Jacques Malaise

The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients.

Cyclosporine and tacrolimus are immunosuppressive drugs largely used in renal transplantation. They are characterized by a wide inter-individual variability in their pharmacokinetics with a potential impact on their therapeutic efficacy or induced toxicity. CYP3A5 and P-glycoprotein appear as important determinants of the metabolism of these drugs. The objective of this study was to investigate the effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood concentrations in stable transplant patients. Stable renal transplant recipients receiving cyclosporine (n = 50) or tacrolimus (n = 50) were genotyped for CYP3A5*3 and *6, and MDR1 C1236T, G2677T/A and C3435T. Dose-adjusted trough blood levels (ng/ml per mg/kg body weight) as well as doses (mg/kg body weight) required to achieve target blood concentrations were compared among patients according to allelic status for CYP3A5 and MDR1. Dose-adjusted trough concentrations were three-fold and 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1/*3 patients for tacrolimus and cyclosporine, respectively. In the case of tacrolimus, the difference was even more striking when considering CYP3A5*1/*1 patients showing dose-adjusted trough concentrations 5.8-fold lower than CYP3A5*3/*3 patients. For both drugs, no association was found between trough blood concentrations or dose requirement and MDR1 genotype. Multiple regression analyses showed that CYP3A5*1/*3 polymorphism explained up to 45% of the variability in dose requirement in relation to tacrolimus use. Given the importance of rapidly achieving target blood concentrations after transplantation, further prospective studies should consider the immediate post-graft period and assess the influence of this specific polymorphism. Beside non-genetic factors (e.g. steroids dosing, drugs interactions), CYP3A5 pharmacogenetic testing performed just before transplantation could contribute to a better individualization of immunosuppressive therapy.

CYP3A5 and ABCB1 Polymorphisms and Tacrolimus Pharmacokinetics in Renal Transplant Candidates: Guidelines from an Experimental Study

Genetic polymorphisms in biotransformation enzyme CYP3A5 (6986G > A, CYP3A5*3; 14690A > G, CYP3A5*6) and drug transporter ABCB1 (1236C > T; 2677G > T/A; 3435C > T) are known to influence tacrolimus (Tac) dose requirements and trough blood levels in stable transplant patients. In a group of 19 volunteers selected with relevant genotypes among a list of 221 adult renal transplant candidates, we evaluated whether consideration of CYP3A5 and ABCB1 genetic polymorphisms could explain the interindividual variability in Tac pharmacokinetics after the first administration of a standard dose (0.1 mg/kg body weight twice a day). Lower area under the time versus blood concentration curves (AUC) or lower trough concentrations were observed among CYP3A5 expressors (n = 9) than among nonexpressors (n = 10) using two different analytical methods for Tac determination (liquid chromatography with tandem mass spectrometry (LC‐MS/MS) and immunoassay). The median AUC0−∞ was 2.6‐ and 2.1‐fold higher in nonexpressors for LC‐MS/MS and immunologic methods, respectively. No difference was observed in Tac pharmacokinetic parameters in relation to ABCB1 polymorphisms. In conclusion, our study confirms the very significant effect of CYP3A5 polymorphism early after the first administration of Tac. It also provides a strong argument for a doubling of the loading dose in patients early identified a priori on the transplantation list as possessing at least one CYP3A5*1 allele.

Sirolimus and tacrolimus trough concentrations and dose requirements after kidney transplantation in relation to CYP3A5 and MDR1 polymorphisms and steroids

Background. CYP3A5 and MDR1 polymorphisms have been shown to influence tacrolimus blood concentrations and dose requirements. The aim is to determine whether these polymorphisms also affect sirolimus trough concentrations and dose requirements after kidney transplantation. Methods. Eighty-five renal transplant recipients receiving sirolimus were included. Twenty-four were treated with a combined sirolimus-tacrolimus regimen. Eighty-one patients received steroids. Sirolimus and tacrolimus were adjusted to a target therapeutic window. CYP3A5 (intron 3) and MDR1 (exons 12, 21, 26) genotypes were correlated to the adjusted trough concentrations and dose requirements for both sirolimus and tacrolimus. Results. There were no significant correlation between adjusted sirolimus trough concentrations or dose requirements and genetic polymorphisms. In a multiple regression model, adjusted-prednisone dose was involved with a positive or negative effect when considering sirolimus dose requirements or adjusted concentrations, respectively. In the subgroup of patients treated by tacrolimus and sirolimus, adjusted tacrolimus doses were higher in patients carrying at least one CYP3A5 *1 allele (median 0.083 vs. 0.035 mg/kg for CYP3A5*3/*3 patients, P<0.05). Adjusted-prednisolone dose and CYP3A5 polymorphism explained up to 61% of the variability in tacrolimus dose requirements. Conclusions. Unlike tacrolimus, sirolimus adjusted trough concentrations and dose requirements seem not affected by CYP3A5 and MDR1 polymorphisms. Adjusted-prednisone dose has a significant impact on tacrolimus and sirolimus dose requirements.

