Hemolytic uremic syndrome due to Shiga toxin-producing Escherichia coli infection.

The leading cause of hemolytic uremic syndrome (HUS) in children is Shiga toxin-producing Escherichia coli (STEC) infection, which has a major outbreak potential. Since the early 2010s, STEC epidemiology is characterized by a decline of the historically predominant O157 serogroup and the emergence of non-O157 STEC, especially O26 and O80 in France. STEC contamination occurs through the ingestion of contaminated food or water, person-to-person transmission, or contact with ruminants or their contaminated environment. The main symptom is diarrhea, which is bloody in about 60% of patients and occurs after a median incubation period of three days. Shiga toxins released by STEC induce a cascade of thrombogenic and inflammatory changes of microvascular endothelial cells. HUS is observed in 5-15% of STEC infection cases, defined by the triad of mechanical hemolytic anemia, thrombocytopenia, and acute renal injury. The diagnosis of STEC infection relies on biological screening for Shiga toxins and STEC in stools and serology. Treatment of STEC-HUS is mainly symptomatic, as no specific drug has proved effective. The effect of antibiotics in STEC infection and STEC-HUS remains debated; however, some bacteriostatic antibiotics might have a beneficial effect. Proofs of evidence of a benefit from complement blockade therapy in STEC-HUS are also lacking. Clinical and bacteriological STEC-HUS surveillance needs to be continued. Ongoing prospective studies will document the role of bacteriostatic antibiotics in STEC infection and STEC-HUS, and of complement blockade therapy in STEC-HUS.

[Hemolytic and uremic syndrome and related thrombotic microangiopathies: Treatment and prognosis]. / Syndromes hémolytiques et urémiques (SHU) et syndromes de microangiopathie thrombotique apparentés : traitement et pronostic.

Major achievements in the understanding of thrombotic microangiopathies (TMA) have not only resulted in a reclassification of TMA but most of all they have culminated in the design of new treatments and have enabled clinicians to better delineate their prognosis. Recent multicenter studies have improved our understanding of the prognosis of atypical hemolytic and uremic syndromes (aHUS). More specifically, they have highlighted the role of genetic testing on predicting the recurrence of aHUS, the risk of chronic kidney disease and the recurrence following kidney transplantation. A major advance consisted of the identification of the alternative complement pathway in the pathogenesis of aHUS, thus paving the way for the use of the C5a inhibitor eculizumab in this indication. Eculizumab has thereafter dramatically improved the management of patients affected with aHUS. During spring 2011, a great epidemic of entero-hemorrhagic Escherichia coli (EHEC) associated HUS occurred in Germany, providing clinicians the opportunity to examine the relevance of antibiotic prophylaxis, plasma exchange and eculizumab in EHEC-associated HUS. In this work, we herein present advances achieved in the setting of therapeutic management and prognosis in HUS and other related TMA syndromes.

[Hemolytic and uremic syndrome and related thrombotic microangiopathies: Epidemiology, pathophysiology and clinics]. / SHU et syndromes de microangiopathie thrombotique apparentés : épidémiologie, physiopathologie et tableaux cliniques.

Thrombotic microangiopathies (TMA) represent an eclectic group of conditions, which share hemolytic anemia and thrombocytopenia as a common defining basis. Remarkable breakthroughs in the physiopathological setting have allowed for a thorough recomposition of the disparate syndromes, which form the constellation of TMA. In this view, clinicians now discriminate thrombocytopenic thrombotic purpura (TTP) defined by a severe deficiency in ADAMTS13, which is rarely associated with a severe renal involvement and the hemolytic and uremic syndrome (HUS) in which renal impairment is the most prominent clinical feature. HUS can result from toxins stemming from bacterial infections of the digestive tract, alternate complement pathway abnormalities, metabolic or coagulation disorders or, lastly, drug and various toxic compounds. The diverse forms of HUS reflect the insights gained in the understanding of the pathophysiological mechanisms underpinning TMA. In this first part, a broad overview of the epidemiological, physiopathological and clinical aspects of HUS and related TMA syndromes is presented.

[Well-being in adulthood of patients with chronic conditions in childhood: The GEDEPAC-2 questionnaire]. / Bien-être à l'âge adulte des enfants atteints de maladies chroniques : le questionnaire GEDEPAC-2.

