OPTIMIZING IMMEDIATE GRAFT FUNCTION IN KIDNEY TRANSPLANTATION

C. Tsagogiorgas¹, M. Schneider², G. Lueg¹, M. Hottenrott¹, P. Schnuelle², B. Yard², S. Hoeger^2
1Clinic For Anaesthesiology And Critical Care, University Hospital Mannheim, Mannheim/GERMANY, ²V. Medical Clinic, University Hospital Mannheim, Mannheim/GERMANY

Body: Introduction. We have previously demonstrated in experimental and clinical studies that the protective effects of dopamine (DA) treatment in kidney transplantation were independent of blood pressure stabilization. Recently, we have developed a non-hemodynamic dopamine derivative, i.e. N-Octanoyl-Dopamine (NOD) that is approximately 40x more effective than DA to protect Human-Umbilical-Vein-Endothelial-Cells (HUVEC) against cold preservation injury. In the present study we tested if NOD is also able to inhibit TNF-a mediated inflammation in vitro. Since warm reperfusion is considered as an important cause of early renal graft loss, we also compared the effect of dopamine and its derivate NOD on acute renal failure (ARF) in vivo. Methods. HUVECs were stimulated with TNF-α in the absence or presence of various concentrations of NOD. Affymetrix Gene Expression Profiling, quantitative PCR, westernblotting and NF-κB activation studies were performed to assess the anti-inflammatory potential of NOD in vitro. In ARF the rats were pre-treated with an intravenous bolus of DA or NOD in equimolar concentrations. Kidneys were clamped for 45 min and renal function was measured. In order to evaluate renal inflammation, the kidneys were harvested after 5 days. Results. Gene expression profiling on cultured HUVEC revealed that a wide range of pro-inflammatory genes were down-regulated by NOD, e.g. adhesion molecules and chemokines. This was most likely mediated via inhibition of NFkB. Although heme-oxygenase-1 (HO-1) was strongly upregulated by NOD, it did not contribute to the anti-inflammatory effect of NOD. While HO-1 was already significantly induced at 1µM of NOD, inhibition of VCAM-1 expression required 50µM. In the ARF model NOD significantly improved renal function compared to DA or saline treated controls (NOD vs. DA/saline: P<0.01 at day 3 and 5). Immunohistochemistry revealed a significantly reduced number of monocytes in both NOD and DA treated animals compared to saline treated rats (P<0.05). Conclusion. Our data demonstrate that NOD has potent anti-inflammatory effects in vitro. In vivo administration of NOD not only mitigates deterioration in renal function but also reduces renal inflammation in the setting of ischemia reperfusion. Since ARF is a genuine problem after ischemia, these data are of high clinical relevance to limit renal damage and clinical complication associated with ARF.

Disclosure: All authors have declared no conflicts of interest.