Esophageal Replacement - Gastric Tube Or Whole Stomach

BACKGROUND The stomach can be used either in its entirely or as a greater curvature tube for esophageal replacement. METHODS The study compares the gastric tube (group A; n = 112) to the whole stomach whose lesser curvature is denuded (group B; n = 100) in terms of technical complication and alimentary comfort. The clinical results are substantiated by assessment of the eating performance of patients and control subjects at a test meal, measurement of the gastric dimensions before and after both tailoring procedures, and intraarterial staining of the gastric wall. RESULTS Major differences between the two groups are cervical anastomosis stenoses (22.3% versus 6% [A versus B]; p = 0.008), fistulas (7.9% versus 1%; p = 0.0209), number of meals and snacks per day (4.6 versus 4; p = 0.0275), sensation of early fullness at meals (52.4% versus 17.8%; p < 0.0001), ratings given to the long-term alimentary comfort (presymptomatic condition = 10 points) (7.6 versus 8.8 out of 10 on average; p < 0.0001), and calories consumed in 1 minute at a test meal (59% [p < 0.05] versus 77% of those consumed by control subjects). The volume of the stomach is reduced by a range of 21.4% to 47.2% after tubulization (group A) whereas it increases by a range of 4.9% to 17.4% after denudation of the lesser curve (group B). Intraarterial staining of the gastric wall reveals the poor vascularity of the upper-most segment of the greater curve. CONCLUSION Slight increase of the gastric capacity and maintenance of the submucosal vascular network account for the better results achieved with the whole stomach.

Efficacy and safety of tacrolimus compared with cyclosporine microemulsion in primary simultaneous pancreas-kidney transplantation: 1-year results of a large multicenter trial

Background. Simultaneous pancreas-kidney transplantation (SPK) transplantation has become an accepted therapy for type 1 diabetic patients with end-stage renal disease. This open-label, multicenter study compared the efficacy and safety of tacrolimus with the microemulsion (ME) formulation of cyclosporine in a clinical setting. The 1-year results are reported here. Methods. The study was conducted in 10 European centers and one center in Israel. One hundred three patients were randomly assigned to tacrolimus and 102 to cyclosporine-ME. All patients received concomitant rabbit anti–T-cell globulin induction therapy, mycophenolate mofetil (MMF), and short-term cortico-steroids. The initial daily oral doses were 0.2 mg/kg for tacrolimus, 7 mg/kg for cyclosporine-ME, and 2 to 3 g for MMF. Results. The 1-year incidence of biopsy-proven kidney or pancreas acute rejection was lower with tacrolimus (27.2%) than with cyclosporine-ME (38.2%; P = 0.09). Pancreas graft survival at 1 year was 91.3% with tacrolimus and 74.5% with cyclosporine-ME (P <0.0005). Renal graft survival was similar in the two study groups. There were no significant treatment-related differences in pancreatic or renal graft function. In total, 34 patients switched treatment from cyclosporine-ME to tacrolimus, but only 6 patients receiving tacrolimus required alternative therapy. Mean doses of MMF at 1 year were also lower in the tacrolimus group (1.36 vs. 1.67 g/day; P = 0.007). Conclusion. These findings support the use of tacrolimus therapy for uremic patients with type 1 diabetes who are undergoing SPK transplantation.

Gadolinium dimeglumine: an alternative contrast agent for digital subtraction angiography.

Abstract. The aim of this study was to evaluate gadolinium diethylenetriaminepenta-acetic acid (Gd-DTPA) as an alternative contrast agent for digital subtraction angiography (DSA) in patients with renal insufficiency or previous anaphylactic reaction to iodinated contrast agents. We performed 34 DSAs in 31 patients by use of the commercially available 0.5-M Gd-DTPA solution (Magnevist, Schering, Berlin, Germany). The contrast material was power- or hand-injected at the same rate as iodinated contrast material, without exceeding a total amount of 0.4 mmol/kg body weight. In 18 studies Gd-DTPA was the sole contrast agent. In 9 cases gadolinium injections were combined with carbon dioxide. Restricted non-ionic contrast medium injections were administered to complete the examinations in 7 cases and for comparative purposes in 1 case. Cerebral and carotid arteries, one superior limb, abdominal aorta, renal arteries, renal transplants, iliac arteries and inferior limbs were imaged, and ten endovascular interventional procedures, including three transjugular intrahepatic percutaneous stent shunts, were performed. No side effects were observed. Diagnostic angiographic images were obtained in all cases except in 5 of the 8 distal run-off studies. Gadolinium-based contrast can produce clinically useful angiograms in patients with a contra-indication to iodine who must undergo angiography.

The influence of genetic polymorphisms of cytochrome P450 3A5 and ABCB1 on starting dose- and weight-standardized tacrolimus trough concentrations after kidney transplantation in relation to renal function.

