Activity and mRNA expression levels of selected cytochromes P450 in various sections of the human small intestine.

AIMS: To characterize mRNA expression levels (17 cytochromes P450) and activity (9 isoforms) of major cytochromes P450 expressed throughout the human small intestine. METHODS: Tissue samples were obtained from 9 deceased subjects and intestinal sections (n = 10) were isolated for each subject. Relative mRNA expression levels were determined using quantitative real-time PCR. Intestinal microsomes were prepared from 5 subsections: duodenum, jejunum (proximal and mid-jejunum) and ileum (proximal and mid-ileum) regions. In vitro incubations were performed with various cytochrome P450 probe substrates: bupropion (CYP2B6), repaglinide (CYP2C8), tolbutamide (CYP2C9), S-mephenytoin (CYP2C19), bufuralol (CYP2D6), chlorzoxazone (CYP2E1), ebastine (CYP2J2), midazolam (CYP3A4/5) and lauric acid (CYP4A11). Metabolite formation was assessed using validated liquid chromatography-tandem mass spectrometry assays. RESULTS: Cytochrome P450 mRNA levels ranked as follows: CYP3A4 > CYP2C9 > CYP2C19 > CYP2J2 > CYP4F2. Cytochrome P450 mRNA transcripts showed different patterns in their relative expression from 1 region to the other but CYP3A4, CYP2C9, CYP2C19 and CYP2J2 displayed the highest levels of mRNA expression (>5%) in all intestinal sections. Cytochrome P450 activities were greater in proximal part of the small intestine with the jejunum showing the greatest drug-metabolism activity. Spearman's correlation analyses indicated that cytochrome P450 mRNA expressions and corresponding cytochrome P450 activities in the human intestine were moderately associated for CYP2C19, CYP2D6 and CYP4A11 (rs  = 0.44-0.56). CONCLUSIONS: Our study provides new and additional information on the expression and activities of selected cytochromes P450 in various sections of the human small intestine.

Perioperative practices in thyroid surgery: An international survey.

BACKGROUND: Perioperative practices in thyroid surgery vary from one specialty, institution, or country to the next. We evaluated the preoperative, intraoperative, and postoperative practices of thyroid surgeons focusing on preoperative ultrasound, vocal cord evaluation, wound drains, and hospitalization duration, among others. METHODS: A survey was sent to 7 different otolaryngology and endocrine/general surgery associations. RESULTS: There were 965 respondents from 52 countries. Surgeon-performed ultrasound is practiced by more than one third of respondents. Otolaryngologists perform preoperative and postoperative vocal cord evaluation more often than endocrine/general surgeons (p < .001). Sixty percent of respondents either never place drains or place drains <50% of the time in thyroid lobectomies (43% for total thyroidectomies). Outpatient thyroid surgery is most frequently performed by surgeons in the United States (63%). CONCLUSION: This epidemiologic study is the first global thyroid survey of its kind and clearly demonstrates the variability and evolving trends in thyroid surgery. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1296-1305, 2017.

First Canadian Case Report of Kidney Transplantation From an HIV-Positive Donor to an HIV-Positive Recipient.

RATIONALE: Kidney transplantation has become standard of care for carefully selected patients living with human immunodeficiency virus (HIV) and end-stage renal disease (ESRD) in the highly active antiretroviral therapy (HAART) era. American and European prospective cohort studies have reported similar patient and graft survival compared with HIV-negative kidney transplant recipients. Despite an increased rate of acute rejection, partially due to drug interactions, HIV immunovirologic parameter generally remains under control during immunosuppression. A few cases of kidney transplantation between HIV-infected patients were done in South Africa and showed favorable results. No cases of kidney transplantation from an HIV-positive donor in Canada have previously been reported. PRESENTING CONCERNS OF THE PATIENT: A 60-year-old Canadian man with HIV infection presented in 2007 with symptoms compatible with acute renal failure secondary to IgA nephropathy. Chronic kidney disease resulted after the acute episode. DIAGNOSES: Hemodialysis was started in 2012. The patient was referred for a kidney transplantation evaluation. INTERVENTIONS: The patient underwent kidney transplantation from an HIV-positive donor in January 2016. The recipient's antiretroviral regimen consisted of abacavir, lamivudine, and dolutegravir. No drug interactions have been reported between these antiretrovirals and the maintenance immunosuppressive regimen used. OUTCOMES: The outcome at 7 months post transplantation was excellent, with good graft function and adequate control of HIV replication, in the absence of opportunistic infections at a time when immunosuppression is at its highest intensity. No acute rejection was reported. An episode of bacteremic graft pyelonephritis due to Enterococcus faecalis was successfully treated after transplantation. NOVEL FINDING: With careful selection of patient, kidney transplantation between HIV-infected patients is a viable option. The use of antiretroviral drugs free of interactions simplified the dosing and management of the immunosuppressive drugs.

