Burkhard Rodeck

Tacrolimus and steroids versus ciclosporin microemulsion, steroids, and azathioprine in children undergoing liver transplantation: randomised European multicentre trial.

BACKGROUND Results of studies in adult recipients of liver allograft suggest that tacrolimus is more efficacious than ciclosporin microemulsion in the prevention of acute rejection. We aimed to compare these drugs in children undergoing liver transplantation. METHODS This 12-month multicentre, open-label, parallel-group, randomised study compared a dual tacrolimus regimen (tacrolimus/corticosteroids, n=93) with a triple ciclosporin microemulsion regimen (ciclosporin microemulsion/corticosteroids/azathioprine, n=92) in children who had had liver transplants (age < or =16 years, bodyweight < or =40 kg). Initial oral daily doses were 0.30 mg/kg for tacrolimus and 10 mg/kg for ciclosporin microemulsion. Primary endpoint was the incidence of and time to first histologically proven acute rejection. We excluded patients from analysis if they did not receive the study drug, or were given incorrect medication. Otherwise patients were analysed in accordance with their random treatment allocation, irrespective of whether they switched medication during the trial. FINDINGS Median age was 22 months (IQR 9-56) in the tacrolimus group and 17 months (9-54) in the ciclosporin microemulsion group. We noted no difference between treatment groups with respect to patient survival (93.4% vs 92.2%; p=0.77) or graft survival (92.3% vs 85.4%; p=0.16) at month 12 after transplant. The acute rejection free rate at study end (Kaplan-Meier method) was 55.5% for patients on tacrolimus and 40.2% for patients on ciclosporin microemulsion (p=0.0288). The Kaplan-Meier estimate of patients free from corticosteroid-resistant acute rejection at study end was 94.0% for tacrolimus-treated patients and 70.4% for ciclosporin-microemulsion-treated patients (p<0.0001). Overall, incidence of adverse events did not differ between groups. INTERPRETATION Tacrolimus is a safe and effective treatment for the prevention of rejection after liver transplantation in children.

Treatment of inherited metabolic disorders by liver transplantation

SummaryAmong the worldwide accepted indications for liver transplantation, inherited metabolic disorders play an increasing role. In some paediatric centres this indication runs second after extrahepatic biliary atresia.The aim of liver transplantation in inherited metabolic disorders is twofold: the first is to save a patients life, the second is to accomplish phenotypic and functional cure of his disease. These aims may be achieved in disorders presenting with cirrhosis, hepatoma, life-threatening progression or failure of other organs with preserved liver function. The timing of liver transplantation has become easier with development of surgical techniques of reduced-size donor livers. These techniques enable the performance of liver transplantation with ABO blood group compatible organs of almost any size if indicated either by deterioration of liver function or impending complications such as hepatoma or life-threatening progression. In comparison with other indications such as extrahepatic biliary atresia, postnecrotic liver cirrhosis or acute liver failure, the results of transplantation in patients with inherited metabolic disorders seem to be better, reaching up to 78–95% actuarial 1-year survival rates. However, lifelong immunosuppressive therapy is necessary. This seems to be acceptable even in disorders with only partial liver function defects.

Liver transplantation in children with chronic end stage liver disease: factors influencing survival after transplantation.

