Peter Schnuelle

Prospective Age‐Matching in Elderly Kidney Transplant Recipients—A 5‐Year Analysis of the Eurotransplant Senior Program

Renal transplantation faces challenges: the organ shortage resulting in extended waiting times and an aging population resulting in death with a functioning graft. The Eurotransplant Senior Program (ESP) allocates kidneys within a narrow geographic area from donors aged ≥65 years to recipients ≥65 years regardless of HLA. This analysis investigates the impact of the ESP on waiting time, graft and patient survival. The ESP group (n = 1406, old to old) was compared to two groups allocated via the Eurotransplant Kidney Allocation System (ETKAS) with either similar donor age (old to any [O/A], donor age ≥65, n = 446) or recipient age (any to old, [A/O], recipient age 60–64, n = 1687). All patients were transplanted between 1999 and 2004. Since initiation of the ESP (1999), availability of elderly donors doubled and waiting time for ESP patients decreased. Local allocation led to shorter cold ischemia time (11.9 vs. >17.0 h, p < 0.001) and less delayed graft function (DGF, ESP 29.7% vs. O/A 36.2%, p = 0.047) but 5–10% higher rejection rates. Graft and patient survival were not negatively affected by the ESP allocation when compared to the standard allocation. The ESP age matching of elderly donors and recipients is an effective allocation system for organs from elderly donors.

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.

Impact of Donor Dopamine on Immediate Graft Function after Kidney Transplantation

Optimizing medical donor management may have a considerable impact on transplantation outcome. This study investigated the effect of donor dopamine on initial graft function in renal allograft recipients, involving 254 consecutive recipients of a cadaver kidney, aged 18–74 years, transplanted between 1990 and 2003. Immunosuppression was based on cyclosporine. Patients were grouped according to donor use of dopamine during intensive care. Delayed graft function (DGF), and serial creatinine concentrations were compared between the groups. Dopamine‐treated and ‐untreated donors were very similar regarding hemodynamics and renal function. Delayed graft function occurred in 47/158 treated and 48/96 untreated kidneys (p = 0.001). Donor dopamine was associated with a more rapid decrease of s‐creatinine, which became obvious on the first postoperative day. Of patients in the treated and untreated group, respectively, 81.9% and 65.8% reached a s‐creatinine level less than 2 mg/dL during the first month (p = 0.005). Donor dopamine remained predictive of a normalized s‐creatinine level [HR 1.71; 95% CI 1.22–2.41] after controlling for confounding factors by multivariate Cox regression. Donor dopamine is associated with improvements of initial graft function after kidney transplantation. The beneficial effect of dopamine is achievable without side‐effects for the recipients, and correlates with superior long‐term graft survival.

Prevention of Cold‐Preservation Injury of Cultured Endothelial Cells by Catecholamines and Related Compounds

The present study was conducted to dissect the underlying mechanisms by which catecholamines protect cells against preservation injury.

IMPACT OF THE BANFF '97 CLASSIFICATION FOR HISTOLOGICAL DIAGNOSIS OF REJECTION ON CLINICAL OUTCOME AND RENAL FUNCTION PARAMETERS AFTER KIDNEY TRANSPLANTATION

BACKGROUNDnData on a systematic correlation of specific pathomorphologic lesions in renal allograft biopsy specimens with clinical outcome parameters are crucial to determine the relevance of kidney biopsy findings after transplantation for graft prognosis. Specific histologic lesions of the revised Banff 97 classification were correlated with clinical follow-up data.nnnMETHODSnThe analysis was done on a series of 48 consecutive renal allograft biopsy specimens. Logistic regression was used to compare for response to rejection treatment dependent on histologic grading. Cox regression was applied to analyze the impact of the histologic findings on graft failure during ongoing follow-up.nnnRESULTSnSeverity of acute rejection was statistically associated with unresponsiveness to antirejection treatment (odds ratio 2.39, 95% confidence interval 1.13-5.03) and predicted an increased risk of graft failure (hazard ratio 2.16, 95% confidence interval 1.48-3.14). Intimal arteritis (hazard ratio 1.85, 95% confidence interval 1.40-2.45) was the only determinate of a poor survival prognosis. Mean serum creatinine level and the need for antihypertensive drugs were significantly higher in the Banff I-III graded groups after 1 and 2 years of follow-up, whereas patients with borderline rejection were not significantly different from the control group.nnnCONCLUSIONnWe confirmed a significant association between the revised Banff 97 classification and graft outcome. Intimal arteritis was the only significant predictor of a poor survival probability. The distinction of borderline rejection and Banff grade I rejection seems to be important from a prognostic point of view.

Hypothermic injury: the mitochondrial calcium, ATP and ROS love-hate triangle out of balance.