RAISONNEMENT: La transplantation rénale fait désormais partie des soins prodigués spécifiquement aux patients porteurs du VIH (virus de l'immunodéficience humaine) et présentant une insuffisance rénale terminale (IRT) à l'ère de la thérapie antirétrovirale. Des études de cohorte prospectives américaines et européennes ont rapporté une survie semblable du greffon et du receveur de la greffe chez ces patients, lorsque comparés aux receveurs d'une greffe non porteurs du VIH. En dépit d'un taux plus élevé de rejet aigu, attribuable en partie aux interactions médicamenteuses, les paramètres immunovirologiques du VIH sont demeurés stables sous traitement par les immunosuppresseurs. Quelques cas de transplantations rénales entre patients séropositifs ont été effectués en Afrique du Sud et ont montré des résultats favorables. À ce jour, on ne rapportait aucun cas de transplantation rénale provenant d'un donneur porteur du VIH au Canada. PRÉSENTATION DU CAS D'UN PATIENT: En 2007, un Canadien de 60 ans porteur du VIH s'est présenté avec des symptômes compatibles à l'insuffisance rénale aigüe secondaire à une néphropathie à IgA. Cet épisode aigu a par la suite évolué vers l'insuffisance rénale chronique. DIAGNOSTIC: L'insuffisance rénale terminale a été diagnostiquée en 2012. Dès lors, un traitement par hémodialyse a été initié et le patient a été recommandé pour une évaluation en vue d'une transplantation. INTERVENTIONS: Le patient a subi une greffe avec un rein provenant d'un donneur séropositif en janvier 2016. Le traitement antirétroviral du receveur était constitué d'abacavir, de lamivudine et de dolutégravir. Aucune interaction médicamenteuse n'a été rapportée entre ces antirétroviraux et le traitement immunosuppresseur de maintien administré. RÉSULTATS: En plus d'une bonne reprise de la fonction du greffon et du contrôle adéquat de la réplication du VIH, on a constaté la réussite de l'intervention lors du suivi du patient effectué 7 mois après la transplantation par l'absence d'infections opportunistes à un moment où l'immunosuppression est à son maximum. Aucun rejet aigu n'a été rapporté par contre, un épisode de pyélonéphrite bactérienne du greffon, attribuable à Enterococcus faecalis, est survenu à la suite de la transplantation, mais l'infection a été traitée avec succès. OBSERVATIONS NOUVELLES: On a constaté que la sélection rigoureuse des patients rendait possible la transplantation rénale entre patients porteurs du VIH. De plus, l'utilisation d'antirétroviraux qui ne causent aucune interaction médicamenteuse a simplifié l'ajustement de la posologie des immunosuppresseurs administrés. CAS DISCUTÉ: Nous rapportons le cas d'un Canadien de 60 ans porteur du VIH et ayant subi une greffe de rein provenant d'un donneur lui aussi séropositif. Le traitement antirétroviral du receveur était composé d'abacavir, de lamivudine et de dolutégravir. Aucune interaction médicamenteuse n'a été rapportée entre les antirétroviraux et le traitement immunosuppresseur de maintien. Sept mois après l'intervention, le patient se portait bien, comme en fait foi un taux de créatinine sérique de 155 µmol/L mesuré lors de la plus récente visite de suivi. La charge virale du patient (quantité d'ARN du VIH dans le sang) s'est avérée indétectable et le compte des lymphocytes T CD4 est demeuré au-dessus de 300 cellules/µl pendant toute la période de suivi. Le patient n'a présenté aucun signe indiquant la présence d'une maladie associée au SIDA, ni d'un rejet aigu du greffon. Enfin, un épisode de pyélonéphrite bactérienne du greffon, attribuable à Enterococcus faecalis, est survenu après la transplantation, mais l'infection a été traitée avec succès. CONCLUSIONS: Nous rapportons la première transplantation de rein réalisée au Canada entre un donneur séropositif et un receveur, lui aussi porteur du VIH. L'évolution du patient après l'intervention s'est avérée excellente, on a constaté une bonne reprise de la fonction du greffon et un contrôle adéquat de la réplication du VIH, une réussite confirmée par l'absence d'infections opportunistes à un moment où l'immunosuppression est à son maximum. De plus, l'utilisation d'antirétroviraux qui ne causent aucune interaction médicamenteuse a simplifié l'ajustement de la posologie des immunosuppresseurs administrés. DÉCOUVERTE: La sélection rigoureuse des patients rend possible la transplantation rénale entre patients séropositifs atteints d'IRT et donneurs eux aussi porteurs du VIH.

