Population pharmacokinetics of ganciclovir after valganciclovir in renal transplant children.

BACKGROUND: Valganciclovir, the ganciclovir prodrug, is an antiviral agent administered orally to prevent or treat cytomegalovirus infection in solid organ transplant recipients. Dosing regimen of valganciclovir is still controversial in children, as the number of patients reaching the Area Under the Curve at steady state (AUCss) target (40 - 60 mg.h/L) remains highly variable. The aim of this study was to determine the population pharmacokinetics of valganciclovir in paediatric renal transplant recipients and propose an appropriate dosing regimen. METHODS: Renal transplant children who received valganciclovir to prevent or treat cytomegalovirus infection at Robert Debré University Hospital were included. Plasma ganciclovir concentrations were determined by high performance liquid chromatography and ultraviolet detection. Population pharmacokinetic analysis was performed with NONMEM software. RESULTS: 104 patients, aged 2 to 20 years, treated with valganciclovir administered at a mean dose of 17.3 ± 6.1 mg/kg to prevent and/or treat cytomegalovirus infection after renal transplantation were included. A total of 1212 samples were available. A two-compartment model with first-order elimination best fitted the data: ganciclovir clearance increased with body surface area, was 15% higher in boys and decreased with increasing creatinine concentration. Central volume of distribution increased with body surface area and was 14% higher in boys. According to the personalized dosing regimen, 65.7% and 65.4% of children were predicted to achieve the AUCss target for cytomegalovirus prophylaxis and treatment, respectively. CONCLUSION: A new pharmacokinetic model was built allowing to propose individualised dose adapted to renal transplanted paediatric patients characteristics.

Leflunomide for BKvirus: Report of Seven Kidney-Transplanted Children.

BACKGROUND: Leflunomide is an immunosuppressive agent commercialized for treatment of rheumatoid arthritis. Because of its immunosuppressive and possible antiviral properties, leflunomide has been evaluated in some case series of BKVAN with favorable results, mostly in adult patients. Leflunomide targeted levels are usually between 50 and 100 mg/L in kidney transplant adult patients. Data in pediatric population are scarce. OBJECTIVE: To assess the effect of leflunomide on BKvirus in kidney-transplanted children. METHODS: Therapeutic drug monitoring of leflunomide is routinely performed by measuring its active metabolite, teriflunomide, using a simple HPLC-UV method. Pediatric kidney transplant patients with at least one teriflunomide sample between 2010 and 2017 were retrospectively included in this study. Viremia control was defined as undetectable BK viremia or a decrease of more than 1 log in the viral load from the baseline after two months of treatment. Adverse events were recorded. RESULTS: A total of 7 patients from 3 centers was included. 6 were only kidney transplant recipients; 1 was a lung-kidney transplant recipient with cystic fibrosis. All patients reported high load BK viremia but none developed BKVAN. For 67% of the patients, complete BK viral clearance was observed during leflunomide treatment with drastic immunosuppressive therapy reduction. Mycophenolate was indeed discontinued in almost all patients. Of note, leflunomide concentrations were significantly higher when viremia was controlled. Only 33% of the observed concentrations were >40 mg/L. The patient with cystic fibrosis had lower concentrations with higher drug doses. No hepatotoxicity was observed in this study and no patient experienced graft rejection. Leflunomide was suspected to cause hemolytic anemia and one patient experienced biological pancreatitis. CONCLUSION: This study evidenced the wide interindividual variability of the exposure and supported the routine practice of leflunomide with a suggested target level of 30-40 mg/L in pediatric kidney transplanted patient. However, because of the very limited number of patients in our series, further investigations are needed to validate this suggestion.

Comparison between valganciclovir and aciclovir/valaciclovir for CMV prophylaxis in pediatric renal transplantation.

Prophylaxis has dramatically decreased the occurrence of cytomegalovirus (CMV) infection after renal transplantation. Optimal regimens of treatment remain controversial, especially in pediatric recipients. The aim of this study was to evaluate the effectiveness of valganciclovir (VGC) versus aciclovir/valaciclovir (ACV) in a pediatric renal transplant population. Data from 101 renal transplantations were retrospectively analyzed. Except those with R-/Dstatus, all patients received prophylaxis either with ACV, n = 39 or VGC, n = 38. Incidences of positive CMV antigenemia and disease, as well as the delay in relation to the prophylaxis, were collected during at least 12 months after the end of treatment. Positive CMV antigenemia was reported in 34 patients (ACV: 16, VGC: 16, no prophylaxis: 2). CMV disease occurred in 15 patients (ACV: 5; VGC: 8) (ns). For the majority of patients under VGC, positive CMV antigenemia occurred within the year following the withdrawal of prophylaxis (VGC: 14; ACV: 5, P <0.05), whereas it occurred during prophylaxis in 11 patients under ACV versus two under VGC (P <0.05). The over-all incidence of positive CMV antigenemia was similar between ACV and VGC prophylaxis. However, VGC was more efficient to prevent early CMV infection while patients treated with ACV had less CMV infection or disease after the end of the prophylaxis.

