Human pregnane X receptor genotype of the donor but not of the recipient is a risk factor for delayed graft function after renal transplantation.

Delayed graft function (DGF) is an important complication in renal transplantation, contributing significantly to decrease in long-term allograft survival. In addition to donor- and recipient-related risk factors such as immunosuppression, altered renal excretion of xenobiotics by membrane transporters may influence DGF. Using DNA samples from recipients and donors, we assessed the impact on DGF of genetic variants in P-glycoprotein (ABCB1), multidrug resistance protein 2 (ABCC2), and the nuclear pregnane X receptor (PXR/NR1I2), which regulates the transcription of enzymes and transporters. In our local cohort of renal transplant recipients (n = 178), DGF occurred in 27.5%. The PXR 8055TT genotype of the donor only (not of the recipient) was significantly associated with an increased risk for DGF. This finding emerged from univariate as well as multivariate logistic regression analysis including 16 nongenetic factors and held true after correction for multiple testing. Our findings provide the first evidence that PXR may be associated with risk of DGF, independent of previously identified risk factors.

A Pneumocystis jirovecii pneumonia outbreak in a single kidney-transplant center: role of cytomegalovirus co-infection.

Pneumocystis jirovecii pneumonia (PCP) and cytomegalovirus (CMV) infection represent possible complications of medical immunosuppression. Between 2005 and 2010, non-human immunodeficiency virus (HIV) PCP patients admitted to a nephrology unit were analyzed for outcome, CMV comorbidity, and patient-to-patient contacts prior to PCP. In contrast to 2002-2004 (no cases) and 2008-2010 (10 cases), a PCP outbreak of 29 kidney-transplant recipients and one patient with anti-glomerular basement membrane disease occurred between 2005 and 2007. None of the patients were on PCP chemoprophylaxis. In four PCP patients, the genotyping data of bronchoalveolar lavage specimen showed an identical Pneumocystis strain. PCP cases had a higher incidence of CMV infection (12 of 30 PCP patients) and CMV disease (four patients) when compared to matched PCP-free controls (p < 0.05). Cotrimoxazole and, if applicable, ganciclovir were started 2.0 ± 4.0 days following admission, and immunosuppressive medication was reduced. In-hospital mortality was 10% and the three-year mortality was 20%. CMV co-infection did not affect mortality. CMV co-infection more frequently occurred during a cluster outbreak of non-HIV PCP in comparison to PCP-free controls. Here, CMV awareness and specific therapy of both CMV infection and PCP led to a comparatively favorable patient outcome. The role of patient isolation should be further investigated in incident non-HIV PCP.

Long-term therapy of acute chronic liver failure to successful transplantation with an extracorporeal liver support system.

We report the case of a 38-year-old Caucasian male who was admitted because of end-stage liver failure due to primary sclerosing cholangitis. Because of the rapidly progressive severe hepatic encephalopathy and development of hepatorenal syndrome type I, the patient was immediately upgraded to a high priority status on the liver transplantation waiting list (T2 status according to Eurotransplant criteria). Intermittent therapy with an extracorporeal liver support system (Prometheus) was initiated in order to bridge the time period until the expected transplantation date. Under therapy with the extracorporeal liver support system, total serum bilirubin decreased significantly from 33 to 15 mg/dL after 8 sessions. Simultaneously the encephalopathy resolved gradually within 3 weeks (10 sessions) from initially grade 3 to grade 1. Extracorporeal detoxification therapy was continued for 51 days (23 sessions) until the patient underwent his successful liver transplantation in good general clinical condition. Prometheus, a new liver support system, seemed to sufficiently replace hepatic detoxification on a long-term basis in this patient with end-stage liver failure in order to bridge the time period until liver transplantation.

Ultraviolet-A-induced transactivation of the vascular endothelial growth factor gene in HaCaT keratinocytes is conveyed by activator protein-2 transcription factor.

Ultraviolet-A radiation represents a significant proportion of the ultraviolet solar spectrum that was recently shown to affect gene expression of epidermal keratinocytes by molecular mechanisms distinct from ultraviolet-B radiation. As ultraviolet-A either alone or in combination with ultraviolet-B may contribute to photocarcinogenesis, we aimed to explore the biologic effects of ultraviolet-A radiation on vascular endothelial growth factor gene expression by the immortalized keratinocyte cell line HaCaT. As keratinocyte-derived vascular endothelial growth factor not only provides the major cutaneous angiogenic activity but may also augment the malignant phenotype of tumor cells, we studied the molecular mechanisms of ultraviolet-A-induced vascular endothelial growth factor expression in HaCaT cells, serving as a transformed preneoplastic epithelial cell line. Whereas ultraviolet-B-mediated vascular endothelial growth factor expression has been previously indicated to be conveyed by indirect mechanisms, ultraviolet-A rapidly induced vascular endothelial growth factor mRNA expression in a fashion comparable to that seen with the transforming growth factor alpha, representing a direct and potent activator of vascular endothelial growth factor gene transcription. Ultraviolet-A was found to readily induce vascular endothelial growth factor promoter-based reporter gene constructs through a consensus element for activator protein-2 transcription factor. The critical role of activator protein-2 was substantiated by demonstration of ultraviolet-A-induced activator-protein-2-dependent nuclear DNA binding activity to this site, and by inhibition of ultraviolet-A-mediated vascular endothelial growth factor gene transcription through insertion of a critical mutation within the activator protein-2 sequence. Together, our data further elucidate photobiologic aspects of ultraviolet-A-induced gene expression by characterizing mechanisms of vascular endothelial growth factor upregulation at the molecular level. In addition, our experiments support the concept of a more general importance of activator protein-2 in ultra- violet-A-mediated responses by keratinocytes or keratinocyte-derived cell lines.