Clinical significance of personalized tacrolimus dosing by adjusting to donor CYP3A-status in liver transplant recipients.

Donor's CYP3A-status (CYP3A5 genotype and CYP3A4 expression) can provide prognostic information regarding tacrolimus-metabolizing capacity of the liver graft and initial tacrolimus dosing for therapeutic blood concentrations in liver transplants. The present work prospectively investigated whether CYP3A-status guided tacrolimus therapy has any potential clinical benefit for recipients in the early postoperative period. METHODS: The contribution of preliminary assaying of donor CYP3A-status to the optimization of initial tacrolimus therapy and to the reduction of adverse events (acute rejection, infection, nephrotoxicity) was investigated in 112 liver transplant recipients (CYPtest group) comparing to 101 control patients on tacrolimus concentration guided therapy. RESULTS: The time for achieving therapeutic tacrolimus concentration was significantly reduced, confirming potential benefit of initial tacrolimus therapy adjusted to donor's CYP3A-status over classical clinical practice of tacrolimus concentration guided treatment (4 vs 8 days, P < 0.0001). Acute rejection episodes (3.6 vs 23.8%, P < 0.0001) and tacrolimus induced nephrotoxicity (8 vs 27%, P = 0.0004) were less frequent in CYPtest group than in control patients, whereas occurrence of infectious disease was not influenced by tacrolimus dosing strategy (3.6 vs 5.9% in CYPtest and control groups, P > 0.05). Acute rejection was often accompanied with tacrolimus blood concentrations lower than 10 ng mL-1 (20/24 of control and 2/4 of CYPtest patients), while nephrotoxicity was associated with high tacrolimus concentrations (>20 ng mL-1 ) in the first week after transplantation (13/27 of control and 2/9 of CYPtest patients). CONCLUSION: CYP3A-status guided therapy significantly improved the risk of misdosing induced early adverse effects (acute rejection, nephrotoxicity).

End-stage renal disease reduces the expression of drug-metabolizing cytochrome P450s.

BACKGROUND: End-stage renal disease is an irreversible status of kidney dysfunction that reduces both renal and non-renal drug clearance. Accumulation of uremic toxins seems to modify the activities of drug-metabolizing cytochrome P450 (CYP) enzymes. The aim of the present work was to refine gene expression analysis for efficient and accurate quantification of CYP mRNAs in patients' leukocytes. METHODS: We compared six liquid-liquid extraction reagents for RNA isolation and five reverse transcriptase kits for RNA-to-cDNA conversion, and developed quantitative polymerase chain reaction methods for duplex measurements of CYP target genes and the reference gene. The expression of CYP1A2, CYP2C9, CYP2C19 and CYP3A4 in patients with end-stage kidney disease (N = 105) and in organ donors with healthy kidney function (N = 110) was compared. RESULTS: Regarding the RNA yield and purity, TRIzol, Trizolate and TRI reagents were equal; however, TRI reagent was the most advantageous in terms of financial cost. Reverse transcription using Maxima First Strand cDNA Synthesis kit appeared to be the most efficient with the widest range for quantification of the target transcript. The refined method with the detection of various CYPs and the reference gene in duplex PCR efficiently quantified even the low-level CYP expression. In leukocytes of patients with end-stage renal disease, all four CYPs were expressed at significantly lower level than in organ donors with normal kidney function (p < 0.0001). CONCLUSIONS: Reduced CYP expression was a direct evidence of transcriptional down-regulation of CYP genes in patients with impaired kidney function.

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.

Personalizing initial calcineurin inhibitor dosing by adjusting to donor CYP3A-status in liver transplant patients.