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.

Immunological monitoring after organ transplantation: potential role of soluble CD30 blood level measurement.

Analysing the relevance of soluble CD30 (sCD30) in the bloodstream before and after transplantation may be important for the monitoring of transplant recipients. In this study, 27 patients (15 pediatric liver and 12 adult kidney graft recipients) were investigated. In the liver graft group, the patients who developed acute rejection during the first month (n=9) had a slightly higher sCD30 value on pre-transplantation baseline (day 0) and post-transplantation day 7, when compared to patients with normal graft function (n=6) (day 0: 102(1.6) U/ml versus 118(1.5) U/ml, p=0.52) and (day 7: 69(1.5) U/ml versus 83(1.6) U/ml, p=0.47). Increased serum sCD30 was shown to correlate with increased interleukin-10 circulating levels between day 0 and day 7 (r=0.53; p=0.04), whereas, no correlation could be evidenced between interferon-gamma (IFN-gamma) and sCD30 (r=0.02; p=0.47). Similarly, in the kidney transplantation group, no significant difference was found in sCD30 levels at day 0 in both groups with graft rejection or normal graft function (n=6) (85(1.3) U/ml versus 77(1.6) U/ml, p=0.66), but sCD30 decreased significantly at day 7 post-transplantation from baseline value in the rejection group (n=6) (77(1.6) versus 35(1.4); p=0.02). We conclude that increased serum sCD30 was correlated with increased IL-10 (interleukin-10) circulating levels, but not with IFN-gamma levels in the post-transplantation period. Neither pre-transplantation sCD30 nor sCD30 at day 7 post-transplantation could be correlated with acute rejection in liver graft recipient. The monitoring of sCD30 might constitute a tool to assess the risk of acute rejection in renal transplant but did not appear as a valuable mean for early immunological monitoring in the small group of liver allograft recipients patients analysed in this study.

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.

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.

Solitary pancreas transplantation for life-threatening allergy to human insulin.

We report on a 30-year-old man, with type 1 diabetes mellitus, who developed generalized allergy to insulin consisting of several bouts of tremor, tachycardia, breathlessness and syncope. Strong positive reactions to protamine and metacresol were demonstrated by skin-prick testing. Symptoms persisted despite the use of antihistamine therapy, Actrapid HM Paraben and Monotard (insulin without protamine and metacresol) and immunosuppression (tacrolimus). He underwent a cadaver pancreas transplantation with portal-enteric drainage in June 2003. Following the antithymocyte globulin induction, immunosuppression consisted in tacrolimus and sirolimus without steroids. The patient subsequently reported a complete resolution of his symptoms and excellent glycaemic control. Thirteen months after transplantation, the patient developed oral ulcerations and severe leucopoenia initially attributed to sirolimus, which was subsequently stopped. A hyperglycaemic episode following corticosteroid therapy for acute rejection therapy required the reintroduction of insulin. Allergic manifestations reappeared promptly. Currently, 2 years after transplantation, the patient is euglycaemic without insulin (glycated haemoglobin 5.8%) and he is free of allergic reactions.

