Single-Nucleotide Polymorphism of CYP3A5 Impacts the Exposure to Tacrolimus in Pediatric Renal Transplant Recipients: A Pharmacogenetic Substudy of the TWIST Trial.

BACKGROUND: The pharmacokinetics of tacrolimus (TAC) and mycophenolic acid (MPA) are highly variable. An impact of single-nucleotide polymorphisms (SNPs) of the genes coding for enzymes and transporters involved in the pharmacokinetics of TAC and/or MPA is intuitively conceivable. Accordingly, we sought to analyze the influence of different SNPs on TAC and MPA exposure in pediatric renal transplant recipients. METHODS: A subpopulation of 37 patients (median age: 12.8 years, range 2.2-18.3 years) participating in the TWIST study was included in the analysis of SNPs of CYP3A5, ABCB1 (MDR1), ABCG2, SLCO1B3 (coding for OATP2), ABCC2 (coding for cMOAT), and UGT1/2. TAC trough concentrations and abbreviated area under the concentration-time curves (AUC) of MPA were measured on days 7, 28, 91, and 183 after transplant. Both of these were adjusted to the respective dose the patient received. RESULTS: The allele frequencies of analyzed SNP's were comparable to those reported previously for white populations. Dose-adjusted trough concentrations of TAC were approximately 60% lower in patients with the CYP3A5*1/*3 allele as compared with the CYP3A5*3/*3 allele (P = 0.004). Steroid-free patients in CYP3A5*3/*3 and CYP3A5*1/*3 carrier subgroups had comparable dose-adjusted TAC concentrations to the subgroup on steroids (P = 0.13). Patients younger than 10 years had a significantly lower median dose-adjusted TAC C0 concentration than patients older than 10 years; this age effect was comparable in heterozygous and homozygous CYP3A5 carriers as well as in patients on and off steroid medication. As for MPA, the genetic variability of transporters or enzymes had no impact on dose-adjusted MPA-AUC due to the low allele frequencies. Patients off steroids had a higher dose-adjusted MPA-AUC (0.18 mg·h/L per mg/m, 0.012-0.27) compared with patients on steroids (0.12 mg·h·L·mg, 0.09-0.19; P = 0.04). CONCLUSIONS: Genetic variability of CYP3A5 has an impact on TAC metabolism in pediatric renal transplant recipients, contributing partly to the variability of TAC exposure. Therefore, adjusting initial TAC dosing to the genotype of CYP3A5 might be of clinical benefit.

Corticosteroid-free Kidney Transplantation Improves Growth: 2-Year Follow-up of the TWIST Randomized Controlled Trial.

BACKGROUND: Corticosteroid withdrawal (CW) after pediatric kidney transplantation potentially improves growth while avoiding metabolic and other adverse events. We have recently reported the results of a 196 subject randomized controlled trial comparing early CW (tacrolimus, mycophenolate mofetil (MMF), daclizumab, and corticosteroids until day 4) with tacrolimus, MMF, and corticosteroid continuation (CC). At 6 months, CW subjects showed better growth with no adverse impact on acute rejection or graft survival (Am J Transplant 2010; 10: 828-836). This 2-year investigator-driven follow-up study aimed to determine whether improved growth persisted in the longer term. METHODS: Data regarding growth, graft outcomes and adverse events were collected at 1 year (113 patients) and 2 years (106 patients) after transplantation. The primary endpoint, longitudinal growth calculated as delta height standard deviation score, was analyzed using a mixed model repeated measures model. RESULTS: Corticosteroid withdrawal subjects grew better at 1 year (difference in adjusted mean change, 0.25; 95% confidence interval, 0.10, 0.40; P = 0.001). At 2 years, growth remained numerically better in CW subjects (0.20 (-0.01, 0.41); P = 0.06), and significantly better in prepubertal subjects (0.50 (0.16, 0.84); P = 0.004). Bacterial and viral infection was significantly more common in CW subjects at 1 year only. Corticosteroid withdrawal and CC subjects received similar exposure to both tacrolimus and MMF at 1 and 2 years. No significant difference in patient or graft survival, rejection, estimated glomerular filtration rate, or other adverse events was detected. CONCLUSION: Early CW effectively and safely improves growth up to 2 years after transplantation, particularly in prepubertal children.

Conversion to tacrolimus once-daily from ciclosporin in stable kidney transplant recipients: a multicenter study.

