Simone Hoeger

Effects of Donor Pretreatment With Dopamine on Graft Function After Kidney Transplantation A Randomized Controlled Trial

CONTEXTnKidney graft function after transplantation can be improved through pharmacological donor pretreatment to limit organ injury from cold preservation.nnnOBJECTIVEnTo determine whether pretreatment of brain-dead donors with low-dose dopamine improves early graft function in human renal transplant recipients.nnnDESIGN, SETTING, AND PATIENTSnRandomized, open-label, multicenter, parallel-group trial of 264 deceased heart-beating donors and 487 subsequent renal transplants performed at 60 European centers between March 2004 and August 2007 (final follow-up, December 31, 2008). Eligible donors were stable under low-dose norepinephrine with a normal serum creatinine concentration on admission.nnnINTERVENTIONSnDonors were randomized to receive low-dose dopamine (4 mug/kg/min).nnnMAIN OUTCOME MEASURESnDialysis requirement during first week after transplantation.nnnRESULTSnDopamine was infused for a median of 344 minutes (IQR, 215 minutes). Dialysis was significantly reduced in recipients of a dopamine-treated graft. Fewer recipients in the treatment group needed multiple dialyses (56/227; 24.7%; 95% CI, 19.0%-30.3%; vs 92/260; 35.4%; 95% CI, 29.5%-41.2%; P = .01). The need for multiple dialyses posttransplant was associated with allograft failure after 3 years (HR, 3.61; 95% CI, 2.39-5.45; P < .001), whereas a single dialysis was not (HR, 0.67; 95% CI, 0.21-2.18; P = .51). Besides donor dopamine (OR, 0.54; 95% CI, 0.35-0.83; P = .005), cold ischemic time (OR, 1.07; 95% CI, 1.02-1.11 per hour; P = .001), donor age (OR, 1.03; 95% CI, 1.01-1.05 per year; P < .001), and recipient body weight (OR, 1.02; 95% CI, 1.01-1.04 per kg; P = .009) were independent explanatory variables in a multiple logistic regression model. Dopamine resulted in significant but clinically meaningless increases in the donors systolic blood pressure (3.8 mm Hg; 95% CI, 0.7-6.9 mm Hg; P = .02) and urine production before surgical recovery of the kidneys (29 mL; 95% CI, 7-51 mL; P = .009) but had no influence on outcome.nnnCONCLUSIONnDonor pretreatment with low-dose dopamine reduces the need for dialysis after kidney transplantation.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00115115.

Effects of Donor Pre-Treatment With Dopamine on Survival After Heart Transplantation A Cohort Study of Heart Transplant Recipients Nested in a Randomized Controlled Multicenter Trial

OBJECTIVESnWe determined the outcome of cardiac allografts from multiorgan donors enrolled in a randomized trial of donor pre-treatment with dopamine.nnnBACKGROUNDnTreatment of the brain-dead donor with low-dose dopamine improves immediate graft function after kidney transplantation.nnnMETHODSnA cohort study of 93 heart transplants from 21 European centers was undertaken between March 2004 and August 2007. We assessed post-transplant left ventricular function (LVF), requirement of a left ventricular assist device (LVAD) or biventricular assist device (BVAD), need for hemofiltration, acute rejection, and survival of recipients of a dopamine-treated versus untreated graft.nnnRESULTSnDonor dopamine was associated with improved survival 3 years after transplantation (87.0% vs. 67.8%, p = 0.03). Fewer recipients of a pre-treated graft required hemofiltration after transplant (21.7% vs. 40.4%, p = 0.05). Impaired LVF (15.2% vs. 21.3%, p = 0.59), requirement of a LVAD (4.4% vs. 10.6%, p = 0.44), and biopsy-proven acute rejection (19.6% vs. 14.9%, p = 0.59) were not statistically different between groups. Post-transplant impaired LVF (hazard ratio [HR]: 4.95; 95% confidence interval [CI]: 2.08 to 11.79; p < 0.001), requirement of LVAD (HR: 6.65; 95% CI: 2.40 to 18.45; p < 0.001), and hemofiltration (HR: 2.83; 95% CI: 1.20 to 6.69; p = 0.02) were predictive of death. The survival benefit remained (HR: 0.33; 95% CI: 0.12 to 0.89; p = 0.03) after adjustment for various risks affecting mortality, including pre-transplant LVAD/BVAD, inotropic support, and impaired kidney function.nnnCONCLUSIONSnTreatment of brain-dead donors with dopamine of 4 μg/kg/min will not harm cardiac allografts but appears to improve the clinical course of the heart allograft recipient. (Prospective Randomized Trial to Evaluate the Efficacy of Donor Preconditioning With Dopamine on Initial Graft Function After Kidney Transplantation; NCT00115115).