Axillary lymph node metastasis in recurrence of papillary thyroid carcinoma: a case report.

Papillary thyroid cancer usually metastasizes to regional lymph nodes and to distant sites such as lungs and bones. We report a case of axillary lymph node metastasis as a result of recurrence of papillary carcinoma in a 62-year-old woman with papillary thyroid cancer extending locally beyond the thyroid capsule. Six years after initial surgical treatment, a lymph node metastasis in the left axillary region was diagnosed with positron tomography. To our knowledge, only one previous case of confirmed axillary metastasis of thyroid cancer has ever been reported. These two cases provide some evidence that thyroid carcinoma may exceptionally spread to axillary lymph nodes. Hypotheses that may account for such unusual localization include hematogenous dissemination or retrograde dissemination to regional lymphatic channels. Thus, when recurrence of thyroid carcinoma is considered, careful clinical examination of the axilla is recommended. Furthermore, thyroid carcinoma must be considered in the differential diagnosis of an axillary mass, especially when breast cancer is ruled out.

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.

Rejection after simultaneous pancreas-kidney transplantation.

BACKGROUND: Simultaneous pancreas-kidney (SPK) transplantation is an accepted therapy for type 1 diabetic patients with end-stage renal disease. This study analyses the occurrence of rejection episodes in patients undergoing SPK. METHODS: The study population was obtained from 205 patients enrolled in the Euro-SPK 001 study and randomized to receive tacrolimus- (n = 103) or cyclosporin microemulsion (ME)-based (n = 102) immunosuppressive therapy. All patients received concomitant antibody induction therapy, mycophenolate mofetil and short-term corticosteroids. RESULTS: After 3 years of follow-up, rejection episodes occurred in 41 patients receiving tacrolimus and in 51 patients receiving cyclosporin-ME. The majority of first rejection episodes in both groups occurred during the first 6 months (93 and 90%, respectively) and in most cases were treated with corticosteroids alone (88 vs 90%). Actuarial rejection-free kidney and/or pancreas graft survival was similar for tacrolimus (54%) and cyclosporin-ME (44%). Human leukocyte antigen (HLA) compatibility (P = 0.003) and graft vessel extension (P = 0.000001) had a significant influence on rejection-free graft survival. Also, rejection influenced pancreas graft survival (P = 0.01), and pancreas graft loss due to rejection influenced patient survival (P = 0.02). In the intent-to-treat analysis of early rejection, significantly fewer tacrolimus- than cyclosporin-ME-treated patients had (i) more than one rejection episode (11 out of 40 vs 24 out of 47; P = 0.03); (ii) first moderate to severe rejection (one out of 40 vs 12 out of 47; P = 0.004); and (iii) refractory rejection (two out of 40 vs 10 out of 47; P = 0.03). Pancreas survival was lower in late rejectors (53%) than non-rejectors (86%; P = 0.002). Also, serum creatinine was highest in late rejectors. CONCLUSION: Tacrolimus-based immunosuppressive therapy demonstrates significant advantages over cyclosporin-ME in terms of the severity of acute rejection in SPK transplant patients.

Metabolic results 3 years after simultaneous pancreas-kidney transplantation.