Renal transplantation in children: critical analysis of age related surgical complications.

To determine age-related risk factors of urological and vascular complications. We performed a retrospective analysis of the data of 202 renal transplantations in 193 children between 1989 and 2007 at a single institution. Out of 193 grafts (combined renal and liver grafts were excluded), we observed urological complications in 42 cases (21.7%) leading to graft loss in one case and vascular complications in 27 cases (13.9%) leading to graft loss in seven. The urological complications were VUR (n=25, 12.4%), ureteral stricture (n=10, 5%), anastomotic leak (n=4, 2%), ureteral necrosis (n=2, 1%), and incrustative pyelitis (n=1, 0.5%). Vascular complications were arterial stricture (n=14, 7.2%), arterial thrombosis (n=4, 2%), venous thrombosis (n=2, 1%), and others (n=7). Donors aged less than six yr were a risk factor of vascular complications leading to graft loss (p=0.0001), whereas patients with PUV had more urological complications (p=0.001). Overall patient and graft survival is 93.1% and 84% at five yr, respectively. Surgical complications remain a major cause of graft loss (12%) and morbidity in children's kidney transplantation (38.9%). Young age of donors is the major risk factor of early graft loss as a result of vascular complication. However, donor selection based on age is limited by the shortage of organs.

Mortality in pediatric renal transplantation: a study of the French pediatric kidney database.

OBJECTIVE AND METHODS: To assess patient survival in pediatric renal transplantation, we retrospectively reviewed 573 transplants in 553 patients, registered from 1995 to 2005. RESULTS: Mean age at transplantation was 9.9 years. Patient survival at 1, 5 and 10 years was respectively 99%, 97% and 96%. Death occurred at a median time of 2.6 years after transplantation. Long-term patient survival was significantly lower in recipients younger than 5 years old. Seventeen patients (3.1%) died. Two deaths occurred while under maintenance dialysis. Among the remaining patients, the two main causes of death were infections (33%) and malignancies (27%). Interestingly, initial disease-related complications were a major cause of death (34%). CONCLUSION: A low mortality rate was observed, with the majority of deaths due to malignancies and infections, and with a notable participation of complications related to the initial disease. No impact of cardiovascular disease was noted with the given follow-up period. Improvements in managing immunosuppression may contribute to reducing mortality in pediatric renal transplantation.

Population pharmacokinetics of mycophenolic acid in kidney transplant pediatric and adolescent patients.

Current data on mycophenolate mofetil (MMF) suggest that there is a pharmacokinetic/pharmacodynamic relationship between the mycophenolic acid (MPA) area under the curve (AUC) during treatment and both the risk of acute rejection and the occurrence of side effects. The aim of this study was to characterize the population pharmacokinetics of MPA in kidney transplant patients between the ages of 2 and 21 years and to propose a limited sampling strategy to estimate individual MPA AUCs. Forty-one patients received long-term oral MMF continuous therapy as part of a triple immunosuppressive regimen, which also included cyclosporine or tacrolimus (n=3) and corticosteroids. Therapy was initiated at a dose of 600 mg/m twice daily. The population parameters were calculated from an initial group of 32 patients. The data were analyzed by nonlinear mixed-effect modeling using a 2-compartment structural model with first-order absorption and a lag time. The interindividual variability in the initial volume of distribution was partially explained by the fact that this parameter was weight-dependent. Fifteen concentration-time profiles from 13 patients were used to evaluate the predictive performance of the Bayesian approach and to devise a limited sampling strategy. The protocol, involving two sampling times, 1 and 4 hours after oral administration, allows the precise and accurate determination of MPA AUCs (bias -0.9 microg.h/mL; precision 6.02 microg.h/mL). The results of this study combine the relationships between the pharmacokinetic parameters of MPA and patient covariates, which may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing pediatric patient care.

Pharmacokinetics and tolerance of mycophenolate mofetil in renal transplant children.

