losartan-potassium and Primary-Graft-Dysfunction

Recent retrospective studies suggest an association of therapy with erythropoiesis-stimulating agents (ESAs) and increased mortality in renal transplant recipients (RTR). Large artery structure and function are significantly impaired in RTR which contributes to their high cardiovascular morbidity and could be altered by erythropoietin. We aimed to examine the influence of ESA therapy on large artery stiffness and endothelial function in RTR.. 63 RTR with chronic allograft dysfunction and renal anemia were randomized to a group receiving darbepoetin alfa (Dar) and a control group (Co). At baseline and after 8 months of treatment (cumulative Dar dose 11.1 µg/kg b.w.) brachial and common carotid artery distensibility coefficients, aortic pulse wave velocity, brachial artery flow-mediated and nitroglycerin-mediated vasodilation were measured as well as the following biomarkers of vascular function: vWF, sVCAM, sICAM, E-selectin, t-PA and PAI-1.. 23 patients in the Dar group and 17 patients in the Co group were available for per-protocol analysis. Hemoglobin increased significantly from 10.9 to 12.6 g/dl after 8 months in the Dar group, whereas it remained stable at 11.3 g/dl in the Co group. Effects on large artery stiffness, endothelial function and biomarkers of vascular function did not differ significantly between the two groups.. Therapy with Dar during 8 months did not significantly impact parameters of large artery stiffness and endothelial function in RTR. These data suggest that therapy with erythropoietin does not deteriorate arterial stiffness and endothelial function in RTR.

Topics: Anemia; Brachial Artery; Darbepoetin alfa; Endothelium, Vascular; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Primary Graft Dysfunction; Risk Factors; Transplantation, Homologous; Treatment Outcome; Vascular Stiffness; Vasodilation

Graft dysfunction of steatotic livers (SL) still remains a major challenge in liver transplantation. Different mechanisms are thought to be involved in the impaired tolerance of SL to ischemia-reperfusion injury. Thus, different pharmacologic strategies may need to be combined to effectively protect SL and to reduce graft dysfunction after transplantation. Therefore, we analyzed the effectiveness of a multidrug donor preconditioning (MDDP) procedure to protect SL from cold ischemia-reperfusion injury.. Liver steatosis was induced by a high-carbohydrate, fat-free diet. A total of 24 Sprague-Dawley rats were divided into 3 groups (n = 8 each), including a control group with nonsteatotic livers (Con), a vehicle-treated SL group (SL-Con), and a SL group undergoing MDDP (SL-MDDP), including pentoxyphylline, glycine, deferoxamine, N-acetylcysteine, erythropoietin, melatonin, and simvastatin. MDDP was applied before liver perfusion with 4°C histidine-tryptophan-ketoglutarate (HTK) solution and organ harvest. After 24 hours of cold storage in HTK, postischemic reperfusion was performed in an isolated liver reperfusion model using 37°C Krebs-Henseleit bicarbonate buffer.. After 60 minutes of reperfusion, SL showed a significant reduction of bile flow as well as a marked increase of liver enzyme levels and apoptotic cell death compared with Con. This was associated with an increased malondialdehyde formation, interleukin-1 production, and leukocytic tissue infiltration. MDDP completely abolished the inflammatory response and was capable of significantly reducing parenchymal dysfunction and injury.. MDDP decreases SL injury after cold storage and reperfusion. The concept of MDDP as a simple and safe preoperative regime, thus may be of interest in clinical use, expanding the donor pool from marginal donors.

Topics: Animals; Antioxidants; Cold Ischemia; Disease Models, Animal; Drug Therapy, Combination; Erythropoietin; Fatty Liver; Female; Glycine Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemic Preconditioning; Liver; Liver Transplantation; Male; Primary Graft Dysfunction; Rats; Rats, Sprague-Dawley; Siderophores; Tissue Donors

Anemia can contribute to chronic allograft injury by limiting oxygen delivery to tissues, particularly in the tubulointerstitium. To determine mechanisms by which erythropoietin (EPO) prevents chronic allograft injury we utilized a rat model of full MHC-mismatched kidney transplantation (Wistar Furth donor and Lewis recipients) with removal of the native kidneys. EPO treatment entirely corrected post-transplant anemia. Control rats developed progressive proteinuria and graft dysfunction, tubulointerstitial damage, inflammatory cell infiltration, and glomerulosclerosis, all prevented by EPO. Normalization of post-transplant hemoglobin levels by blood transfusions, however, had no impact on chronic allograft injury, indicating that EPO-mediated graft protection went beyond the correction of anemia. Compared to syngeneic grafts, control allografts had loss of peritubular capillaries, higher tubular apoptosis, tubular and glomerular oxidative injury, and reduced expression of podocyte nephrin; all prevented by EPO treatment. The effects of EPO were associated with preservation of intragraft expression of angiogenic factors, upregulation of the anti-apoptotic factor p-Akt in tubuli, and increased expression of Bcl-2. Inhibition of p-Akt by Wortmannin partially antagonized the effect of EPO on allograft injury and tubular apoptosis, and prevented EPO-induced Bcl-2 upregulation. Thus non-erythropoietic derivatives of EPO may be useful to prevent chronic renal allograft injury.

Topics: Anemia; Animals; Apoptosis; Biomarkers; Blood Transfusion; Chronic Disease; Erythropoietin; Glomerulonephritis; Hematinics; Hemoglobins; Histocompatibility; Kidney; Kidney Diseases; Kidney Transplantation; Mice; Primary Graft Dysfunction; Proteinuria; Rats; Rats, Inbred Lew; Rats, Inbred WF; Time Factors

Ischemia/reperfusion (I/R) injury is an important cause of renal graft dysfunction. Increases in cold and warm ischemia times lead to a higher risk of early posttransplant complications including delayed graft function and acute rejection. Moreover, prolonged cold ischemia is a predictor of long-term graft loss in kidney transplant patients.. Darbepoetin alfa (DA) and carbamylated nonerythropoietic derivative of erythropoietin (CEPO) protective effects were evaluated in a model of I/R injury after kidney transplantation in both syngeneic and allogeneic combinations. The effects of wortmannin (phosphorylated Akt [p-Akt] inhibitor) administration were also investigated. Serum creatinine was evaluated at 16, 24, 48 hr and at 4 and 7 days posttransplant. Animals were killed 24 hr or 7 days after transplant and kidneys were processed for histological analysis, immunohistochemistry assessment of erythropoietin receptor (EPOR) and β-common chain receptor expression, granulocyte infiltration, nitrotyrosine staining, p-Akt expression, peritubular capillary (PTC) density, apoptosis, antioxidant, and antiapoptotic gene expression.. DA and CEPO significantly reduced serum creatinine, tubular injury, tubular nitrotyrosine staining, and prevented I/R-induced tubular apoptosis, but only when given both to the donor and to the recipient. DA and CEPO cytoprotection was associated with prevention of I/R-induced drop of p-Akt expression in tubuli, and almost complete preservation of capillary density in the tubulointerstitium of the graft. CEPO was more effective than DA in reducing tubular oxidative stress and preserving PTCs.. DA and CEPO when given both to the donor and to the recipient, prevented renal graft dysfunction, tubular oxidative stress, and apoptosis after I/R injury in kidney transplantation. Their cytoprotection was mediated by tubular p-Akt activation and PTC density preservation.

Topics: Androstadienes; Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Cold Temperature; Darbepoetin alfa; Erythropoietin; Graft Survival; Hematinics; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules; Oxidative Stress; Primary Graft Dysfunction; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred Lew; Reperfusion Injury; Tissue Donors; Transplantation, Homologous; Wortmannin