Minoxidil for Treatment of Resistant Hypertension in Chronic Kidney Disease--A Retrospective Cohort Analysis.

Resistant hypertension is still a challenge and reserve antihypertensive agents are often necessary to achieve blood pressure control. One reserve antihypertensive is minoxidil, a direct vasodilator that is known for its strong blood pressure-lowering effect, but contemporary studies are sparse. The authors retrospectively analyzed 54 inpatients with uncontrolled hypertension despite the combined use of current antihypertensive agents. To investigate the effect of minoxidil when added to other antihypertensive agents, blood pressure was evaluated at the time minoxidil treatment was initiated and at discharge. Minoxidil treatment was associated with a significant reduction in blood pressure from 162.4±15.1/83.2±12.7 mm Hg to 135.8±12.2/72.8±6.9 mm Hg (P<.0001). This effect was sustained across all analyzed subgroups. Although the well-known adverse events of minoxidil limit its widespread use, these data show that minoxidil as a reserve antihypertensive agent still has a niche indication in the particular subgroup of patients with treatment-resistant or uncontrolled hypertension.

Donor Desmopressin Treatment Does Not Affect Transplant Outcome in the Fischer to Lewis Rat Renal Transplant Model.

OBJECTIVES: Retrospective studies suggest that donor desmopressin (DDAVP) treatment improves renal transplant outcome. The present study tests the hypothesis that desmopressin neutralizes the graft's endothelium from proinflammatory angiopoietin 2 containing Weibel-Palade bodies in the donor, resulting in reduced Weibel-Palade body release at the time of reperfusion in the recipient. MATERIALS AND METHODS: Using rat models, we examined the influence of desmopressin treatment on the expression of vasopressin 2 receptors and adhesion molecules in brain-dead donors, with renal function examined in allogeneic recipients. The influence of desmopressin on the expression of adhesion molecules also was tested in vitro. RESULTS: Vasopressin 2 receptors were restricted to collecting ducts and distal tubules and only scarcely found in the renal vasculature. Vasopressin 2 receptor expression was down-regulated in brain-dead rats by desmopressin. Renal expression of vascular cellular adhesion molecule 1 and intercellular adhesion molecule 1 were significantly reduced in these rats. In contrast, angiopoietin 2 did not influence the expression of adhesion molecules in in vitro cultured endothelial cells after tumor necrosis factor ? stimulation. Donor desmopressin treatment improved neither renal function nor histology in allogeneic renal transplant recipients. CONCLUSIONS: Our data do not support the hypothesis that the clinically observed salutary effect of desmopressin is mediated by depletion of Weibel-Palade bodies in renal allografts.

Optimized donor management and organ preservation before kidney transplantation.

Kidney transplantation is a major medical improvement for patients with end-stage renal disease, but organ shortage limits its widespread use. As a consequence, the proportion of grafts procured from extended criteria donors (ECD) has increased considerably, but this comes along with increased rates of delayed graft function (DGF) and a higher incidence of immune-mediated rejection that limits organ and patient survival. Furthermore, most grafts are derived from brain dead organ donors, but the unphysiological state of brain death is associated with significant metabolic, hemodynamic, and pro-inflammatory changes, which further compromise patient and graft survival. Thus, donor interventions to preserve graft quality are fundamental to improve long-term transplantation outcome, but interventions must not harm other potentially transplantable grafts. Several donor pretreatment strategies have provided encouraging results in animal models, but evidence from human studies is sparse, as most clinical evidence is derived from single-center or nonrandomized trials. Furthermore, ethical matters have to be considered especially concerning consent from donors, donor families, and transplant recipients to research in the field of donor treatment. This review provides an overview of clinically proven and promising preclinical strategies of donor treatment to optimize long-term results after kidney transplantation.

Dominant negative (DeltaN) p63alpha induces drug resistance in hepatocellular carcinoma by interference with apoptosis signaling pathways.

p63 belongs to the family of p53-related transcription factors expressing a variety of isoforms. The Trp63 gene has two promoters that drive the expression of two major p63 isoform subfamilies. Isoforms of the TAp63 subfamily show pro-apoptotic activities, whereas members of the N-terminally truncated (DeltaN) p63 subfamily have anti-apoptotic functions. We have previously shown an important role for TAp63alpha in the induction of apoptosis and chemosensitivity of hepatocellular carcinoma (HCC). Here, we investigated the molecular mechanisms accounting for the oncogenic role of DeltaNp63alpha in HCC. DeltaNp63alpha can directly interfere with the transcriptional activation function of the TA (containing the transactivation domain) isoforms of the p53 family and consequently inhibit transactivation of pro-apoptotic target genes. DeltaNp63alpha negatively regulates the genes encoding for the death receptor CD95 and the pro-apoptotic Bcl-2 family member BAX. Thus, DeltaNp63alpha expression in HCC interferes with both the death receptor and the mitochondrial apoptosis activity of the TA isoforms. In addition and of clinical relevance, DeltaNp63alpha inhibits activation of p53 family target genes and apoptosis induced by chemotherapeutic drugs. Chemotherapeutic treatment induces expression of Bax, Bim, Noxa, Puma and Perp; this is antagonized by DeltaNp63alpha. Our data suggest that the DeltaNp63alpha isoform represses apoptosis-related genes of the extrinsic and intrinsic apoptosis signaling pathways, thereby contributing to chemoresistance of HCC.