Mycophenolate mofetil (MMF) is a prodrug that is hydrolyzed to the active immunosuppressant mycophenolic acid (MPA). The drug is now widely prescribed for adult renal transplant recipients and its use has been extended to pediatric patients, although pharmacological data in this age group are limited. Nine pediatric renal transplant recipients received MMF with corticosteroids and either cyclosporine or tacrolimus a median of 55 months (range 7.5-124 months) months after transplantation. The pharmacokinetic parameters of MPA and MPA glucuronide (MPAG) were determined at steady state by high-performance liquid chromatography after administration of MMF at the oral dose of 494+/-142 mg/m(2) twice daily. MPA was rapidly absorbed, with a peak concentration at 1.4 h. The mean plasma concentration of MPA at steady state was 4.7+/-1.3 microg/ml. The areas under the plasma concentration-time curves (AUCs) over 12 h (between two administrations) were 57.0+/-15.3 microg.h/ml for MPA and 1,515+/-722 microg.h/ml for MPAG, and the apparent oral clearance was 11.7+/-7.0 and 0.5+/-0.4 l/h for MPA and MPAG, respectively. Assuming that the pharmacokinetics of MPA was dose dependent, the mean concentration at steady state and the AUC for MPA were calculated for the recommended dosage schedule of 600 mg/m(2) every 12 h and were 6.3+/-2.7 microg/ml and 75.2+/-32.9 microg.h/ml, respectively. The tolerance of MMF was studied prospectively with a follow-up of 1.1+/-0.2 years. Gastrointestinal disorders requiring dosage reduction or discontinuation of therapy, observed in five of nine patients, occurred at an incidence higher than expected from adult data. Our results suggest that the dose of 600 mg/m(2) every 12 h extrapolated from adult data for use in pediatric patients would be associated with plasma levels and AUCs higher than expected and may be associated with a higher incidence of side-effects, primarily gastrointestinal.

Post graft development of short children treated with growth hormone before kidney graft.

Sixteen prepubertal patients with chronic renal failure (CRF) were given daily recombinant human growth hormone (rhGH) treatment (1.2 IU/kg per week) for 2.6+/-1.6 years until kidney transplant. Therapy was then discontinued and the patients followed for a further 3. 5+/-1.4 years. During treatment, mean height increased from -3.0+/-0. 9 standard deviation score (SDS) to -1.9+/-1.4 SDS (P<0.001) at the time of transplantation, corresponding to a mean height gain of +1. 2+/-0.9 SDS. After discontinuation of rhGH therapy, prepubertal children continued a partial catch-up growth with a height gain of +0.5+/-0.8 SDS for the follow-up period. Conversely, negative changes of height were observed in pubertal transplanted children: -0.5+/-0.4 SDS in patients grafted at early stages of puberty (P2-P3) and -0.15+/-0.9 SDS in patients grafted at late stages of puberty (P4-P5). These data confirmed the benefit of rhGH therapy in CRF patients. Nevertheless, only early initiation of rhGH treatment led some of these patients to their target height at transplantation, thus preserving their potential growth. Reinitiation of rhGH therapy after transplantation should be considered in order to complete catch-up growth to target height in prepubertal children.

Thiopurine methyltransferase activity and its relationship to the occurrence of rejection episodes in paediatric renal transplant recipients treated with azathioprine.

AIMS: Azathioprine is a prodrug commonly used in combination therapy to prevent allograft rejection after renal transplantation. After conversion to 6-mercaptopurine, the drug is metabolized into 6-thioguanine nucleotides (6-TGN) and catabolized by thiopurine methyltransferase (TPMT), an enzyme under monogenic control. The aim of this study was to evaluate the inter- and intraindividual variability of red blood cell thiopurine methyltransferase and 6-TGN concentrations and their relationship to the clinical effects of azathioprine in paediatric patients. METHODS: In the present study, the inter- and intraindividual variations in red blood cell TPMT activity and 6-TGN concentrations and their relationship to the actions of azathioprine were evaluated during the first year after renal transplantation in 22 paediatric patients. RESULTS: 6-TGN concentration reached steady-state values after 6 months and correlated negatively with TPMT activity (P=0.004). Initial TPMT activity (median: 20.8 nmol h-1 ml-1, range 7.8-34.6) and 6-TGN concentration at steady-state (median: 80 pmol 8 x 10(8-1) cells, range not detected to 366) were not related to the occurrence of rejection episodes during the period of the study. In contrast, TPMT activity and the percentage difference in TPMT activity from the day of transplantation determined at month 1 were higher in the patients with rejection episodes by comparison with those that did not reject during the first 3 months or the first year following transplantation (P<0.005). CONCLUSIONS: We report a relationship between TPMT activity and occurrence of rejection in paediatric kidney transplant patients undergoing azathioprine therapy. These data suggest a link between high red blood cell TPMT activity and poor clinical outcome probably caused by rapid azathioprine catabolism.