AIMS: Inter-individual variability in dose requirements of calcineurin inhibitors (CNI) has been linked to genetic polymorphisms of CYP3A enzymes. CYP3A5*3, CYP3A4*1B and CYP3A4*22 alleles of liver grafts may explain about one third of the inter-individual differences in pharmacokinetics of ciclosporin and tacrolimus in recipients. However, non-genetic factors, influencing CYP3A expression, can contribute to the variability of CYP3A function due to phenoconversion. The present study evaluated the association between CYP3A4 expression combined with CYP3A5 genotype of donor livers and recipients' CNI therapy after transplantation. METHODS: The contribution of donors' CYP3A5 genotype and CYP3A4 expression to the blood concentrations and dose requirements of CNIs was evaluated in 131 liver transplant recipients. RESULTS: The recipients with grafts from normal CYP3A4 expresser donors carrying CYP3A5*3/*3 required CNI maintenance doses more or less similar to the bodyweight-controlled starting doses (9.1 mg kg(-1) of ciclosporin and 0.1 mg kg(-1) of tacrolimus). The patients transplanted with grafts from low CYP3A4 expressers required substantial reduction (by about 50%, 4.2 mg kg(-1) of ciclosporin, 0.047 mg kg(-1) of tacrolimus, P < 0.001), while the recipients with grafts from high expressers or with grafts carrying at least one copy of the functional CYP3A5*1 allele required an increase (by about 50% [12.8-13.8 mg kg(-1)] for ciclosporin and 100% [0.21 mg kg(-1) ] for tacrolimus, P < 0.001) of the initial CNI dose for achieving target blood concentrations. CONCLUSIONS: Donor livers' CYP3A-status, taking both CYP3A5 allelic variations and CYP3A4 expression into account, can better identify the risk of CNI over- or underexposure, and may contribute to the avoidance of misdosing-induced graft injury in the early post-operative period.

[Automated measurement of biomarkers for the diagnosis of acute myocardial infarction]. / Automatizáltan mérheto biomarkerek az akut myocardialis infarctus diagnosztikájában.

INTRODUCTION: Cardiac biomarkers have a prominent role in the diagnosis of acute myocardial infarction. AIM: The aim of the authors was to study the diagnostic effectiveness of automated measurement of cardiac biomarkers. METHOD: Myeloperoxidase, high-sensitivity C-reactive protein, myoglobin, heart-type fatty acid binding protein, creatine kinase, creatine kinase MB, high-sensitivity troponin I and T were measured. RESULTS: The high-sensitivity troponin I was the most effective (area under curve: 0.86; 95% confidence interval: 0.77-0.95; p<0.001) for the diagnosis of acute myocardial infarction. Considering a critical value of 0.35 ng/mL, its sensitivity and specificity were 81%, and 74%, respectively. Combined evaluation of the high-sensitivity troponin T and I, chest pain, and the electrocardiogram gave the best results for separation of acute myocardial infarction from other diseases (correct classification in 62.5% and 98.9% of patients, respectively). CONCLUSIONS: Until a more sensitive and specific cardiac biomarker becomes available, the best method for the diagnosis of acute myocardial infarction is to evaluate electrocardiogram and biomarker concentration and to repeat them after 3-6 hours.

Recurrence of primary sclerosing cholangitis after liver transplantation - The Hungarian experience.

INTRODUCTION: Recurrence of primary sclerosing cholangitis (rPSC) after liver transplantation (OLT) significantly affects long-term graft survival. We aimed to evaluate the incidence of rPSC and clinical data of these patients in Hungary. PATIENTS AND METHODS: We retrospectively analyzed data of 511 whole liver transplantations from 1995 to 2011. During the study period, 49 OLTs were performed in 43 adult patients with end-stage PSC (10%). RESULTS: Out of 49 OLT, 24 cases were excluded, rPSC was diagnosed in six patients (12%). Patients with rPSC had significantly higher mortality (p = 0.009) and graft loss (p = 0.009) in comparison to patients without recurrent disease. Younger recipient age, higher donor BMI was observed in the rPSC group. One patient was diagnosed with de novo IBD, the remaining five patients had worsening IBD activity in the posttransplant period. PreOLT colectomy was performed in 21% of the control and none of the rPSC group. PostOLT colectomy was performed in two rPSC patients due to severe therapy resistant colitis. CONCLUSIONS: Recurrent PSC significantly affects long-term mortality and graft loss. Younger age at OLT, higher donor BMI and severe active IBD may be associated with PSC recurrence. PreOLT total colectomy might have protective effect against rPSC.

