed at the end of the second study year. Bioinformatics work up and transcription factor analysis of the experimentally obtained data will be finalized in the mid third year. This study is designed to ultimately answer the clinically important question of whether incidence and duration of ARTF can modified. The applicant has set up an infrastructure over the last three years that provides an unique opportunity for the successful management of this research application.