[Passage from sandimmun to neoral in kidney transplantation in children]. / Passage du Sandimmun au Néoral en transplantation rénale chez l'enfant.

BACKGROUND: The cyclosporine microemulsion formulation Neoral, which allows a better absorption and a more regular pharmacokinetic profile, is proposed for replacing the original formulation, Sandimmun. The present study reports the results of conversion from Sandimmun to Neoral in children with a kidney graft, a population for which information remains limited. METHODS AND PATIENTS: Twenty children, 2.5 to 10.5 years of age, who had a kidney graft with a stable renal function for between six months to five years (m = 2.6) were the subjects of this study. The patients were switched from Sandimmun to Neoral at the same dose, adjusted afterwards on a cyclosporine trough level. RESULTS: After six months, the mean dose decreased from 9.1 mg/kg/d to 8.4 mg/kg/d, i.e., 12.5%. After one year, the mean dose was 7 mg mg/kg/d, i.e., 28%. Of the 65% of patients who had a decreased dose, most of them had the highest dose of Sandimmun at the start. Mean serum creatininemia levels slightly increased from 85.6 to 89.5 mumol/L after six months (P = 0.03). None of the patients had a rejection crisis during the first six months under Neoral. Blood pressure did not change significantly, hirsutism improved in two cases but increased or appeared in two cases as well. Gingival hypertrophy increased or appeared in four cases. DISCUSSION: A decrease in the dose was decided on either to maintain the trough CsA blood level in the desired range or because of the appearance of a symptom suggesting a side effect of cyclosporine, especially the increase of creatinemia. The trough level did not appear to be the best index for adapting the dose. CONCLUSION: In stable pediatric kidney transplant recipients, the switch from Sandimmun to Neoral provided a reduction in drug dosage in 65% of cases without an increase in adverse events.

[Surgical aspects of renal transplantation in children]. / Aspects chirurgicaux de la transplantation rénale chez l'enfant.

Review of a series of 90 renal transplantations performed in 86 children revealed 3 cases of early or late mortality and 28 cases of major surgical complications, predominantly vascular (13 cases) and urological complications (12 cases). The time to onset, the diagnosis and the management of these complications are reviewed. This study again emphasizes the importance of graft selection (donor age) and the value of living related donor renal transplantation.

[Treatment of anemia in hemodialyzed children using recombinant human erythropoietin (Eprex). Results of a French multicenter clinical trial]. / Traitement de l'anémie des enfants hémodialysés par l'érythropoïétine humaine recombinante (Eprex). Résultats de l'essai clinique multicentrique français.

Intravenous recombinant human erythropoietin (Eprex Cilag) was used in 28 hemodialyzed children, treated in 3 French paediatric centers, from November 1989 to November 1990. Transfusion dependency disappeared in all cases: the number of transfusions decreased from 7.3 unit/patient/year to 0.6 unit/pt/year. The mean haemoglobin concentration for the whole group increased from 6.6 +/- 0.8 g/dl, to 9.2 +/- 1.2 at 6 months and 9.7 +/- 0.7 g/dl at 1 year. Twenty-two out of 28 children reached the target haemoglobin value of 9.6 g/dl (6 mmol/dL) within a mean time of 16.5 weeks. Poor responses were due to either a premature withdrawal of treatment because of renal transplantation, or too low a dosage for the age. The study showed indeed that the dose requirement was significantly dependent on physical development: the mean dosage required to maintain haemoglobin concentration at the target value was 300 U/kg/week in children weighing less than 20 kg, 222 U/kg/week in 20-30 kg children, and 135 U/kg/week in those weighing more than 30 kg (p = 0.02). The only complication was an increase in blood pressure, observed in 43% of cases. The increase of anti-hypertensive medication was always successful in controlling blood pressure, and hospitalization was required in only one case. The improvement in general condition was obvious, and in several cases, the cognitive abilities seemed to improve. The growth deficit remained unchanged.

[Ambulatory blood pressure measurement in children and adolescents with kidney transplants]. / Ambulante Blutdruckmessung bei nierentransplantierten Kindern und Jugendlichen.