This 24-week, open, single-arm, prospective, multicenter study evaluated the effects of conversion from ciclosporin to Tacrolimus QD in adult kidney transplant patients. Stable patients receiving ciclosporin were converted to Tacrolimus QD at 0.1mg/kg/day. Relative change in renal function (primary endpoint) was assessed using estimated creatinine clearance (eCrCl) with a noninferiority margin set at -10%. A total of 346 patients were enrolled; and 301 patients were treated per protocol (PPS) in the hyperlipidemia (n=42), hypertrichosis (n=106), hypertension (n=77) and gingival hyperplasia (n=76) groups. Relative change in eCrCl was -0.6% in all PPS patients (95% CI, -2.2; 0.9) and -5.3% in the hyperlipidemia (CI, -9.59; -0.97), 0.9% in the hypertrichosis (CI, -2.59; 4.45), -0.1% in the hypertension (CI, -3.8; 3.68), and -1% in the gingival hyperplasia groups (CI, -4.63; 2.65) (PPS), meeting noninferiority criteria. There was no acute rejection. Decreases in serum lipids and blood pressure were moderate but without meaningful change in the number of treatment medications. Substantial decreases in severity of ciclosporin-related cosmetic side effects were evident from investigator and patient self-report of symptoms. Renal function remained stable after conversion to Tacrolimus QD. The effect of conversion on cardiovascular parameters was not clinically meaningful, however, marked improvement in ciclosporin-related cosmetic side effects was observed. (ClinicalTrials.gov number: NCT00481481).

Association of pre-transplant dialysis duration with outcome in kidney transplant recipients: a prevalent cohort study.

INTRODUCTION: Dialysis treatment prior to transplantation may contribute to premature mortality and graft loss in kidney-transplanted patients. In this prevalent cohort study (TransQol-HU Study), we analyzed the association between pre-transplant dialysis duration versus mortality and death-censored graft loss in kidney-transplanted patients. METHODS: Data from 926 kidney-transplanted patients followed at a single outpatient transplant center were analyzed. Socio-demographic parameters, laboratory data, medical history, donor characteristics and information on co-morbidities were collected at baseline. Data on 5-year outcome (graft loss, mortality) were collected. RESULTS: In multivariate analyses, pre-transplant dialysis duration was an independent risk factor for mortality (HR(for each month increase) = 1.011; 95% CI: 1.005-1.016) and also for death-censored graft loss (HR(for each month increase) = 1.008; 95% CI: 1.001-1.015) after adjustment for several co-variables. In the multivariate model, patients with less than 1 year (HR = 0.498; 95% CI: 0.302-0.820; P = 0.006) and 1-3 years (HR = 0.577; 95% CI: 0.371-0.899; P = 0.015) of pre-transplant dialysis had significantly better survival after transplantation compared to those with more than 3 years on dialysis. CONCLUSIONS: These findings add further strength to existing evidence about the significant association between longer pre-transplant dialysis duration and poor outcome in kidney-transplanted patients.

Impaired renal function is associated with mortality in kidney-transplanted patients.

INTRODUCTION: To date, only a few, at times conflicting, reports suggested that renal function and mortality are associated in kidney-transplanted patients. In our prevalence cohort study, we tested the hypothesis that renal function is associated with mortality in transplanted patients. METHODS: Data from 985 transplanted patients were analyzed. Socio-demographic parameters, laboratory data, medical and transplant history, type of immunosuppression and estimated glomerular filtration rate were tabulated at baseline. Data on 5-year outcome were collected prospectively. RESULTS: In multivariate Cox proportional hazard models, the estimated glomerular filtration rate measured at baseline significantly predicted mortality [hazard ratio (HR)(for each 10 ml/min decrease) = 1.271; 95% confidence interval (CI): 1.121-1.440] after adjustment for several covariables. Additionally, in multivariate Cox proportional hazard models, chronic kidney disease stage 4-5 (HR = 2.678; 95% CI: 1.494-4.802) significantly increased the mortality hazard compared to chronic kidney disease stage 1-2. CONCLUSIONS: Renal function is significantly and independently associated with mortality over 5 years in kidney-transplanted patients among whom mycophenolate mofetil use was very prevalent.

[The first successful adult right-lobe living donor liver transplantation in Hungary]. / Az elsô sikeres élô donoros felnôttkori jobb lebenyes májtranszplantáció Magyarországon.