Background/Aims: Catecholamines prevent hypothermic cell death which accounts for severe tissue damage and impaired allograft function after prolonged organ preservation. Here, we identified cellular processes which govern hypothermia-mediated cell death in endothelial cells and how they are influenced by dopamine. Methods: Lactate dehydrogenase assay, intracellular ATP, reactive oxygen species and reduced thio-group measurement, intracellular calcium measurement and mitochondrial calcium staining were performed in the study. Results: Intracellular ATP was almost completely depleted within 12 hrs of hypothermic preservation in untreated human umbilical vein endothelial cells (HUVEC), while dopamine pre-treatment significantly delayed ATP depletion. 4 hrs after hypothermia a redox imbalance was observed in untreated cells, which increased with the duration of hypothermia. The redox imbalance was primarily caused by depletion of SH reduction equivalents and was significantly inhibited by dopamine. In addition, hypothermia-induced Ca2+ influx and mitochondrial Ca2+ accumulation were both prevented by dopamine. The protective effect of dopamine was abrogated by ionomycin and sodium azide and partly by oligomycin and CCCP. Conclusions: Our data demonstrated that loss of intracellular ATP, generation of a redox imbalance and accumulation of intracellular Ca2+ underlie cold preservation injury. Dopamine improves the redox balance, prevents intracellular Ca2+ accumulation and delays ATP depletion.

Perioperative fluid management in renal transplantation: a narrative review of the literature

Adequate volume maintenance is essential to prevent acute renal failure during major surgery or to ensure graft function after renal transplantation. The various recommendations on the optimum fluid therapy are based, at best, on sparse evidence only from observational studies. This article reviews the literature on perioperative fluid management in renal transplantation. Crystalloid solutions not exerting any specific side‐effects are the first choice for volume replacement in kidney transplantation. The use of colloids should be restricted to patients with severe intravascular volume deficits necessitating high volume restoration. The routine application of albumin, dopamine, and high dose diuretics is no longer warranted. Mannitol given immediately before removal of the vessel clamps reduces the requirement of post‐transplant dialysis, but has no effects on graft function in the long term. There is insufficient evidence on the best use of dialysis, but it seems peritoneal dialysis pretransplant is associated with less delayed graft function, whereas the preference of dialysis post‐transplant is not yet well‐founded. This review article should provide better guidance for fluid management in kidney transplantation until best‐evidence guidelines can be established based upon more research.

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).

Dopamine treatment in brain-dead rats mediates anti-inflammatory effects: the role of hemodynamic stabilization and D-receptor stimulation

Brain death (BD) is associated with profound inflammation in end‐organs. Dopamine (DA) treatment reduces this inflammatory response, but the underlying mechanisms remain thus far largely unknown. In this study, we investigated if the anti‐inflammatory effect of DA was related to hemodynamic stabilization and by which receptors it was mediated. BD was induced in F344 donor rats. DA was given either before BD for 24u2003h or after BD induction during a definite time. Adrenergic or D‐receptor blockers were administered to inhibit the receptor stimulation mediated by DA. Hemodynamic changes were recorded and kidneys were harvested after 6u2003h of BD. Mean arterial pressure was completely normalized by DA treatment. DA pretreatment before BD induction and treatment during BD both significantly inhibited the monocyte infiltration. The anti‐inflammatory as well as its blood pressure stabilizing effect was abrogated by concomitant application of adrenergic receptor blockers. In contrast, concomitant application of D‐receptor blockers only abrogated the anti‐inflammatory effect, but did not affect blood pressure stabilization. In contrast, pergolide and adrenergic receptor blockers completely normalized the blood pressure, but did not affect renal inflammation. Hence, DA might reduce BD‐induced monocyte infiltration possibly by hemodynamic stabilization, D‐receptor activation, or a combination of both.

Modulation of brain dead induced inflammation by vagus nerve stimulation.

Because the vagus nerve is implicated in control of inflammation, we investigated if brain death (BD) causes impairment of the parasympathetic nervous system, thereby contributing to inflammation. BD was induced in rats. Anaesthetised ventilated rats (NBD) served as control. Heart rate variability (HRV) was assessed by ECG. The vagus nerve was electrically stimulated (BD + STIM) during BD. Intestine, kidney, heart and liver were recovered after 6 hours. Affymetrix chip‐analysis was performed on intestinal RNA. Quantitative PCR was performed on all organs. Serum was collected to assess TNFα concentrations. Renal transplantations were performed to address the influence of vagus nerve stimulation on graft outcome. HRV was significantly lower in BD animals. Vagus nerve stimulation inhibited the increase in serum TNFα concentrations and resulted in down‐regulation of a multiplicity of pro‐inflammatory genes in intestinal tissue. In renal tissue vagal stimulation significantly decreased the expression of E‐selectin, IL1β and ITGA6. Renal function was significantly better in recipients that received a graft from a BD + STIM donor. Our study demonstrates impairment of the parasympathetic nervous system during BD and inhibition of serum TNFα through vagal stimulation. Vagus nerve stimulation variably affected gene expression in donor organs and improved renal function in recipients.