Arterial hypertension (HT) is a common complication after renal transplantation. We evaluated ambulatory blood pressure profiles during 24 h in 30 pediatric patients (pts) aged 6-22 years who had been transplanted 2 months to 7 years previously. Creatinine clearance was 14-121 (median 57) ml/min/1.73 m2. Twenty-three pts were being treated with ciclosporin. Sixteen pts received antihypertensive drugs. Using the monitor Nippon Collins 630 (Baxter), blood-pressure (BP) values were taken every 20 min during the day and overnight (10 p.m.-7 a.m.). Five out of 10 pts with elevated office BP readings were normotensive by ambulatory blood pressure monitoring (ABPM). Ambulatory hypertension was discovered in one child with normal office BP. Echocardiography was performed in 23 pts. Five of six pts with significant left-ventricular hypertrophy (LVH), but none of the 17 pts without LVH had ambulatory HT (p less than 0.01). The physiological decline of BP during the night was significantly reduced when compared to 21 subjects of similar age with essential HT (-9.2% vs. -15.4%; p less than 0.02); no correlation was found with renal function or prednisone dose. Ciclosporin tended to reduce the day-night gradient (-14.5% vs. -9.2%; p = 0.11). One child showed a severe nocturnal BP rise of 25 mmHg. We conclude that abnormalities of nyctohemeral BP rhythm, as described in transplanted adults, can be observed to a lesser extent in children. ABPM allows a better evaluation of BP compared to office BP and, thus, may contribute to a better management of these patients.

Immunogenicity of hepatitis B vaccine (HEVAC B) in children with advanced renal failure.

The immune response after hepatitis B (HB) vaccine HEVAC B was studied in 33 children (mean age 10 +/- 4 years) with advanced renal failure. Responders and protected patients were defined by antibody titres to HB surface antigen (anti-HBs) of greater than 10 and 50 mIU/ml, respectively. All received the initial recommended three injections at monthly intervals, and 23 received a booster injection (IB) 11 +/- 1 months after the third injection (I3). Loss of protection after I3 led to additional injections in 8 patients (25%). Vaccine was well tolerated and no HB infection occurred during the follow-up period (19 +/- 10 months). The percentage of responders was 91% 2 +/- 1 months after I3, and 100% 1 month, 13 +/- 1 months and 26 +/- 2 months after IB. The percentages of protected patients at these dates were 91%, 95%, 100% and 100%. Anti-HBs titres 1-3 months after I3 were useful for indicating those patients likely to have a rapid decline in anti-HBs titres, thus requiring serial anti-HBs determinations and additional injections to prevent a loss of protection. We conclude that at the expense of a reinforced vaccination schedule in 25% of patients, HEV AC B vaccine can safely achieve a sustained protection in more than 90% of uraemic children.

[The intellectual development of children with severe early kidney insufficiency]. / Développement intellectuel des enfants atteints d'insuffisance rénale grave précoce.

Recent studies have suggested that patients with neonatal onset of severe renal failure may be at risk for mental retardation. We studied the intellectual development of 13 pediatric patients with neonatal onset of severe renal failure who immediately received active medical therapy. The verbal, performance, and overall intelligence quotient (IQ) was determined using the Weschler-PPSI and the WISC-R at a mean age of 7 years and 4 months (4 years 5 months to 15 years 8 months). Mean overall IQ was 89 (73 to 106), mean verbal IQ was 94.7 (79 to 124) and mean performance IQ was 85.6 (69 to 112). Overall IQ was greater than 100 (101 to 106) in three patients (23%), and under 100 in ten patients (77%), with values of 87 to 92 in six cases (46%) and 73 to 84 in four cases (31%). A significant negative correlation (p less than 0.05) was found between the IQ and the length of hospital or medical institution stays during the first year of life. We found no significant correlation either between IQ and severity of renal failure, quality of growth or nutritional status before the age of two, or between IQ and dose of aluminum ingested. Our results suggest that early severe renal failure does not induce severe mental retardation. However, in 77% of studied children the IQ was within the lower portion of the normal range or under this normal range. This proportion is greater than that seen in normal children from similar socioeconomic backgrounds. Reducing hospital stays and separations from home, as well as even more active nutritional management, may help to improve these children's mental abilities.

Hickman catheter for haemodialysis in paediatric patients.

Twelve Hickman catheters were inserted in nine children in order to establish access for haemodialysis or plasmapheresis. Catheters were implanted either through the external or internal jugular vein and the tip located in the right atrium or superior vena cava. Mean blood flow was 25-55 ml/min with single lumen catheters and 83-100 ml/min with double lumen catheters. Three catheters had to be removed because of obstruction, whilst seven remained in situ until an arteriovenous fistula had matured or renal function was restored. Infection in two cases was successfully treated with antibiotics and transient obstruction by urokinase instillation. Following catheter removal, angiographic studies showed that with one exception all catheterized vessels were obstructed, but this did not prevent from ipsilateral arteriovenous fistulas to mature satisfactorily.