BACKGROUND: Simultaneous pancreas-kidney (SPK) transplantation has become accepted therapy for patients with type 1 diabetes and end-stage renal disease. This 3-year study compared the metabolic effects of tacrolimus- and cyclosporin microemulsion (ME)-based immunosuppressive therapy in this clinical setting. METHODS: The study population comprised the 205 patients enrolled in the Euro-SPK 001 study. Glucose metabolism parameters [fasting blood glucose, fasting C-peptide and glycated haemoglobin (HbA1c)], blood lipids (total cholesterol and triglycerides) and pancreatic enzymes (lipase and amylase) were monitored at regular intervals during the study. Blood pressure was also carefully monitored and compared with target levels for diabetic patients. RESULTS: Fasting C-peptide and HbA1c levels were within the normal ranges in the two treatment groups throughout the 3 years. Fasting blood glucose was higher during the first 2 months post-transplant in the tacrolimus group than in the cyclosporin-ME group, but no differences were seen thereafter. From month 2 post-transplant, mean levels of total cholesterol were significantly lower among patients receiving tacrolimus than among those in the cyclosporin-ME group. In addition, patients receiving cyclosporin-ME showed serological features of mild pancreatitis, with elevated blood amylase and lipase levels during the first 6 months post-transplant. The two regimens were comparable with respect to hypertension. CONCLUSIONS: Except for lipid profiles, no major differences in metabolic effects or blood pressure control were observed over the 3 years in SPK transplant patients receiving immunosuppression based on tacrolimus or cyclosporin-ME. In view of the potential risk of hypertension, antihypertensive strategies should be implemented for all patients.

Cytomegalovirus: occurrence, severity, and effect on graft survival in simultaneous pancreas-kidney transplantation.

BACKGROUND: This analysis of the Euro-SPK 001 study examined the occurrence and effect of cytomegalovirus (CMV) infection during the first 3 years after simultaneous pancreas-kidney (SPK) transplantation. METHODS: In this multicentre study, 205 SPK transplant patients were randomized to immunosuppressive treatment with tacrolimus (n = 103) or cyclosporin microemulsion [(ME), n = 102]. All patients received antibody induction therapy, mycophenolate mofetil and short-term corticosteroids. The choice of CMV prophylaxis and treatment was at the discretion of each investigator. RESULTS: The overall incidence of CMV infection was 34%, with equal distribution in the tacrolimus and cyclosporin-ME groups. Fewer CMV infections occurred with ganciclovir (22%) than aciclovir (43% P = 0.007) or no prophylaxis (42%, P = 0.008). The rates of CMV infection according to donor and recipient CMV serological status were: D-/R- 11%; D-/R+ (40%, P = 0.004); D+/R+ (37%, P = 0.002); and D+/R- (52%, P<0.001). In the three at-risk subgroups, infection rates were lower among patients receiving ganciclovir (22%) than among those receiving aciclovir or no prophylaxis (64%; P<0.0001). Acute rejection was more common among CMV-infected patients (66 vs 41% without infection, P = 0.001) and in those not receiving ganciclovir prophylaxis. The 3-year actuarial rejection-free survival rate was 61.4% with ganciclovir and 42.2% with no prophylaxis or aciclovir alone (P = 0.002). No differences were observed in actuarial patient, kidney or pancreas survival between CMV and non-CMV infection groups. CONCLUSIONS: Our findings confirm that the incidence of CMV infection is the same in tacrolimus- and cyclosporin-ME-treated SPK recipients. Ganciclovir prophylaxis effectively prevented CMV infection, especially in higher risk groups, and was associated with a reduced incidence of rejection compared with aciclovir/no prophylaxis.

Efficacy and safety of tacrolimus compared with cyclosporin microemulsion in primary SPK transplantation: 3-year results of the Euro-SPK 001 trial.