MicroRNA profile before and after antiviral therapy in liver transplant recipients for hepatitis C virus cirrhosis.

BACKGROUND AND AIM: Management of hepatitis C virus (HCV) recurrence is a major challenge after liver transplantation. Significant dysregulated expression of HCV receptors (i.e. claudin-1, occludin, tetraspanin CD81, scavenger receptor type B1) has been shown recently during HCV infection. This might facilitate hepatocytic entry and reinfection of HCV. MicroRNAs (miRs) play role in the regulation of gene expression. We aimed to characterize miR expression profiles related to HCV infection and antiviral therapy in adult liver transplant recipients, with special emphasis on miRs predicted to target HCV receptors. METHODS: Twenty-eight adult liver transplant recipients were enrolled in the study. Paired biopsies were obtained at the time of HCV recurrence and at the end of antiviral treatment. MiRs for HCV receptors were selected using target prediction software. Expression levels of miR-21, miR-23a miR-34a, miR-96, miR-99a*, miR-122, miR-125b, miR-181a-2*, miR-194, miR-195, miR-217, miR-221, and miR-224 were determined by reverse transcription-quantitative polymerase chain reaction. RESULTS: miR-99a* and miR-224 expressions were increased in HCV recurrence samples, while miR-21 and miR-194 were decreased in comparison to normal liver tissue. Increased expressions of miR-221, miR-224, and miR-217 were observed in samples taken after antiviral therapy when compared with HCV recurrence samples. High HCV titer at recurrence was associated with higher level of miR-122. CONCLUSIONS: Samples at recurrence of HCV and after antiviral therapy revealed distinct HCV-related miR expression profiles, with significant dysregulation of those miRNAs potentially targeting mRNAs of HCV receptors. In particular, miR-194 and miR-21 might be involved in the regulation of HCV receptor proteins' expression during HCV infection and antiviral therapy.

[Hepatitis C virus recurrence after liver transplantation in Hungary. Trends over the past 10 years]. / Hepatitis C-vírus-fertozés kiújulása májátültetés után. Mi változott az elmúlt 10 évben?

INTRODUCTION: Management of hepatitis C virus recurrence is a challenge after liver transplantation. AIM: The aim of the authors was to analyse the outcome of liver transplantation performed in hepatitis C virus positive patients during the past ten years and to compare recent data with a previous report of the authors. METHOD: The authors retrospectively evaluated the data (donors, recipients, perioperative characteristics, patient and graft survival, serum titer of hepatitis C virus RNA, histology) of 409 patients who underwent liver transplantation between 2003 and 2012. RESULTS: 156 patients were transplanted due to hepatitis C virus associated liver cirrhosis (38%). Worse outcome was observed in these patients in comparison to hepatitis C virus negative recipients. The cumulative patient survival rates at 1, 5, and 10 year were 80%, 61%, 51% in the hepatitis C virus positive group and 92%, 85%, 79% in the hepatitis C virus negative group, respectively (p<0.001). The cumulative graft survival rates at 1, 5 and 10 year were 79%, 59% and 50% in hepatitis C virus positive and 89%, 80% and 70% in hepatitis C virus negative patients (p<0.001). Hepatitis C virus recurrence was observed in the majority of the patients (132 patients, 85%), mainly within the first year (83%). The authors observed recurrence within 6 months in 71 patients (56%), and within 3 months in 26 patients (20%). The mean hepatitis C virus recurrence free survival was 243 days. Higher rate of de novo diabetes was detected in case of early recurrence. The cumulative patient survival rates at 1, 3, 5, 10 years were 98%, 89.5%, 81% and 65% when hepatitis C virus recurrence exceeded 3 months and 64%, 53%, 30.5% and 30.5% in patients with early recurrence (p<0.001). CONCLUSIONS: Poor outcome of liver transplantation in hepatitis C virus positive patients is still a challenge. Hepatitis C virus recurrence is observed earlier after liver transplantation in comparison with a previous report of the authors. De novo diabetes occurs more frequently in case of early recurrence. Despite an immediate start of antiviral treatment, early recurrence has a significant negative impact on the outcome of transplantation.