BACKGROUND: In France, chronic diseases affect 3 million children. In children with chronic conditions, long-term somatic outcome has been well described, but little is known about the psychosocial aspects of well-being. METHODS: Our aim was to build a self-administered questionnaire of global well-being in adults who had a chronic disease since or during childhood using a multidimensional and nonspecific approach. The questionnaire was constructed by a multidisciplinary group (epidemiologists, clinicians, sociologist, statistician). Items were built in compliance with reference data from the French general population (national surveys, free access) to allow comparative analysis adjusted for age and sex (and eventually other confounding factors) by indirect standardization (qualitative variables) or Z-scores (quantitative variables). RESULTS: The GEDEPAC-2 includes 108 items exploring 11 domains: education, employment, housing, material security, social links, civic engagement, leisure, environment, physical health/risky behavior, health-related quality of life and sex life. Factual questions and satisfaction scales jointly explore social well-being. Quality of life is analyzed in terms of physical quality of life, mental quality of life, fatigue and burden of treatment by 3 questionnaires validated in French (SF-12; MFI-20; Burden of Treatment Questionnaire). Experience of transition from pediatric to adult healthcare is described in 21 items. Paper and electronic versions were developed. CONCLUSION: Built in a multidimensional approach to well-being and in line with the available reference data, GEDEPAC-2 will facilitate the implementation of future studies on impact in adulthood of chronic disease in childhood.

Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.

BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).

Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome.

Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor-protein (MCP), C3 and factor B (CFB). At 5 years, death-censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M-TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence-related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies.

Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation.

Eculizumab (anti-C5) has been sporadically reported as an efficient therapy for atypical hemolytic uremic syndrome (aHUS). However, the lack of series precludes any firm conclusion about the optimal use of anti-C5 for preventing or treating aHUS posttransplant aHUS recurrence. We thoroughly studied 22 renal transplant recipients with aHUS who received off-label therapy with anti-C5, including 12 cases, which have not been reported yet. Nine patients, all carrying a complement genetic abnormality associated with a high risk of aHUS recurrence, received prophylactic anti-C5 therapy to prevent posttransplant recurrence. Eight of them had a successful recurrence-free posttransplant course and achieved a satisfactory graft function, while the remaining patient experienced early arterial thrombosis of the graft. Thirteen renal transplant recipients were given anti-C5 for posttransplant aHUS recurrence. A complete reversal of aHUS activity was obtained in all of them. Importantly, the delay of anti-C5 initiation after the onset of the aHUS episode inversely correlated with the degree of renal function improvement. Three patients in whom anti-C5 was subsequently stopped experienced a relapse. Altogether these data suggest that long-term eculizumab is highly effective for preventing and treating posttransplant aHUS recurrence. Our study also indicates that anti-C5 should be promptly started if a recurrence occurs.

[Atypical hemolytic-uremic syndrome related to abnormalities within the complement system]. / Syndrome hémolytique et urémique lié à des anomalies du complément.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) disorder characterised by the association of haemolytic anaemia, thrombocytopenia and acute renal failure. Atypical forms (non-shigatoxin related forms) may be familial or sporadic, frequently with relapses and most of them lead to end stage renal failure. During the last years, different groups have demonstrated genetic predisposition to atypical HUS (aHUS) involving five genes encoding for complement components which play a role in the activation or control of the alternative pathway: encoding factor H (CFH), accounting for 30% of aHUS; CD46 (encoding membrane cofactor protein [MCP]) accounting for approximately 10% of aHUS; CFI (encoding factor I) accounting for an estimated 5-15% of patients; C3 (encoding C3) accounting for approximately 10% of aHUS; and rarely CFB (encoding factor B). Predisposition to aHUS is inherited with incomplete penetrance. It is admitted that mutations confer a predisposition to develop aHUS rather than directly causing the disease and that a second event (genetic or environmental) is required for disease manifestation. HUS onset follows a triggering event in most cases (frequently banal seasonal infection and pregnancy). Uncontrolled C3 convertase leads to increased deposition of C3b on vascular endothelium and participates to the prothrombotic state. The phenotype of aHUS is variable ranging from mild forms, with complete recovery of renal function to severe forms with end stage renal disease within the first year after the onset. Overall, the outcome is severe with a mortality rate of 10% and with more than 60% of patients on dialysis. The most severe prognosis was in the CFH mutation group. There is a high risk of recurrence of the disease after renal transplantation in patients with mutations in CFH, CFI, CFB and C3. Plasma therapy may allow complete haematological remission but frequently with persistent renal damage. Some patients are plasma resistant and some are plasma dependent. The recent progress in the determination of the susceptibility factors for aHUS, have allowed to propose new diagnostic tests including a molecular genetic testing and may permit to consider some new specific treatments in this disease (human plasma-derived CFH or complement inhibitors).

