Report of the first international liver transplantation society expert panel consensus conference on renal insufficiency in liver transplantation

No abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64330/1/21877_ftp.pd

Islamisasi di wajo studi kasus : la sangkuru patau (arung matoa wajo ke XII)

vii, 66 hlm,; ilus,; 30 cm

Islamisasi di wajo studi kasus : la sangkuru patau (arung matoa wajo ke XII)

vii, 66 hlm,; ilus,; 30 cm

Optimizing everolimus exposure when combined with calcineurin inhibitors in solid organ transplantation

The mammalian target of rapamycin (mTOR) inhibitor everolimus is a narrow therapeutic index drug for which optimal exposure levels are essential. The consistent pharmacokinetic profile of everolimus allows trough concentration (C0) measurement to be an appropriate and reliable index for therapeutic drug monitoring (TDM). Exposure-response analyses of data from early fixed-dose trials demonstrated that rates of biopsy-proven acute rejection (BPAR) are significantly higher if everolimus C0 declines below 3 ng/mL, an observation confirmed in subsequent concentration-controlled trials. Evidence for the most favorable upper limit is less clear but with reduced-exposure calcineurin inhibitor (CNI) therapy, an upper limit of 8 ng/mL appears to balance efficacy and safety outcomes. The recommended C0 range is 3-8 ng/mL in kidney, liver and heart transplantation patients, based on LC-MS/MS monitoring in whole blood. Randomized clinical trials based on this target range have demonstrated rates of BPAR comparable to a regimen of mycophenolic acid with standard-exposure CNI. Everolimus exhibits moderate intrapatient pharmacokinetic variability, and it can be challenging to maintain stable concentrations within target range in some individuals. Many factors can influence everolimus exposure for a given dose, including hepatic function, activity of the drug efflux pump P-glycoprotein, the rate of everolimus metabolism, drug-drug interactions (predominantly with CYP3A4 and P-glycoprotein inhibitors, including cyclosporine), intake of fatty food, and patient adherence to the prescribed regimen. Trough concentration levels should be monitored 4-5days after the first dose and after any change in everolimus dose, with additional monitoring in response to any change in concomitant medication or other clinical circumstances which could alter everolimus exposure. Although LC-MS/MS is the gold standard for everolimus monitoring, various immunoassays are widely used due to their relative simplicity and lower cost, and results can show considerable discrepancies with reference methods due to issues such as interassay variability and cross-reactivity. Method standardization will be important in the future to improve the consistency and reproducibility of results between centers. In conclusion, based on an extensive program of clinical trials, the optimal exposure range for everolimus in combination with reduced-exposure CNI therapy has been established and can be achieved in most transplant recipients through careful, planned TDM

Angiotensin II regulation of vascular endothelial growth factor and receptors Flt-1 and KDR/Flk-1 in cyclosporine nephrotoxicity

Angiotensin II regulation of vascular endothelial growth factor and receptors Flt-1 and KDR/Flk-1 in cyclosporine nephrotoxicity.BackgroundVascular endothelial growth factor (VEGF) is involved in angiogenesis, wound healing and inflammation. VEGF exerts its effect via the tyrosine kinase receptors Flt-1 and KDR/Flk-1. We have previously shown that VEGF is up-regulated in a chronic cyclosporine (CsA) nephrotoxicity model. Our current study examined the role of angiotensin II (Ang II) blockade with enalapril (E) or losartan (L) on VEGF in this model.MethodsPair-fed salt-depleted rats were administered vehicle, CsA, CsA + nilvadipine, CsA + hydralazine/hydrochlorthiazide (HCTZ), CsA + E or CsA + L, and were sacrificed at 7 or 28 days. Physiologic and histologic changes were studied in addition to the mRNA expression of VEGF and its receptors Flt-1 and KDR/Flk-1 by Northern blot, and the protein expression of VEGF by Western blot.ResultsWhile all groups achieved similar blood pressures and creatinine clearances, the amelioration in nephrotoxicity was observed only with Ang II blockade. VEGF mRNA and protein expressions increased with CsA and became significantly reduced with Ang II blockade. Flt-1 expression was similar in all groups; it decreased early and remained low. On the other hand, KDR/Flk-1 mRNA expression was higher at seven days in all groups, except in the +E and +L groups where it was significantly lower, and then became further down-regulated at 28 days.ConclusionsThe increased VEGF expression in chronic CsA nephrotoxicity seems to be related to up-regulation of Ang II. In addition, VEGF probably exerted its effect via the KDR/Flk-1 receptor. The actions of VEGF in this model remain speculative, but may be related to its effect on macrophage infiltration or matrix deposition