[Kidney function and liver transplantation]. / Veseérintettség májátültetés során.

INTRODUCTION: In liver cirrhosis renal function decreases as well. Hepatorenal syndrome is the most frequent cause of the decrease, but primary kidney failure, diabetes mellitus and some diseases underlying endstage liver failure (such as hepatitis C virus infection) can also play an important role. In liver transplantation several further factors (total cross-clamping of vena cava inferior, polytransfusion, immunosuppression) impair the renal function, too. AIM: The aim of this study was to analyse the changes in kidney function during the first postoperative year after liver transplantation. METHOD: Retrospective data analysis was performed after primary liver transplantations (n = 319). RESULTS: impaired preoperative renal function increased the devepolment of postoperative complications and the first year cumulative patient survival was significantly worse (91,7% vs 69,9%; p<0,001) in this group. If renal function of the patients increased above 60 ml/min/1,73 m2 after the first year, patient survival was better. Independently of the preoperative kidney function, 76% of the patients had impaired kidney function at the first postoperative year. In this group, de novo diabetes mellitus was more frequently diagnosed (22,5% vs 9,5%; p = 0,023). CONCLUSIONS: Selection of personalized immunosuppressive medication has a positive effect on renal function.

[Progress of the liver transplantation programme in Hungary]. / A hazai májátültetési program fejlodése.

The history of organ transplantation in Hungary dates back to 50 years, and the first succesful liver transplantation was performed in the United States in that time as well. The number of patients with end stage liver disease increased worldwide, and over 7000 patients die in each year due to liver disease in Hungary. The most effective treatment of end-stage liver disease is liver transplantation. The indications of liver transplantation represent a wide spectrum including viral, alcoholic or other parenchymal liver cirrhosis, but cholestatic liver disease and acute fulminant cases are also present in the daily routine. In pediatric patients biliary atresia and different forms of metabolic liver disorders represent the main indication for liver transplantation. The results of liver transplantation in Hungary are optimal with over 80% long-term survival. For better survival individual drug therapy and monitoring are introduced in liver transplant candidates.

[Comparison of seven estimated glomerular filtration rate equations in kidney patients]. / Hét, becsült glomerulusfiltrációs ráta egyenletének összehasonlítása vesebetegekben.

INTRODUCTION: The degree of glomerular filtration rate determines the stages of chronic renal disease and, therefore, knowledge on its estimation is essential. AIMS: Two standardized creatinine based estimated glomerular filtration rate equations and five equations based on the immunoturbidimetric determination of cystatin C were compared. METHODS: The distribution of the analytes and the equations, their relations, as well as the differences among the estimated glomerular filtration rates and their chronic kidney disease stages assignments were studied. RESULTS: The equations based on cystatin C classified more patient into stage 1, while the creatinine based ones more into stages 2, 3 and 4. The equations published as Grubb1, Grubb2 and Larsson classified more patients while the equations created by Tan and Sjöström classified fewer into stage 5 compared to the creatinine based equations. The equations of Grubb1 and Grubb2 resulted in the most similar stage assignment. The occurrence of stages between 3 and 5 was the lowest using the equation of Sjöström. CONCLUSIONS: The different equations for the estimation of glomerular filtration rate modify significantly the chronic kidney disease stage assignment which may have an influence on the treatment and outcome measures of the patients.