Atorvastatin donor pretreatment prevents ischemia/ reperfusion injury in renal transplantation in rats : Possible role for aldose-reductase inhibition

Background. The aim of the present study was to evaluate the effect of donor pretreatment with atorvastatin on ischemia/reperfusion (I/R) injury in renal transplantation in rats. Methods. Donor rats were pretreated orally with atorvastatin or vehicle 2 days prior to explantation. Kidneys were stored for 24 hr at 4°C in University of Wisconsin solution and transplanted into isogeneic or allogeneic recipients. Results. Donor treatment with atorvastatin improved initial graft function, reduced renal inflammation, and the number of TUNEL-positive cells in renal tissue after prolonged cold storage and isogeneic transplantation. In the allogeneic transplantation model, donor treatment with atorvastatin reduced renal inflammation in grafts harvested after 5 days, but no improvement of long-term graft survival (24 weeks) could be observed. A genome wide gene expression profile of donor kidneys from atorvastatin treated or vehicle treated rats revealed a fivefold downregulation of aldose reductase in all atorvastatin treated animals (P<0.01). Donor treatment with an aldose-reductase inhibitor improved kidney function and reduced renal inflammation after prolonged cold storage and isogeneic transplantation. Conclusion. Our data suggest that downregulation of aldose reductase in renal tissue might underlie the protective effect of donor atorvastatin treatment. Donor pretreatment with a statin or an aldose reductase inhibitor could offer a new treatment strategy to prevent transplantation associated tissue injury.

The additional detrimental effects of cold preservation on transplantation-associated injury in kidneys from living and brain-dead donor rats.

Backround. Brain death and cold preservation are major alloantigen-independent risk factors for transplantation outcome. The present study was conducted to assess the influence of these factors on transplantation-associated injury independently or in combination. Methods. Brain death was induced in F344 rats. Renal grafts were harvested after 6 hr and either directly transplanted in unilateral nephrectomized Lewis recipient or subjected to 24 hr of cold preservation in University of Wisconsin solution before implantation. Allografts obtained from living donor rats were also subjected to cold preservation or not. DNA damage was assessed before implantation by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining. Ten days after transplantation, renal histology was performed according to Banff 97 classification. The expressions of cytokines and adhesion molecules were analyzed by quantitative polymerase chain reaction. Results. Cold preservation significantly increased the number of terminal deoxynucleotide transferase-mediated dUTP nick-end labeling positive cells in renal allografts. Ten days after transplantation, histology revealed a higher degree of tubulitis and vasculitis scores when the grafts were subjected to cold storage. Vasculitis was aggravated when the graft was obtained from brain death (BD) donors. BD, but not cold preservation alone, was associated with papillary necrosis. This was more frequently observed after cold preservation. Immunohistology showed an increase in MHC class II+ cells after cold preservation. The combination of BD and cold preservation revealed a higher degree of VEGF and IL-10 expression. Conclusions. Our Study emphasizes that cold ischemia time should be limited when renal allografts from brain-dead donors are transplanted.