BACKGROUND: Single-centre and retrospective studies suggest superiority of tacrolimus over cyclosporin as cornerstone immunosuppressive therapy for simultaneous pancreas-kidney (SPK) transplantation. This open-label, multicentre trial compared the efficacy and safety of tacrolimus with cyclosporin microemulsion (ME) in diabetic patients with end-stage renal disease undergoing their first cadaveric SPK transplantation. The 3-year results are reported. METHODS: Patients were recruited from 10 centres in Europe and one centre in Israel: 103 were randomized to receive tacrolimus (initial dose: 0.2 mg/kg/day p.o.) and 102 to cyclosporin-ME (7 mg/kg/day p.o.). All patients received concomitant rabbit anti-T-cell globulin induction, mycophenolate mofetil (MMF) and short-term corticosteroids. RESULTS: Fewer patients receiving tacrolimus (36.9%) than cyclosporin-ME (57.8%) were discontinued from treatment (P = 0.003). The initial episodes of biopsy-proven rejection were moderate or severe in just one out of 31 (3%) tacrolimus-treated patients compared with 11 out of 39 (28%) patients receiving cyclosporin-ME (P = 0.009). While 3-year patient and kidney survival rates were similar in the two treatment groups, pancreas survival was superior with tacrolimus (89.2 vs 72.4%; P = 0.002). Thrombosis resulted in pancreas graft loss in 10 patients receiving cyclosporin-ME and in only two treated with tacrolimus (P = 0.02). Overall adverse event frequency was similar in both groups, but MMF intolerance was more frequent with tacrolimus and hyperlipidaemia more frequent with cyclosporin-ME. CONCLUSIONS: In this 3-year study, tacrolimus was more effective than cyclosporin-ME in preventing moderate or severe kidney or pancreas rejection after SPK transplantation. It also provided superior pancreas survival and reduced the risk of pancreas graft thrombosis.

Secondary effects of immunosuppressive drugs after simultaneous pancreas-kidney transplantation.

BACKGROUND: This report examines the early and late secondary effects of tacrolimus, cyclosporin microemulsion (ME), mycophenolate mofetil (MMF) and rabbit anti-thymocyte globulin (rATG) in simultaneous pancreas-kidney (SPK) recipients. METHODS: Of the 205 patients participating in the Euro-SPK 001 study, 103 were randomized to tacrolimus (0.2 mg/kg) and 102 to cyclosporin-ME (7 mg/kg). All patients received rATG for 4 days [ATG-Fresenius (ATG-F) 4 mg/kg/day or Thymoglobulin (Thymo-S) 1.25 mg/kg/day] plus MMF and short-term corticosteroids. RESULTS: Thymo-S induction therapy was associated with a lower white cell count in the first 3 months than was seen with ATG-F, while ATG-F caused a lower initial nadir in platelet count. Both polyclonal preparations were well tolerated and no clinically relevant differences were observed with respect to side effects such as infections and malignancies. High cyclosporin-ME trough levels were associated with pancreas graft thrombosis, and concentrations >150 ng/ml were associated with poor renal allograft function. Treatment discontinuation was higher with cyclosporin-ME (57.8%) than with tacrolimus-based therapy (36.9%) due to more frequent toxicity, graft loss and lack of efficacy requiring a switch to tacrolimus. The main reason for withdrawal in the tacrolimus group was MMF discontinuation; MMF-related side effects resulted in more frequent dose reductions to <2 g/day and discontinuations in the tacrolimus group, and indirectly indicate a higher dose-corrected exposure to mycophenolic acid, as previously observed in kidney transplant patients. CONCLUSIONS: Short-term induction therapy is effective and well tolerated in patients undergoing SPK transplantation. Tacrolimus was the preferred immunosuppressive agent, resulting in fewer cases of pancreas graft loss and drug discontinuation compared with cyclosporin-ME.

A large, prospective, randomized, open-label, multicentre study of corticosteroid withdrawal in SPK transplantation: a 3-year report.

BACKGROUND: Simultaneous pancreas-kidney (SPK) transplantation is the treatment of choice for selected diabetic patients. Corticosteroids are an important element of immunosuppressive protocols, but their long-term use has detrimental effects on patients' health, necessitating eventual discontinuation. METHODS: This prospective study evaluated the safety and feasibility of corticosteroid withdrawal in 205 SPK transplant recipients randomized to immunosuppressive treatment with either tacrolimus and mycophenolate mofetil (MMF) (n = 103) or cyclosporin microemulsion (ME) and MMF (n = 102). RESULTS: Corticosteroid withdrawal was successful in the majority of in-study patients (66% tacrolimus, 73% cyclosporin-ME). Compared with out-of-study patients or those continuing corticosteroid therapy, in-study patients withdrawn from corticosteroids experienced fewer pancreas or kidney graft losses, fewer episodes of acute rejection and were less likely to be withdrawn from the study. Acute rejection occurred after corticosteroid withdrawal in two patients who had a previous rejection and in five patients who were rejection-free before corticosteroid withdrawal. No rejection episodes were associated with graft loss or immediate serious consequences. Overall, corticosteroid withdrawal was achieved with an increase in the dose of both MMF and tacrolimus. CONCLUSIONS: A long-term survey of corticosteroid withdrawal in SPK transplantation with multifactorial analyses is necessary to confirm these early results and to evaluate the positive effects on glucose metabolism and hypertension.