Abstract Background: Cytochrome P450 3A5 (CYP3A5) and ABCB1 polymorphisms have been shown to influence tacrolimus (Tc) blood concentrations in the stable phase after organ transplantation. We hypothesized that Tc pharmacokinetics may be affected by genetic mutations subsequent to starting doses. Methods: We retrospectively analyzed data from a cohort of 59 kidney transplant recipients, in whom CYP3A5 (intron 3) and ABCB1 (exons 12, 21 and 26) genotypes were correlated to dose- and weight-standardized Tc trough concentrations obtained after initial Tc doses. Renal function, expressed as glomerular filtration rate (GFR) (MDRD equation), on days 7 and 14 after transplantation was evaluated and its relationship with Tc concentrations was analyzed. Results: Dose- and weight-standardized Tc trough concentrations were lower in patients carrying the CYP3A5 *1 allele (p<0.01). There was no statistically significant association with ABCB1 polymorphisms. In a multivariate analysis, both the presence of at least one CYP3A5 *1 allele (p=0.006) and age at the time of transplantation (p=0.010) were significant independent variables affecting Tc trough blood concentrations standardized to the first dosages (model r2=0.23). GFR was not affected by Tc concentrations. Conclusions: Prospective trials are needed to prove that a genetic approach to Tc pharmacokinetics and its related side effects during the early period after grafting may improve patient outcome. Clin Chem Lab Med 2006;44:1192–8.

Biotransformation enzymes and drug transporters pharmacogenetics in relation to immunosuppressive drugs: impact on pharmacokinetics and clinical outcome

Immunosuppressive drugs commonly used after organ transplantation to prevent acute rejection including tacrolimus, cyclosporine, sirolimus, and mycophenolic acid are characterized by a narrow therapeutic index and broad interindividual variability in their pharmacokinetics. Adequate immunosuppression aims to reach an optimal benefit–risk ratio. Therapeutic drug monitoring represents a crucial step in routine practice to maintain blood concentrations within the target window, because the bioavailability of these drugs depends on their absorption, distribution, biotransformation, and elimination. Single nucleotide polymorphisms (SNPs) in genes encoding biotransformation enzymes (CYP3A) and drug transporters (ABCB1) have opened up a promising way for the selection of individual dosages. The relationship of these SNPs with immunosuppressive drug pharmacokinetics was extensively studied after kidney, liver, heart, and lung transplantations. Patient susceptibility to nephrotoxicity in the long term was also reported in relation to some SNPs, which could allow effective assessment of individual risk and selection of treatment according to patient parameters. Further studies are needed to provide evidence that a genetic analysis combined with therapeutic drug monitoring has the potential to optimize drug use after transplantation.

Therapeutic monitoring of mycophenolate mofetil in organ transplant recipients: is it necessary?

Adequate immunosuppression minimising the risk of organ rejection with acceptable tolerability of the used drugs is a crucial step in organ transplantation. The primary goal is to maintain a consistent time-dependent target concentration by tailoring individual dosage leading to the best efficacy and tolerability combination. The use of therapeutic drug monitoring (TDM) to optimise immunosuppressive therapy is routinely employed for maintenance drugs such as cyclosporin and tacrolimus. The question whether therapeutic monitoring of mycophenolic acid (MPA) in organ transplant recipients treated with mycophenolate mofetil is necessary is not definitely answered. The correlation of mycophenolic acid pharmacokinetic parameters with efficacy and toxicity makes the therapeutic monitoring of this drug promising. However, further studies are mandatory to draw the best guidelines in order to achieve higher levels of evidence that MPA-TDM may improve patient outcome.

Liver Procurement Without In Situ Portal Perfusion: A Safe Procedure for More Flexible Multiple Organ Harvesting

The outcome after liver transplantation when grafts were retrieved from the donor by the classical aortic and portal cooling (APC) method was compared with the outcome when exclusively aortic in situ perfusion (AC) was used. Retrospectively, 163 donor hepatectomies performed over a 20-month period were reviewed to analyze overall graft (APC n = 78, AC n = 85) and patient outcome. The global graft and patient survival rates were not significantly lower in the APC group, except for 3-month graft survival (APC 72%, AC 87%; P = 0.015). However, this could be unrelated to the technique. In a subgroup of 140 cases (APC n = 64, AC n = 76), a more detailed analysis was performed. Populations of donors and recipients were similar. The graft injury and the immediate graft function were not significantly different between both groups. A multivariate analysis shows that low donor weight (P = 0.007), donor hypernatremia (P = 0.014), and in situ portal perfusion (P = 0.045) were significant determinants of a higher postoperative peak of glutamic pyruvic transaminase. In summary, in this series, routine human liver procurement using exclusive aortic perfusion seemed to be at least as safe as using a combined aortic and portal perfusion technique. This simplified method may also represent some advantages for combined pancreas and intestinal harvesting in the future.