Donor dopamine pretreatment inhibits tubulitis in renal allografts subjected to prolonged cold preservation

Background. In the present study, we used the Brown-Norway (BN) to Lewis model as a model for acute rejection, to test the hypothesis that dopamine (DA) treatment of BN donors significantly reduces the inflammatory response after renal transplantation. Methods. BN and Lewis rats (isograft controls) were treated for 24 hr with DA (5 &mgr;g/kg/min) or NaCl (0.9%), respectively. After 24 hr of cold storage in University of Wisconsin (UW) solution, renal allografts were orthotopically transplanted into Lewis recipients. All recipients received immunosuppression until they were sacrificed. Allografts were harvested one, three, five, and 10 days after transplantation and analyzed by light microscopy, immunohistochemistry (CD3, major histocompatibility complex [MHC] class II, ED1, P-selectin and intercellular adhesion molecule [ICAM]-1) and by RNase protection assay for cytokine mRNA. Results. Ten days after transplantation Banff tubulitis scores were significantly lower in DA-treated than in NaCl-treated allografts. No significant differences were found in Banff interstitial infiltration scores. The numbers of MHC class II+ and CD3+ cells were significantly decreased in DA-treated animals as assessed by immunohistochemistry. No differences were found in the number of ED1+, P-selectin+, and ICAM-1+ cells. The expression of Lt&agr;, tumor necrosis factor, interleukin-1&bgr;, and interleukin-2 mRNA was significantly reduced in DA-treated animals. Conclusion. Our data indicate that donor DA treatment significantly inhibits tubulitis in renal allografts subjected to prolonged cold preservation. A reduced number of infiltrating MHC class II+ and CD3+ cells together with decreased cytokine expression could diminish renal scarring, reduce allograft immunogenicity, and hence improve transplantation outcome.

Inhibition of VCAM-1 expression in endothelial cells by CORM-3: The role of the ubiquitin–proteasome system, p38, and mitochondrial respiration

Carbon monoxide (CO) abrogates TNF-α-mediated inflammatory responses in endothelial cells, yet the underlying mechanism thereof is still elusive. We have previously shown that the anti-inflammatory effect of CO-releasing molecule-3 (CORM-3) is not completely mediated via deactivation of the NF-κB pathway. In this study, we sought to explore other potential mechanisms by which CORM-3 downregulates VCAM-1 expression on TNF-α-stimulated HUVECs. By genome-wide gene expression profiling and pathway analysis we studied the relevance of particular pathways for the anti-inflammatory effect of CORM-3. In CORM-3-stimulated HUVECs significant changes in expression were found for genes implicated in the proteasome and porphyrin pathways. Although proteasome activities were increased by CORM-3, proteasome inhibitors did not abolish the effect of CORM-3. Likewise, heme oxygenase-1 inhibitors did not abrogate the ability of CORM-3 to downregulate VCAM-1 expression. Interestingly, CORM-3 inhibited MAPK p38, and the p38 inhibitor SB203580 downregulated VCAM-1 expression. However, downregulation of VCAM-1 by CORM-3 occurred only at concentrations that partly inhibit ATP production and sodium azide and oligomycin paralleled the effect of CORM-3 in this regard. Our results indicate that CORM-3-induced downregulation of VCAM-1 is mediated via p38 inhibition and mitochondrial respiration, whereas the ubiquitin-proteasome system seems not to be involved.

Donor desmopressin is associated with superior graft survival after kidney transplantation.