Estimation of drug-metabolizing capacity by cytochrome P450 genotyping and expression.

Many undesired side effects or therapeutic failures of drugs are the result of differences or changes in drug metabolism, primarily depending on the levels and activities of cytochrome P450 (P450) enzymes. To assess whether P450 expression profiles can reflect hepatic drug metabolism, we compared P450 mRNA levels in the liver or peripheral leukocytes with the corresponding hepatic P450 activities. A preliminary P450 genotyping for the most frequent polymorphisms in white populations (CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2D6*3, CYP2D6*4, CYP2D6*6, and CYP3A5*3) was carried out before P450 phenotyping, excluding the donors with nonfunctional alleles of CYP2C9, CYP2C19, and CYP2D6 and those with a functional CYP3A5*1 allele from a correlation analysis. The hepatic mRNA levels of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 displayed a strong association with P450 activities in the liver, whereas the expression of CYP1A2, CYP2C9, CYP2C19, and CYP3A4 in leukocytes was proven to reflect the hepatic activities of these P450 species. The leukocytes were found to be inappropriate cells for the assessment of hepatic CYP2B6 and CYP2D6 activities. Combining the results of P450 genotyping and phenotyping analyses, patients' drug-metabolizing capacities can be estimated by the P450 expression in the liver and in leukocytes with some limitations. Patients' genetic and nongenetic variations in P450 status can guide the appropriate selection of drugs and the optimal dose, minimizing the risk of harmful side effects and ensuring a successful outcome of drug therapy.

Diagnostic accuracy of serum parathyroid hormone levels in kidney transplant recipients with moderate-to-advanced CKD.

BACKGROUND/AIMS: Elevated parathyroid hormone (PTH) is used to diagnose high turnover bone disease in chronic kidney disease (CKD). The diagnostic accuracy of PTH in kidney transplant recipients with CKD is unknown. METHODS: We examined kidney transplant recipients with CKD stages 3 (n = 498) and 4 (n = 141) to determine the sensitivity and specificity of the Kidney/Dialysis Outcome Quality Initiative (K/DOQI)-recommended PTH levels in detecting elevated serum ß-CrossLaps (CTX) or osteocalcin (OC) levels. We performed receiver-operator curve analyses to determine CKD stage-specific PTH levels that provide optimal diagnostic accuracy. RESULTS: PTH below the lower limits of the K/DOQI ranges (35 and 70 pg/ml in CKD stages 3 and 4, respectively) showed sensitivity of >90% in diagnosing increases in biochemical markers. The upper limits (70 and 110 pg/ml), however, showed poor specificity. A specificity of >90% for detecting increased biochemical markers was seen with PTH of >140 and >240 pg/ml in CKD stages 3 and 4, respectively. CONCLUSION: Currently applied cutoffs for PTH in kidney transplant recipients with CKD stages 3 and 4 do not appear to adequately detect increased biochemical markers of bone turnover. Diagnostic uncertainty exists in patients with CKD stage 3 and PTH between 35 and 140 pg/ml, and CKD stage 4 and PTH between 70 and 240 pg/ml.

Association between the malnutrition-inflammation score and post-transplant anaemia.