The authors report on their experiences related to the first adult live donor liver transplantation performed in Hungary. The transplantation was done between brother and sister on 19th of November, 2007. The right lobe of the 33-year-old healthy male's donor liver (segments 5-8) was removed and implanted into the 23-year-old female suffering from cirrhosis on the ground of autoimmune hepatitis. The implantation of the right liver lobe was done after own hepatectomy in orthotopic position. Liver function has improved rapidly following the transplantation. The donor was discharged on the 10th post-operative day with stable liver function. He had full rehabilitation, got back to work, and control check-ups showed a significant liver regeneration. Two years after transplantation, the recipient also lives an active life with compensated liver function and she is under regular medical check-up. With the case report, authors overview the indications and techniques of living donor right-lobe liver transplantation.

[Gastrointestinal cytomegalovirus infections in organ transplant patients]. / A gastrointestinalis traktus cytomegalovirus-fertozése szervtranszplantált betegeken.

Cytomegalovirus (CMV) is a major pathogen of immunocompromised organ transplant patients. 80-90% of all transplant patients are infected by the virus; however, the incidence of CMV disease is 30-40%. Gastrointestinal CMV disease occurs in 10% of all transplants involving any part of the gastrointestinal tract. Mucosal injury, ulcerations, erosions, hemorrhage, gastrointestinal dysmotility, rarely gastrointestinal masses, perforations are the most common pathological findings of the CMV disease. The method of specific diagnostics is endoscopy with mucosal biopsy. The biopsy samples must be investigated histopathologically for specific cytomegalic cells with intranuclear ("owl's eye") and intracytoplasmatic inclusions. Different microbiological, immunohistochemical and molecular biological assays can be performed to detect CMV in the mucosa. In case of gastrointestinal CMV disease, both gastroenterological and antiviral treatment are needed by ganciclovir i.v. and/or valganciclovir orally. The prevention of the disease should be achieved by general prophylaxis in high-risk patients (oral valganciclovir, in special cases hyperimmune globulin), and by preemptive therapy using microbiological surveillance in middle-risk patients.

Patient outcomes in two steroid-free regimens using tacrolimus monotherapy after daclizumab induction and tacrolimus with mycophenolate mofetil in liver transplantation.

INTRODUCTION: Long-term steroid administration may predispose liver transplant recipients to infectious and metabolic complications. Maintaining effective immunoprophylaxis while minimizing the negative consequences of steroid therapy could be a key factor in improving clinical outcomes. METHODS: Six hundred two patients were randomized to receive tacrolimus (TAC) immunosuppression with a single-steroid bolus and two doses of daclizumab (DAC) or mycophenolate mofetil (MMF). RESULTS: The incidence of biopsy-proven acute rejection was 19.7% in the TAC/DAC group and 16.2% in the TAC/MMF group (ns). Three-month patient and graft survival were similar. Steroid use at month-3 was low at 5.5% in the TAC/DAC group and 3.9% in the TAC/MMF group. Significantly higher incidences of causally related adverse events (AEs) and significantly more dose modifications, interruptions, or discontinuations due to an AE were reported with TAC/MMF. Study withdrawal due to leucopenia was significantly higher with TAC/MMF (0.0% vs. 1.7%. Por=2 fasting plasma glucose values >or=7.0 mmol/L) were low at 9.5% (TAC/DAC) and 11.0% (TAC/MMF). CONCLUSION: Both TAC-based regimens allowed optimization of immunoprophylaxis while eliminating some of the negative consequences associated with steroids. Efficacy outcomes were comparable; however, TAC monotherapy after DAC induction was associated with significantly less leucopenia and less bacterial infection than a dual regimen incorporating MMF.

Experimental results and clinical impact of using autologous rectus fascia sheath for vascular replacement.