Impact of HLA matching on the outcome of simultaneous pancreas-kidney transplantation.

BACKGROUND: Simultaneous pancreas-kidney (SPK) transplantation has become the therapy of choice for type 1 diabetic patients with end-stage renal disease. The current analysis examined the impact of human leukocyte antigen (HLA) matching on graft outcome following SPK transplantation. The study population was obtained from patients enrolled in the Euro-SPK 001 study. METHODS: The effect of HLA matching on graft function and survival was assessed in 180 SPK recipients in whom complete donor-recipient HLA data were available. A group of 45 patients with 0-3 HLA mismatches (MM) was compared with a group of 135 patients with 4-6 MM. RESULTS: There were no differences in 3-year kidney, pancreas or patient survival between the 0-3 and 4-6 MM groups. Biological parameters of kidney and pancreas graft function were similar in both groups. Significantly more patients with 0-3 MM (66%) were rejection-free at 3 years than was the case among those with 4-6 MM (41%; P = 0.003). The relative risk of acute rejection was 2.6 times higher among patients with 4-6 MM than among those with 0-3 MM. CONCLUSIONS: There was no evidence that HLA matching was associated with improved kidney or pancreas survival. However, a higher rate of acute rejection was observed with poor HLA match, which may impact long-term survival.

Spectrum of surgical complications after simultaneous pancreas-kidney transplantation in a prospectively randomized study of two immunosuppressive protocols.

BACKGROUND: Simultaneous pancreas-kidney transplantation (SPK) has evolved as an effective treatment for patients with end-stage nephropathy due to type 1 diabetes mellitus. This report analyses the spectrum of surgical complications among patients receiving tacrolimus and cyclosporin microemulsion (ME)-based therapy for SPK transplantation. METHODS: The analysis included 205 patients randomly assigned to tacrolimus (n = 103) or cyclosporin-ME (n = 102) in the Euro-SPK 001 study. Surgical complications were defined as any intervention in the 3-month post-operative course related to the transplant procedure. RESULTS: In the tacrolimus vs cyclosporin-ME group, repeat laparotomy was required by fewer patients (26 vs 43%, respectively; P = 0.01) and at a later stage post-transplant (26+/-26 vs 14+/-17 days; P = 0.05). Also, thrombosis of graft vessels (2 vs 9%; P = 0.03) and repeat laparotomy for intra-abdominal haemorrhage within the first 3 months (8 vs 22%; P = 0.005) occurred significantly less frequently with tacrolimus vs cyclosporin-ME. A donor age of > or =45 years was a significant determinant for surgical complications requiring repeat laparotomy, regardless of the type of immunosuppression. Portal anastomosis was the safest method of endocrine venous drainage, and Roux-en-Y loop for enteric exocrine drainage was associated with a higher re-operation rate than duodenoenterostomy. Repeat laparotomy had no impact on patient survival, but significantly reduced kidney and pancreas graft survival in the cyclosporin-ME group (kidney: P<0.01; pancreas: P<0.001) and in both groups combined (P < or = 0.05 and P<0.001, respectively). CONCLUSIONS: The immunological benefits of tacrolimus compared with cyclosporin-ME treatment result in a lower incidence of repeat laparotomies post-transplant and a reduced in-hospital stay. Fewer repeat laparotomies translate into improved pancreas and kidney graft survival.