BACKGROUND: Post-transplant anaemia (PTA) is common and is associated with adverse consequences. The protein-energy wasting (PEW) syndrome is associated with erythropoietin resistance in patients on maintenance dialysis. We assessed the association between PEW and PTA in a large prevalent cohort of stable kidney-transplanted patients. METHODS: Data from 942 prevalent kidney-transplanted patients were analysed. Socio-demographic parameters, laboratory results, transplantation-related data and medication were obtained from the charts. Biomarkers reflecting nutritional status and inflammation [serum leptin, albumin, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and C-reactive protein] were measured. Anthropometric measures and the malnutrition-inflammation score (MIS) were also tabulated. Anaemia was defined according to the guidelines of the American Society of Transplantation. RESULTS: Mean age was 51 ± 13 years, 57% were males and 22% had diabetes. The prevalence of PTA was 33%. The haemoglobin (Hb) level significantly and negatively correlated with the MIS (rho = - 0.316), marginally with serum TNF-α (rho = - 0.079) and serum IL-6 (rho = - 0.075) and positively with serum transferrin (r = 0.298), serum albumin (r = 0.274), abdominal circumference (r = 0.254) and serum leptin (rho = - 0.152), P < 0.05 for all. In a multivariable linear regression model, MIS was independently associated with Hb (beta = - 0.118, P = 0.004) in patients with estimated glomerular filtration rate (eGFR) lower than or equal to 60 mL/min/1.73 m(2), but not in patients with higher eGFR. CONCLUSIONS: The MIS is independently associated with PTA in the kidney-transplanted population with eGFR lower than or equal to 60 mL/min/1.73 m(2).

[New-onset diabetes mellitus and liver transplantation, with special consideration of recurrent hepatitis C]. / De novo diabetes és májátültetés, különös tekintettel a hepatitis C-vírus kiújulására.

UNLABELLED: New-onset diabetes is a common complication after liver transplantation. AIM: We aimed to analyze the incidence and rate of known risk factors and the impact of new-onset diabetes mellitus on postoperative outcome. METHODS: We retrospectively evaluated the files of 310 patients who underwent liver transplantation between 1995 and 2009. Definition of new-onset diabetes included: repeated fasting serum glucose >6.8 mmol/l and/or sustained antidiabetic therapy that was present 3 months after transplantation. RESULTS: New-onset diabetes occurred in 63 patients (20%). Differences between the new-onset and the control group were the donor body mass index (24+/-3 vs. 22.4+/-3.6 kg/m 2 , p = 0.003), donor male gender (58% vs. 33%, p = 0.002), and recipient age (47.6+/-7.2 vs. 38.3+/-14.6 year, p<0.001), body mass index (26.7+/-3.8 vs. 23.3+/-5.6 kg/m 2 , p<0.001), male gender (60% vs. 44%, p = 0.031). The 66% of patients with new-onset diabetes were transplanted with cirrhosis caused by hepatitis C virus infection, while in the control group the rate was 23% (p<0.001). Cumulative patient survival rates at 1, 3, 5 and 8 year were 95%, 90.6%, 88% and 88% in the control group, and 87%, 79%, 79% and 64% in the de novo group, respectively (p = 0.011). Cumulative graft survival rates at 1, 3, 5 and 8 year in the control group were 92%, 87%, 86% and 79%, in the de novo diabetes group the rates were 87%, 79%, 79%, 65%, respectively (p = NS). In case of early recurrence (in 6 months), majority of patients developed new-onset diabetes (74% vs. control 26%, p = 0.03). More patients had more than 10 times higher increase of the postoperative virus titer correlate to the preoperative titer in the de novo diabetes group (53% vs. 20%, p = 0.028). Mean fibrosis score was higher in new-onset group one year after the beginning of antiviral therapy (2.05+/-1.53 vs. 1.00+/-1.08, p = 0.039). CONCLUSIONS: Risk factors for new-onset diabetes after transplantation are older age, obesity, male gender and cirrhosis due to hepatitis C infection. The early recurrence, viremia and more severe fibrosis after antiviral therapy have an impact on the occurrence of new-onset diabetes in hepatitis C positive patients.

Evaluation of the malnutrition-inflammation score in kidney transplant recipients.