Vascular complications are major causes of graft failure in liver transplantation. The use of different vascular grafts is common but the results are controversial. The aim of this study was to create an 'ideal' arterial interponate for vascular replacements in the clinical field. An autologous, tubular graft prepared from the posterior rectus fascia sheath was used for iliac artery replacement in dogs for 1, 3, 6 and 12 months. Forty-one grafts were implanted and immunosuppression was used in separate groups. The patency rate was followed by Doppler ultrasound. Thirty-seven grafts remained patent, 2 cases with thrombosis and 2 cases with stenosis occurred. There was no evidence of necrosis or aneurysmatic formation. The histological analysis included conventional light microscopic and immunohistochemical examinations for CD34 and factor VIII. The explanted grafts showed signs of arterialisation, appearance of elastin fibres, and smooth muscle cells after 6 months. Electron microscopy showed intact mitochondrial structures without signs of hypoxia. In conclusion, the autologous graft presents acceptable long-term patency rate. It is easy to handle and the concept of beneficial presence of the anti-clot mesothelium until endothelialisation seems to work. The first clinical use was already reported by our group with more than 2 years survival.

[Subcapsular hematoma and rupture of the liver graft]. / Subcapsularis haematoma és graftruptura májátültetés után.

Subcapsular hematoma and/or rupture of the graft is uncommon but serious complication of liver transplantation. It may develop spontaneously or following parenchymal injuries or percutaneous transhepatic invasive procedures. This report describes three cases of subcapsular hematoma and/or rupture of the graft with different courses among 350 liver transplantations. In the first case, the patient died due to graft rupture caused by a pseudoaneurysm after biopsy. In the second case, a small injury of the donor liver resulted in a deep rupture, which required partial resection of the graft. The patient died in sepsis later. The third patient presented with a large subcapsular haematoma during transplantation, which was successfully treated. The authors' strategies developed intraoperatively for the management of hematomas. These involve opening and removing of the haematoma, haemostasis with Argon coagulation, which resulted in an adherent Glisson's capsule to the parenchyma and covering with collagen fleece coated with fibrinogen and thrombin.

[Surgical aspects of pediatric liver transplantation. Living donor liver transplant program in Hungary]. / A gyermekkori májátültetés sebészeti alapjai. Az élodonor-program elso lépései Magyarországon.

Because of the long waiting time for pediatric liver transplantation, new techniques of liver transplantation were invented. Split and living-donor related liver transplantation are common today and the Kaplan-Meier (3 years) overall survival is over 80%. By splitting the liver, two recipients can be transplanted. In general, the left lobe is used for the pediatric, the right lobe for the adult recipient. There are a lot of combinations depending on the donor and recipient weight. The accepted liver volume is approx. 1% of the recipient body weight. The results of the Hungarian pediatric program improve, 27 transplantations were done using 14 partial liver grafts and living donor program was started. Using strict protocols and improving surgical skills, the overall pediatric survival was over 80% in the last 5 years.

[Biliary complications following orthotopic liver transplantation. The Hungarian experience]. / Epeúti szövodmények májtranszplantáció után.

INTRODUCTION: The authors summarize the characteristics of biliary complications following liver transplantation in the Hungarian liver transplant program. Aims were to analyze the frequency and the types of biliary complications as well as their effect on the patient and graft survival. The authors observed the known risk factors in the Hungarian practice, and they also try to find unknown risk factors for biliary complications. They review the therapy of biliary complications. METHOD: In the retrospective study, patients were divided into two groups, with and without biliary complication after liver transplantation. These two groups were compared with many factors, and with the survivals. The biliary complication group was divided into two parts: those who had an early and those with a late biliary complication. These two new groups were also compared with the controls. The results are summarized in tables and statistical figures. Categorical variables are evaluated by chi 2 -test, continuous ones are with Levine Test (for homogenicity of means), Student T test and Mann-Whitney U-test. Cumulative survivals are computed with Kaplan-Meier log rank analysis. RESULTS: Biliary complication appeared in 25% of the patients. The most frequent complications were stenosis (18%), biliary leakage (9%), biliary necrosis (6%), and ischaemic type of biliary lesions (3%). The 5-year survival is worse when biliary complications were diagnosed (55%) than without such a complication (66%). In the biliary complication group the retransplantation rate was higher (15%). The most frequent treatments were interventional radiologic methods (69%), surgical methods (17%), and the ERCP. CONCLUSIONS: The rate of biliary complications met the international reviews. Risk factors for biliary complications were cholangitis, hepatic artery thrombosis and stenosis, high rate of intraoperative blood transfusions, and acute rejection. Biliary complications frequently associated with the initial poor function of the transplanted graft. Early biliary complications have a negative impact on patient survival, while late complications influence a decreased quality of life. Biliary complications were treated mostly by interventional radiologic procedures.

