Context Kidney graft function after transplantation can be improved through pharmacological donor pretreatment to limit organ injury from cold preservation. Objective To determine whether pretreatment of brain-dead donors with lowdose dopamine improves early graft function in human renal transplant recipients. Design, Setting, and Patients Randomized, open-label, multicenter, parallelgroup 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. Interventions Donors were randomized to receive low-dose dopamine (4 µg/kg/min). Main Outcome Measures Dialysis requirement during first week after transplantation. Results Dopamine 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; PϽ.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; PϽ.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 donor's 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. Conclusion Donor pretreatment with low-dose dopamine reduces the need for dialysis after kidney transplantation.
ObjectivesTo establish arterial spin labelling (ASL) for quantitative renal perfusion measurements in a rat model at 3 Tesla and to test the diagnostic significance of ASL and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in a model of acute kidney injury (AKI).Material and MethodsASL and DCE-MRI were consecutively employed on six Lewis rats, five of which had a unilateral ischaemic AKI. All measurements in this study were performed on a 3 Tesla MR scanner using a FAIR True-FISP approach and a TWIST sequence for ASL and DCE-MRI, respectively. Perfusion maps were calculated for both methods and the cortical perfusion of healthy and diseased kidneys was inter- and intramethodically compared using a region-of-interest based analysis.Results/SignificanceBoth methods produce significantly different values for the healthy and the diseased kidneys (P<0.01). The mean difference was 147±47 ml/100 g/min and 141±46 ml/100 g/min for ASL and DCE-MRI, respectively. ASL measurements yielded a mean cortical perfusion of 416±124 ml/100 g/min for the healthy and 316±102 ml/100 g/min for the diseased kidneys. The DCE-MRI values were systematically higher and the mean cortical renal blood flow (RBF) was found to be 542±85 ml/100 g/min (healthy) and 407±119 ml/100 g/min (AKI).ConclusionBoth methods are equally able to detect abnormal perfusion in diseased (AKI) kidneys. This shows that ASL is a capable alternative to DCE-MRI regarding the detection of abnormal renal blood flow. Regarding absolute perfusion values, nontrivial differences and variations remain when comparing the two methods.
Since stimulation of transient receptor potential channels of the vanilloid receptor subtype 1 (TRPV1) mitigates acute kidney injury (AKI) and endogenous N-acyl dopamine derivatives are able to activate TRPV1, we tested if synthetic N-octanoyl-dopamine (NOD) activates TRPV1 and if it improves AKI. These properties of NOD and its intrinsic anti-inflammatory character were compared with those of dopamine (DA). TRPV1 activation and anti-inflammatory properties of NOD and DA were tested using primary cell cultures in vitro. The influence of NOD and DA on AKI was tested in a prospective, randomized, controlled animal study with 42 inbred male Lewis rats (LEW, RT1), treated intravenously with equimolar concentrations of DA or NOD one hour before the onset of warm ischemia and immediately before clamp release. NOD, but not DA, activates TRPV1 channels in isolated dorsal root ganglion neurons (DRG) that innervate several tissues including kidney. In TNFα stimulated proximal tubular epithelial cells, inhibition of NFκB and subsequent inhibition of VCAM1 expression by NOD was significantly stronger than by DA. NOD improved renal function compared to DA and saline controls. Histology revealed protective effects of NOD on tubular epithelium at day 5 and a reduced number of monocytes in renal tissue of DA and NOD treated rats. Our data demonstrate that NOD but not DA activates TRPV1 and that NOD has superior anti-inflammatory properties in vitro. Although NOD mitigates deterioration in renal function after AKI, further studies are required to assess to what extend this is causally related to TRPV1 activation and/or desensitization.
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 chipanalysis was performed on intestinal RNA. Quantitative PCR was performed on all organs. Serum was collected to assess TNFa 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 TNFa 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, IL1b 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 TNFa through vagal stimulation. Vagus nerve stimulation variably affected gene expression in donor organs and improved renal function in recipients.
Treatment of organ donors with catecholamines reduces acute rejection episodes and improves long-term graft survival after renal transplantation. The aim of this study was to investigate the effect of catecholamine pre-treatment on ischemia/reperfusion (I/R)- and cold preservation injury in rat kidneys. I/R-injury was induced by clamping the left kidney vessels for 60 min along with a contralateral nephrectomy. Cold preservation injury was induced by storage of the kidneys for 24 h at +4 degrees Celsius in University of Wisconsin solution, followed by syngeneic transplantation. Rats were pre-treated with either dopamine (DA), dobutamine (DB), or norepinephrine (2, 5, and 10 microg/kg/min, each group) intravenously via an osmotic minipump for 24 h before I/R- and cold preservation injury. Pre-treatment with DA (2 or 5 microg/kg/min) and DB (5 microg/kg/min) improved recovery of renal function after I/R-injury and dose dependently reduced mononuclear and major histocompatibility complex class II-positive cells infiltrating the kidney after I/R-injury. One day after I/R-injury, upregulation of transforming growth factor (TGF)-beta 1 and 2 and phosphorylation of p42/p44 mitogen-activated protein kinases was observed in kidneys of animals treated with DA or DB. DA (5 microg/kg/min) and DB (5 microg/kg/min) pre-treatment reduced endothelial cell damage after 24 h of cold preservation. Only DA pre-treatment improved renal function and reduced renal inflammation after 24 h of cold preservation and syngeneic transplantation. Our results demonstrate a protective effect of pre-treatment with catecholamines on renal inflammation and function after I/R- or cold preservation injury. This could help to explain the potent organoprotective effects of catecholamine pre-treatment observed in human kidney transplantation.
Summary 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 24 h 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 6 h 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.
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.
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