Background. A recent randomized trial showed that pretreatment of the brain-dead donor with low-dose dopamine improves immediate kidney graft function, by limiting injury from cold storage (ClinicalTrials.gov Identifier: NCT00115115). This study determines whether donor exposure to desmopressin (1-deamino-8-d-arginine-vasopressin [DDAVP]) before organ retrieval affects renal transplant outcome. Methods. This retrospective multicenter cohort study, nested in the database of the dopamine trial, includes 264 deceased heart-beating donors with confirmed brain death and corresponding 487 renal allograft recipients transplanted at 60 European centers between March 2004 and August 2007. We assessed differences in delayed graft function, biopsy-proven acute rejections, and 2-year kidney graft survival in recipients of a DDAVP-exposed versus unexposed graft. Results. DDAVP was associated with improved graft survival (85.4% vs. 73.6%, P=0.003). This survival benefit persisted after censoring for death with functioning graft (91.1% vs. 82.0%, P=0.01) and after adjustment for confounders including covariate adjustment from propensity scoring (hazard ratio 0.40, 95% confidence interval [CI] 0.21–0.77; P=0.006). Delayed graft function (odds ratio 0.97, 95% CI 0.57–1.65; P=0.92) and biopsy-proven acute rejections (odds ratio 1.32, 95% CI 0.70–2.49; P=0.40) were unaffected. The survival effect was enhanced after a shorter cold ischemic time less than 14 hr (91.3% vs. 77.8%, P=0.008) and after dopamine pretreatment (92.7% vs. 78.6%, P=0.006). By contrast, prolonged cold ischemic time more than or equal to 14 hr (91.2% vs. 86.5%, P=0.39) and assignment to the nondopamine group (89.7% vs. 84.8%, P=0.37) abrogated the survival advantage. Conclusions. Donor DDAVP seems to improve renal allograft survival. Combined use of donor DDAVP and low-dose dopamine should receive further evaluation.

N-Octanoyl Dopamine for Donor Treatment in a Brain-death Model of Kidney and Heart Transplantation.

Background This study investigated the potential use of N-octanoyl dopamine (NOD) in donor management to ameliorate the damage caused by brain death and ischemia-reperfusion injury in a rat model of kidney and heart transplantation. Methods Brain-dead Fisher rats were treated for 6 hours with either saline or saline plus NOD. Orthotopic kidney and heterotopic heart transplantation were performed in different Lewis recipient rats. The right donor kidneys were stored for biochemical analysis. Blood samples were taken from the donor and on several days after transplantation from the recipient. All grafts were harvested after 7 days. Results There was no effect on donor heart rate and blood pressure under NOD treatment. The release of lactate dehydrogenase (LDH) during brain death was reduced in the NOD group. The right kidneys from NOD-preconditioned animals revealed diminished expression of the proinflammatory cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, there was no difference in renal infiltration with ED1 (CD68) or major histocompatibility complex (MHC) class II–positive cells. Recipients receiving a renal allograft from NOD-treated donors had a significantly better renal function at day 1 after transplantation. Banff-grading after 7 days showed significantly reduced scores for tubulitis and vasculitis in the grafts of these recipients. In the heart allograft recipients, lower plasma LDH levels were observed. Conclusions Donor preconditioning with NOD leads to better graft function and reduced acute rejection in untreated renal allograft recipients without displaying adverse effects on heart allografts.

Brain Death-Induced Inflammation: Possible Role of the Cholinergic Anti-inflammatory Pathway

Brain death is accompanied by a systemic inflammatory response leading to inflammation in end-organs. Experimental studies in rats have demonstrated that brain death per se has adverse effects on immediate renal function in recipients. This points out that brain death-induced inflammation is an undesired event, affecting organ function and therefore should be prevented or limited in brain-dead donors. Apart from tissue ischemia, cytokine release from the brain and increased intestinal permeability leading to systemic immune activation may explain brain death-induced inflammation. Although not thoroughly studied, failure of the cholinergic anti-inflammatory pathway during brain death represents a further alternative to explain excessive inflammation in brain-dead donors. In this chapter, we discuss the inflammatory reflex, show the beneficial effect of activating the cholinergic anti-inflammatory pathway in a variety of experimental models including brain death, and finally we discuss the different modalities for activating the cholinergic anti-inflammatory pathway as therapeutic interventions. We conclude that stimulation of the anti-inflammatory pathway in brain-dead donors has the potential to reduce the proinflammatory status of the graft and thus to improve organ quality. Hence, more preclinical studies are warranted to assess the benefits, or adverse effect of this modality on organ function before its implementation as new donor management strategy into clinical practice.