[Investigation of redox homeostasis in liver and renal transplant recipients]. / Redox homeostasis vizsgálata máj- és vesetranszplantáció során.

The time course of free radical reactions is evaluated by the authors. Within pretransplant patients as of their poorly functioning metabolism free radical overproduction may be observed, hence their antioxidant capacity decreases. When the graft is functioning well, the free radical-antioxidant balance of homeostasis is reestablished. During the early postoperative period, when symptoms (acute rejection, infection, acute tubular necrosis, cholestasis) appear, free radical reactions increase. The authors demonstrate, this is strengthened by the fact that the mediator [interleukin-6 (IL-6), C-reactive protein, serum amyloid-A], and enzyme levels that take part in the free radical processes rise. The monitoring of these parameters during the early postoperative period is a good early indicator for acute rejection and for the effect of therapy. During acute rejection just as during infection most of these parameters increased significantly compared to the healthy control. They show the activation of the immune system but they are not useful for differential diagnosis, with the exception of IL-6 which we measured in larger quantities during bacterial infection but not so in acute rejection. For the prediction of early renal graft function we used urinary enzyme levels (dipeptidyl-aminopeptidase, glutathione-S-transferase). Tissue damage is followed by enzyme increasing and antioxidant capacity depletion. With choosing of adequate tests, the perioperative redox homeostasis of the transplanted patients can be monitored and with dosing the antioxidants the uncontrolled forming of reactive oxygen metabolites can also be decreased and checked.

[Cytomegalovirus infection after solid-organ transplantation, its risk factors, direct and indirect effects and prevention strategies]. / A cytomegalovírus-fertozés rizikófaktorai, hatásai és a megelozés lehetoségei transzplantációt követoen.

The human cytomegalovirus is widely prevalent among human population and it is the most common viral pathogen that affects both the graft's and solid-organ transplant recipient's survival. The risk is highest in donor-seropositive, recipient-seronegative pairing transplantation. These recipients carry increased risk of developing symptomatic primary CMV infection; however, other risk factors may have an impact on cytomegalovirus activation as well: intensity of immunosuppression, type of organ transplanted, rejection and/or treatment for rejection, HLA-mismatch between recipient and donor, certain HLA-types of the recipient, female sex etc. Cytomegalovirus infection in transplant patients has been associated with both direct (symptoms) and indirect effects which are derived from the immunomodulating impact of the virus such as cellular effects and cytokine expression or systemic immune suppression leading to other opportunistic infections. Prevention of the direct and indirect effects of cytomegalovirus infection is the therapeutic goal in transplanted patients. Most transplant centers use either universal prophylaxis or preemptive therapy to prevent the infection. The advantages and disadvantages of these two preventive strategies and current evidence-based recommendations for preventing cytomegalovirus disease in solid-organ transplant recipients are discussed according to others' and the authors' own observations. According to recommendations of the American and Canadian Societies of Transplantation, most of the centers--after analyzing of the CMV-infection risk factors of the recipients--divide them into three groups: high-, moderate- and low-risk groups. The preventive strategy is attached to the risk-group type. In the high-risk group (R-/D+ and lung transplant patients) the use of the universal prophylaxis is necessary. The patients administered anti-lymphocyte antibodies (ATG, ALG or OKT3) need selective (subtype of universal) prophylaxis. Among the moderate-risk patients (R+/D+ or R+/D-) the doctors may choose either universal prophylaxis or preemptive therapy. Selection of a strategy requires consideration of patient-specific factors as well as practical considerations such as available resources. For avoidance of the indirect effects of CMV infection universal prophylaxis is preferred. The use of preventive proceedings in low-risk patients is the matter of the center's decision.

HLA-DQ3 is a probable risk factor for CMV infection in high-risk kidney transplant patients.