BACKGROUND: Chronic protein-energy wasting, termed malnutrition-inflammation complex syndrome, is frequent in patients with chronic kidney disease and is associated with anemia, morbidity, and mortality in patients on maintenance dialysis therapy. The Malnutrition-Inflammation Score (MIS) recently has been developed and validated in dialysis patients. STUDY DESIGN: Observational cross-sectional study. SETTING & PARTICIPANTS: 993 prevalent kidney transplant recipients. PREDICTOR: MIS computed from change in body weight, dietary intake, gastrointestinal symptoms, functional capacity, comorbid conditions, decreased fat store/Systemic Global Assessment, signs of muscle wasting/Systemic Global Assessment, body mass index, serum albumin level, and serum transferrin level. OUTCOMES: Markers of inflammation and malnutrition, including serum C-reactive protein, interleukin 6, tumor necrosis factor alpha, serum leptin, prealbumin, body mass index, and abdominal circumference. The relationship was modeled by using structural equation models. RESULTS: Mean age was 51 +/- 13 years, 57% were men, and 21% had diabetes. Median time from transplant was 72 months. MIS significantly correlated with abdominal circumference (r = -0.144), serum C-reactive protein level (r = 0.094), serum interleukin 6 level (r = 0.231), and serum tumor necrosis factor alpha level (r = 0.102; P < 0.01 for all). A structural equation model with 2 latent variables (malnutrition and inflammation factor) showed good fit to the observed data. LIMITATIONS: Single-center study, lack of information about vascular access, presence of nonfunctioning kidney transplant, relatively high refusal rate. CONCLUSIONS: Our results confirm that MIS reflects both energy-protein wasting and inflammation in kidney transplant recipients. This simple instrument appears to be a useful tool to assess the presence of protein-energy wasting in this patient population.

[The role of marginal donors in liver transplantation. The Hungarian experience]. / Marginális donorok szerepe a magyar májátültetési programban.

UNLABELLED: Availability of suitable donor organs has always limited liver transplantations. Use of marginal donors (Extended Donor Criteria) for liver transplantation is an alternative to overcome the organ shortage. The aim of this study was to analyze the characteristics of organ donation in Hungary with special regard to marginal donors. METHODS: We reviewed data from donors and recipients between January 2003 and December 2008 retrospectively. Extended donor criteria were adopted from international recommendations. RESULTS: During this period, 1078 donors were reported to the clinic. 835 (77.4%) donors were excluded from liver transplantation and 243 (22.6%) were implanted. From the 243 transplantations 40 recipients (16%) received marginal graft, 203 (84%) received non-marginal graft. Extended Donor Criteria status had no negative impact on the patient and graft survival, postoperative graft dysfunction, and other complications. Recurrence of Hepatitis C occurred earlier in those patients who received marginal graft. CONCLUSION: There is an increasing number of patients waiting for liver transplantation in Hungary. There is no significant difference in morbidity and mortality of patients receiving marginal or non-marginal graft. Use of marginal grafts should be avoided in Hepatitis C virus positive recipients. Acceptance of older donors for liver transplantation should be considered.

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.

[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.

[Crosstalk between cholesterol homeostasis and drug metabolism]. / A koleszterinhomeosztázis és a gyógyszer-metabolizmus kapcsolata.

Nowadays cardiovascular diseases are among the major causes of mortality in the developed world. High cholesterol level in blood and atherosclerosis play the main role in progression of cardiovascular diseases. Reducing serum cholesterol level has been shown to avoid deleterious effects, whereas in serious diseases it improves the outcome. A widely used, statin-based therapy induces a decrease in de novo cholesterol biosynthesis in the liver. Another possibility for lowering serum cholesterol level is to block the uptake of dietary cholesterol from intestine (e.g. ezetimibe). Coadministration of statins and cholesterol uptake inhibitors provides an efficient therapeutical strategy. Several therapeutic agents, reducing serum cholesterol level, are able to regulate the expression of not only cholesterogenic enzymes, but of the major drug metabolizing enzymes, cytochromes P450. The crosstalk between cholesterol homeostasis and drug metabolism is mediated by nuclear receptors, activating target genes in response of endogenous and exogenous ligands. Better understanding of the crosstalk between cholesterol homeostasis and drug metabolism is essential for developing an adequate strategy in therapy and in novel drug development.