To identify pretransplant factors that are influencing survival after orthotopic liver transplantation a Cox proportional hazards regression model was applied to 118 children with chronic terminal liver failure transplanted at Medical School Hannover during the period of 1978 to 1994. The response variable was survival, as covariates a total of 19 pretransplant variables were entered--i.e. age, diagnosis (biliary cirrhosis, metabolic cirrhosis, postnecrotic cirrhosis, cryptogenetic cirrhosis) sex, laparotomy prior to OLT, height, weight, standard deviation scores for height and weight, date of first OLT, serum alanine aminotransferase, asparagine aminotransferase, albumin, total bilirubin, cholinesterase activity, glomerular filtration rate, and prothrombin time. Significant independent predictors of survival after OLT were bilirubin (P=0.0024), SDS for weight (P=0.034), and albumin (P=0.039). In a subsequent discriminant analysis cut off points for these variables could be identified--i.e., bilirubin >340 micromol/L, SDS for weight <-2.2 and albumin < 33 g/L. Patients with one or more of these risk factors were grouped as urgent indication group (n=76) and those with no risk factor as elective indication group (n=42). Comparing the posttransplantation survival in these groups there is a statistically significant difference at 1 year (57% vs. 90.5%) and 4 years (49% vs. 90.5%) after OLT (P=0.0001, log rank test). It is concluded that the risk of OLT is much higher if liver function is very poor. Optimal nutritional support prior to transplantation is mandatory to optimise the clinical status of the children and to improve the results of OLT.

Basiliximab in pediatric liver transplantation: A pharmacokinetic-derived dosing algorithm

Abstract: The pharmacokinetics and immunodynamics of basiliximab were assessed in 37 pediatric de novo liver allograft recipients to rationally design a dose regimen for this age‐group. In part one of the study, patients were given 12 mg/m2 basiliximab by bolus intravenous injection after organ perfusion and on day 4 after transplant. An interim pharmacokinetic evaluation supported a fixed‐dose approach for part two of the study in which infants and children received two 10‐mg doses of basiliximab and adolescents received two 20‐mg doses. Blood samples were collected over a 12‐week period for screening for anti‐idiotype antibodies and analysis of basiliximab and soluble interleukin‐2 receptor (IL‐2R) concentrations. Basiliximab clearance in infants and children < 9 yr of age (n = 30) was reduced by ≈ 50% compared with adults from a previous study and was independent of age to 9 yr, weight to 30 kg, and body surface area to 1.0 m2. Clearance in children and adolescents 9–14 yr of age (n = 7) approached or reached adult values. An average of 15% of the dose was eliminated via drained ascites fluid, and drug clearance via this route averaged 29% of total body clearance. Patients with > 5 L of ascites fluid drainage tended to have lower systemic exposure to basiliximab. CD25‐saturating basiliximab concentrations were maintained for 27 ± 9 days in part one of the study (mg/m2 dosing) with infants exhibiting the lowest durations. CD25 saturation lasted 37 ± 11 days in part two of the study, based on the fixed‐dose regimen (p = 0.004 vs. mg/mg2 dosing), but did not show the age‐related bias observed in part one of the study. Anti‐idiotype antibodies were detected in four patients, but this did not influence the clearance of basiliximab or duration of CD25 saturation. All 40 enrolled patients were included in the intent‐to‐treat clinical analysis. Episodes of acute rejection occurred in 22 patients (55%) during the first 12 months post‐transplant. Three patients experienced loss of their graft as a result of technical complications, and six patients died during the 12‐month study. Basiliximab was well tolerated by intravenous bolus injection, with no cytokine‐release syndrome or other infusion‐related adverse events. Hence, basiliximab was safe and well tolerated in pediatric patients undergoing orthotopic liver transplantation. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients < 35 kg in weight should receive two 10‐mg doses and those ≥ 35 kg should receive two 20‐mg doses of basiliximab by intravenous infusion or bolus injection. The first dose should be given within 6 h after organ perfusion and the second on day 4 after transplantation. A supplemental dose may be considered for patients with a large volume of drained ascites fluid relative to body size.

Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation

Mutations within the low density lipoprotein (LDL)‐receptor gene result in familial hypercholesterolemia, an autosomal dominant inherited disease. Clinical homozygous affected subjects die of premature coronary artery disease as early as in early childhood. We identified a girl at the age of five yr with clinical homozygous familial hypercholesterolemia presenting with achilles tendon xanthomas and arcus lipoides. Her total cholesterol reached up to 1050 mg/dL. Molecular characterization of the LDL‐receptor gene revealed a homozygous p.W577R mutation. Despite intensive treatment interventions with the combination of diet, statins, colestipol, and LDL‐apheresis, the patient developed symptomatic coronary artery disease at the age of 16 yr. Subsequently, orthotopic liver transplantation was performed to cure the defective LDL‐receptor gene. Clinical follow‐up for almost nine yr post‐transplantation revealed excellent liver function, normal liver enzymes, normal LDL‐cholesterol, and regression of both tendon xanthomas and symptomatic coronary artery disease. In conclusion, liver transplantation can effectively reduce LDL‐cholesterol in a familial hypercholesterolemia recipient with subsequent regression of xanthomas and atherosclerosis. Timing is extremely important in these exceptional cases to exclude the demand for heart transplantation due to severe coronary artery disease. In addition, the identification of the LDL‐receptor as etiology of clinical homozygous hypercholesterolemia is a prerequisite once liver transplantation is considered as therapeutic option.

Dual versus triple therapy of Helicobacter pylori infection: results of a multicentre trial

OBJECTIVE To compare dual therapy (omeprazole and amoxicillin) with triple therapy (omeprazole, amoxicillin, and clarithromycin) in the treatment ofHelicobacter pylori infection. The efficacy of 1 mg/kg/day omeprazole was randomly compared with 2 mg/kg/day. STUDY DESIGN 252 patients (median age, 11.0 years; range, 3–18) presenting with chronic abdominal pain underwent endoscopy and a 13C-urea breath test. Gastric biopsy specimens were taken for histological examination and for the rapid urease test. Patients were treated for two weeks: group A (n = 63) received amoxicillin (50 mg/kg; maximum, 2 g/day), group B (n = 73) received amoxicillin and clarithromycin (20 mg/kg; maximum, 1 g/day). Both groups were randomly treated with either 1 or 2 mg/kg omeprazole (maximum, 80 mg/day). Diagnostic procedures were repeated four weeks after the end of treatment. RESULTS 11 patients were excluded; 136 patients were H pyloripositive (56%), 105 of whom were re-examined after treatment.Helicobacter pylori was eradicated in 52% of group A and 83% of group B. The dose of omeprazole had no influence on the eradication rate. Specificity and sensitivity of the rapid urease test were 94% and 93%, respectively. Specificity and sensitivity of the 13C-urea breath test were 93% and 95%, respectively. CONCLUSIONS Dual therapy can no longer be recommended. Triple therapy is more effective than dual therapy in the eradication of H pylori infection. The lower dose of 1 mg/kg omeprazole was as effective as 2 mg/kg.

Improvement of Growth After Growth Hormone Treatment in Children Who Undergo Liver Transplantation

Background Chronic liver insufficiency in children is frequently associated with growth retardation. Growth resumes after successful orthotopic liver transplantation in the majority of children with previous chronic liver failure. However, a subgroup of children demonstrates stunted growth even after orthotopic liver transplantation. The current study was conducted to determine whether administration of recombinant human growth hormone might benefit these patients. Methods Ten children were identified who met the criteria of growth failure despite normal transplant function in a cohort of 60 transplantation patients: height standard deviation score (hSDS) for chronological age less than −2, and growth velocity SDS (gvSDS) for chronological age equaling 0. Seven of these patients were treated with subcutaneous injections of recombinant human growth hormone at 4.0 U/m2 body surface area per day for at least 1 year. Two patients in this group showed insufficient growth hormone response to stimulation (arginine, clonidine) before therapy. Treatment was begun after a median time of 4.6 years after liver transplantation (2.55–8.4 years). Five children were treated with cyclosporin A and prednisolone and two with tacrolimus and prednisolone for maintenance immunosuppression. Results Within 3 months of treatment, median serum levels of insulin-like growth factor (IGF)-I increased from 0.05 to 0.71 (P < 0.02). Within 1 year, median hSDS improved from −2.7 (range, −5.6 to −2.3) to −2.1 (−4.5 to −1.4;P < 0.03). Median annual growth rate increased from 3.9 cm/year (range, 3–6) in the year before treatment to 8.2 cm/year (range, 6.1–10.4;P < 0.02) after the beginning of recombinant human growth hormone therapy. All patients tolerated treatment without side effects. During the cumulative treatment time of 14 years no rejection episode was observed. Conclusions Short-statured prepubertal liver transplant recipients who do not show sufficient compensatory growth after transplantation benefit from treatment with recombinant human growth hormone. Treatment with the hormone was safe without any side effects.