BACKGROUND: Cytomegalovirus (CMV) infection in transplant patients with special risk factors remains a major hazard. CMV-seronegative recipients with seropositive donors have the highest risk of developing acute CMV disease. We suggest that the HLA-type may influence the occurrence and the severity of primary CMV infection of these recipients and the measurement of the special HLA-types may be useful in the prediction of acute infection. METHODS: Since 1999 1213 cadaver kidney transplantations have been performed in our clinic. 163 of 1213 recipients were CMV-seronegative (13%) and 129 of them received the kidney from seropositive donors. All 129 patients received CMV infection prophylaxis. Of 129 CMV-seronegative patients 49 developed acute CMV infection (38%) during the first posttransplant year. CMV infection was diagnosed by CMV antigenemia test and serologic measurements (ELISA). The particular HLA-genotypes of the recipients were studied before the transplantation. The occurrence and the severity of CMV infection was investigated in association with HLA-types. RESULTS: We found different acute CMV infection distribution in the careers and non-careers of investigated HLA-types: HLA-A2, HLA-B12, HLA-Cw7, HLA-DR6 and HLA-DR11, but the differences were not significant in these HLA-types (P = 0.26, P = 0.37, P = 0.83, P = 0.07 and P = 0.37). While investigating HLA-DQ3, we found that of 68 DQ3-positive patients 32 (47%), of 61 DQ3-negative patients 17 (28%) had acute CMV infection and this difference was found to be significant. This result was confirmed by univariate and multivariate Cox Regression (P = 0.001) and the appropriate significance level was considered by Bonferroni correction. CONCLUSIONS: HLA-DQ3 was found to be an independent predictor of CMV infection. Our data suggest that patients positive for HLA-DQ3 are more susceptible to CMV infection than a comparable group of patients negative for HLA-DQ3. This result was not due to rejection and/or treatment for rejection and was not influenced by induction therapy. Although we found more symptomatic infections among DQ3+ patients the difference was not significant (P = 0.19). Comparing the gender proportion among all 1213 kidney recipients and among CMV-seronegative recipients we found that the proportion of males is significantly higher among CMV-seronegative recipients (P < 0.001).

[The first successful combined heart-kidney transplantation in Hungary]. / Az elso sikeres kombinált szív- és veseátültetés Magyarországon.

Combined heart-kidney transplantation has become a new therapeutic solution for patients with coexisting, irreversible heart and kidney failure. Though this combined approach has several theoretical advantages over sequential transplantation, it remains to be established whether it has a jeopardizing impact on patient and graft outcome. The authors report their experience of the first successful combined heart-kidney transplantation in Hungary from a single donor and review the literature in order to clarify this issue. Young male patient candidate for heart transplantation was suffering from concurrent end stage kidney disease. Donor was selected on the basis of weight and size matching, AB0 compatibility and negative T-cell cross-match. The heart was grafted first, and after the hemodynamic stabilization kidney from the same donor was transplanted. The surgical procedure was uneventful. Heart and kidney function recovered quickly, and the patient is doing very well with good cardiac and renal function even a year following the double organ transplantation. The first Hungarian experience showed that combined heart-kidney transplantation is a therapeutic solution for patients with end stage heart and kidney failure. The lower rate of rejection compared to single heart or kidney transplantation, known from the literature as well, supports their current approach to immunosuppression.

[Imaging techniques for the pre- and postoperative evaluation of recipients with living-donor liver transplantation]. / Elo donoros májátültetés recipienseinek pre- és posztoperatív képalkotó vizsgálatai.

Whole-liver transplantation is a worldwide-accepted method for treatment of end-stage liver disease. As a result of the shortage of cadaveric livers, split-liver transplantation and living-donor liver transplantation are becoming more common. Preoperative imaging of the donors and recipients are indispensable for surgery planning, while postoperative imaging highly contributes to the success of transplantation by follow-up the transplanted organ and early diagnosis of possible sequelae. The authors delineate both pre- and postoperative imaging of recipients of living-donor transplantation, including the role of conventional x-ray, ultrasound, CT and MRI techniques, and also the different possibilities in the field of interventional radiology.

[The role of imaging methods in the pre- and intra-operative evaluation, and in post-operative follow-up of living donors in liver transplantation in Hungary]. / A képalkotó módszerek szerepe az élô donoros májtranszplantáció donorjelöltjeinek pre- és intraoperatív vizsgálatában, valamint posztoperatív követésében Magyarországon.