A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy

OBJECTIVE: To compare outcomes with early corticosteroid withdrawal (CSWD) and chronic low dose corticosteroid therapy (CCS). SUMMARY BACKGROUND DATA: Final, 5-year results from the first randomized, double-blind, placebo-controlled trial of early CSWD (at 7 days posttransplant) are presented. METHODS: Adult recipients of deceased and living donor kidney transplants without delayed graft function were randomized to receive prednisone (5 mg/d after 6 months posttransplant) or CSWD. Blinding was maintained for 5 years. This clinical trial is registered at www.clinicaltrials.gov (NCT00650468). RESULTS: Results in 386 patients CSWD (n = 191), CCS (n = 195) are presented (CSWD; CCS). No differences were observed at 5 years in the proportion of patients experiencing: primary end point (composite of death, graft loss, or moderate/severe acute rejection) (30/191 (15.7%); 28/195 (14.4%)), patient death (11/191(5.8%);13/195 (6.7%)), death-censored graft loss (11/191 (5.8%); 7/195(3.6%)), biopsy confirmed acute rejection (BCAR) (34/191 (17.8%); 21/195 (10.8%), P = 0.058), moderate/severe acute rejection (15/191 (7.9%); 12/195 (6.2%)). Kaplan Meier analyses of the primary end point and its components also showed no differences; but BCAR was higher with CSWD (P = 0.04). Increased BCAR episodes were primarily corticosteroid-sensitive Banff 1A rejections: the incidence of antibody-treated BCAR was similar between groups (11/191 (5.8%); 13/195 (6.7%)). No differences in renal function were observed at 5 years: mean serum creatinine (1.5 +/- 0.6; 1.5 +/- 0.7 mg/dL), or Cockroft Gault calculated creatinine clearance (58.6 +/- 19.7; 59.8 +/- 20.5 mL/min). CSWD was associated with improved serum triglycerides (evaluated by mean and median change from baseline) at all time points (except at 5 years measured by mean change). Weight change also demonstrated changes favoring CSWD (median change from baseline at 5 years: 5.1 vs. 7.7 kg, P = 0.05). New onset diabetes after transplant (NODAT) was similar with respect to proportions who required treatment (23/107 (21.5%)); 18/86 (20.9%); however, fewer CSWD patients required insulin for NODAT at 5 years (4/107 (3.7%)); 10/86 (11.6%), P = 0.049). Changes in HgA1c values (from baseline) were lower in CSWD patients at all time points except 4 years. CONCLUSIONS: Early CSWD, compared with CCS, is associated with an increase in BCAR primarily because of mild, Banff 1A, steroid-sensitive rejection, yet provides similar long-term renal allograft survival and function. CSWD provides improvements in cardiovascular risk factors (triglycerides, NODAT requiring insulin, weight gain). Tacrolimus/MMF/antibody induction therapy allows early CSWD with results comparable to long-term low dose (5 mg/d) prednisone therapy

Randomized Trial of Everolimus-Facilitated Calcineurin Inhibitor Minimization Over 24 Months in Renal Transplantation

TRANSPLANTATION957933-942TRPLAUnited State