Prediction of survival in extrahepatic biliary atresia by hepatic duplex sonography

BACKGROUND The clinical course of biliary atresia patients is extremely variable. To optimize conservative treatment and correctly schedule liver transplantation, noninvasive investigations that are predictive of individual survival and that can be performed regularly are needed. In this study, the prognostic value of Doppler sonography was investigated in these patients. METHODS Thirty biliary atresia patients (age range, 1 month to 15.2 years; mean, 4.0 years) and 38 control subjects underwent standardized Doppler sonography of liver and spleen. Biochemical tests of liver function and of fibrogenesis were performed in parallel. Individual clinical outcome was registered 1 and 2 years later. RESULTS In control subjects, maximum portal flow velocity (Vmax) was more than 16 cm/sec, and the hepatic vein flow pattern was triphasic. Among children with biliary atresia, those with diminished portal Vmax, a flattened hepatic vein flow curve, or a hepatic artery resistance index of 0.8 or more had significantly lower indices of hepatic protein synthesis (albumin, cholinesterase), higher bilirubin levels, and higher concentrations of markers of connective tissue turnover (procollagen peptides, laminin P1) than did those with normal Doppler sonography measurements. The rate of survival without transplantation during the following 2 years was significantly lower in children with abnormal Doppler findings. From portal and hepatic vein flow measurements, patient survival 2 years later could be predicted with an accuracy of 93%. CONCLUSIONS In children with extrahepatic biliary atresia, Doppler sonography of the hepatic blood flow is a noninvasive indicator of disease severity. Moreover, it allows a highly accurate prediction of patient survival for the following 2 years.

Continuous arteriovenous haemofiltration in critically ill children

We report 24 children with acute renal failure treated with continuous arteriovenous haemofiltration (CAVH) between 1987 and 1991. The median age was 2.9 years (range 3 days to 9 years). The main causes of the acute renal failure were: open heart surgery (n=11) and liver failure of different origins before and after liver transplantation (n=10). The indication for CAVH was oliguria or fluid overload in all children. The femoral vessels were used as vascular access in most instances. Different filters were used, depending on the size of the patient and an average ultrafiltration of 130±89 ml/h was achieved, which resulted in a fluid clearance of 4.0±2.6 ml/min per 1.73 m2. In 18 patients uraemia was adequately controlled. Nine children survived after recovery of their renal function; 15 (62.5%) died as a consequence of multiorgan failure. We conclude that CAVH is an effective method to support critically ill children with acute renal failure.

Conversion from cyclosporin to FK 506 after liver transplantation

Thirty-seven liver-grafted patients with steroid-resistant acute or chronic graft rejection or with cyclosporin-related complications were converted from CyA to FK 506. The clinical outcome of the patients primarily depended on the degree of liver dysfunction present at initiation of FK 506 treatment. In patients switched to FK 506 for treatment of acute or early chronic graft rejection, CyA nephrotoxicity, or CyA malabsorption, the FK 506 therapy was associated with a clear improvement in the clinical course. In contrast, in patients with advanced chronic graft rejection, a lower response rate to the conversion in immunosuppression was observed. The lower response rate was associated with a higher patient mortality. These studies demonstrate that FK 506 represents a valuable alternative immunosuppressant for liver-grafted patients. The conversion from CyA to FK 506 should take place before serious — and potentially irreversible — disturbances in liver function are observed.