The evaluation protocol for liver donors can vary from centre to centre, but the main points are the same. Medical history, physical examination, common laboratory tests and psychosocial evaluation are followed by imaging, and specific haemostasis and viral serology tests. The first imaging examinations have the aim of excluding any disease; conventional chest radiography and abdominal ultrasound are performed. Liver volume, fat content, and vascular and biliary anatomy are then evaluated with contrast-enhanced, multiphase, multidetector row CT/CTA and MR cholangiography. Ultrasound guided liver biopsy, and in some cases digital subtraction angiography, should also be performed. During the first phase of the donor operation, intraoperative investigations are done: cholangiography for the final evaluation of the biliary tree and ultrasound of the hepatic and portal venous system to help draw the resection plane. Donors have regular imaging examinations in the early postoperative period for early detection of complications: mainly US or CT to check the remnant hepatic vascularisation and fluid collections in the operated area, or X-ray for thoracic disorders. It is recommended that regular checkups are performed in the late postoperative period. The paper describes the imaging protocol for donor evaluation applied at our institute at the beginning of our living related liver transplantation programme.

Drug-induced liver graft toxicity caused by cytochrome P450 poor metabolism.

UNLABELLED: What is already known about this subject. The activity of drug-metabolizing enzymes, primarily cytochrome P450 enzymes, can determine a patient's response to a drug. Therapeutic failure or drug toxicity in the postoperative period after liver transplantation is influenced by the drug metabolizing capacity of the graft. Dose adjustment or selection of an alternative drug, which is not a substrate for the polymorphic enzyme may prevent the development of side-effects in recipients of poor metabolizer liver grafts. What this study adds. A validated analytical system with metabolomic tools has been developed to estimate the drug-metabolizing capacity of transplanted liver, which allows the prediction of potential poor metabolizer phenotypes of donors and facilitates the improvement of individual recipient therapy. In the test of drug-metabolizing status, one of the liver grafts was found to be a CYP2C9 poor metabolizer, while the other was a CYP2C19 poor metabolizer. Rationalization of the medication resulted in the recovery of both the grafts and the recipients within 1 week. AIMS: The drug-metabolizing capacity of transplanted liver highly influences drug efficacy or toxicity, particularly in the early postoperative period. The aim of our study was to predict therapeutic failures or severe adverse drug reactions by phenotyping for cytochrome P450 (P450) polymorphism resulting in reduced or no activity of the key drug-metabolizing enzymes. METHODS: A validated analytical system with metabolomic tools has been developed for estimation of the drug-metabolizing capacity of transplanted liver, which allows the prediction of potential poor metabolizer phenotypes of donors and facilitates improvement of the individual recipient therapy. RESULTS: Of the 109 liver donors in Hungary, the frequency of poor metabolizers was found to be 0.92%, 5.5% and 8.3% for CYP2C9, CYP2C19 and CYP2D6, respectively. In the present study, two liver grafts transplanted in paediatric recipients were reported to be poor metabolizer phenotypes. The liver grafts presented normal function in the early postoperative days; 2 weeks after transplantation, however, increasing liver enzymes were detected. Histological investigation of a liver biopsy suggested drug toxicity. The test of drug metabolizing status showed one of the liver grafts to be a CYP2C9 poor metabolizer, and the other was found to be a CYP2C19 poor metabolizer. Rationalization of the medication resulted in the recovery of both the grafts and the recipients within 1 week. CONCLUSIONS: Prospective investigation of the P450 status may lead to the optimization of drug choice and/or dose for a more effective therapy, avoid serious adverse effects, and decrease medical costs. Phenotyping donor livers and tailored medication can contribute to the improvement of graft and recipient survival.

[Malignant tumors following renal transplantation]. / A veseátültetést követoen kialakuló rosszindulatú daganatok.

Patient survival time following renal and other solid organ transplantation has been increasing recently, in part due to modern immunosuppressive regimens. However, the probability of malignant tumor formation is also increasing proportionally to survival time, as a side effect of long-term immunosuppression. The primary factor of increased tumor risk is the deficient antitumoral and antiviral function of the immune system. The frequency of posttransplantation tumors is 2 to 4-fold compared to the non-transplanted population, and the distribution of tumor types is also different. The most frequent tumor types--skin cancer, lymphoma, Kaposi's sarcoma, oral cancer, anogenital tumors, etc.--are often associated with oncogenic viruses. Treatment options and the prognosis of posttransplant tumors are worse than in the normal population. The increasing frequency of posttransplantation tumors is an important factor determining the long-term fate of transplant patients. The reduction of carcinogenic agents, the early diagnosis and treatment of tumors and precancerous conditions, low dose immunosuppression and the usage of immunosuppressive agents with an oncologically favorable, anti-proliferative effect will help reduce the risk of posttransplant tumor formation.