A randomized trial to assess the impact of early steroid withdrawal on growth in pediatric renal transplantation: the TWIST study.

Minimizing steroid exposure in pediatric renal transplant recipients can improve linear growth and reduce metabolic disorders. This randomized multicenter study investigated the impact of early steroid withdrawal on mean change in height standard deviation score (SDS) and the safety and efficacy of two immunosuppressive regimens during the first 6 months after transplantation. Children received tacrolimus, MMF, two doses of daclizumab and steroids until day 4 (TAC/MMF/DAC, n=98) or tacrolimus, MMF and standard-dose steroids (TAC/MMF/STR, n=98). Mean change in height SDS was 0.16 +/- 0.32 with TAC/MMF/DAC and 0.03 +/- 0.32 with TAC/MMF/STR. The mean treatment group difference was 0.13 (p < 0.005 [95% CI 0.04-0.22]), 0.21 in prepubertal (p = 0.009 [95% CI 0.05-0.36]) and 0.05 in pubertal children (p = ns). Frequency of biopsy-proven acute rejection was 10.2%, TAC/MMF/DAC, and 7.1%, TAC/MMF/STR. Patient and graft survival and renal function were similar. Significantly greater reductions in total cholesterol and triglycerides but significantly higher incidences of infection and anemia were found with TAC/MMF/DAC (p < 0.05 all comparisons). Early steroid withdrawal significantly aided growth at 6 months more so in prepubertal than pubertal children. This was accompanied by significantly better lipid and glucose metabolism profiles without increases in graft rejection or loss.

Population pharmacokinetics and pharmacogenetics of tacrolimus in de novo pediatric kidney transplant recipients.

The aim of this study was to develop a population pharmacokinetic model of tacrolimus in pediatric kidney transplant patients, identify factors that explain variability, and determine dosage regimens. Pharmacokinetic samples were collected from 50 de novo pediatric kidney transplant patients (age 2-18 years) who were on tacrolimus treatment. Population pharmacokinetic analysis of tacrolimus was performed using NONMEM, and the impact of variables (demographic and clinical factors, and CYP3A4-A5, ABCB1, and ABCC2 polymorphisms) was tested. The pharmacokinetic data were described by a two-compartment model that incorporated first-order absorption and lag time. The apparent oral clearance (CL/F) was significantly related to body weight (allometric scaling); in addition, it was higher in patients with low hematocrit levels and lower in patients with CYP3A5*3/*3. The population pharmacokinetic-pharmacogenetic model developed in de novo pediatric kidney transplant patients demonstrated that, in children, tacrolimus dosage should be based on weight, hematocrit levels, and CYP3A5 polymorphism. Individualization of therapy will enable the optimization of tacrolimus exposure, with resultant beneficial effects on kidney function in the initial post-transplantation period.

The high frequency of complement factor H related CFHR1 gene deletion is restricted to specific subgroups of patients with atypical haemolytic uraemic syndrome.

BACKGROUND: Deletion of the complement factor H related 1 (CFHR1) gene is a consequence of non-allelic homologous recombination and has been reported to be more frequent in atypical haemolytic uraemic syndrome (aHUS) patients than in the normal population. Therefore, it is considered a susceptibility factor for the disease. aHUS is associated with hereditary or acquired abnormalities that lead to uncontrolled alternative pathway complement activation. We tested the CFHR1 deletion for association with aHUS in a population of French aHUS cases and controls. Furthermore, we examined the effect of the deletion in the context of known aHUS risk factors. METHODS AND RESULTS: 177 aHUS patients and 70 healthy donors were studied. The number of CFHR1 alleles was quantified by multiplex ligation dependant probe amplification (MLPA). The frequency of the deleted allele was significantly higher in aHUS patients than in controls (22.7% vs 8.2%, p<0.001). The highest frequency was in the subgroup of patients exhibiting anti-factor H (FH) autoantibodies (92.9%, p<0.0001 vs controls) and in the group of patients exhibiting a factor I (CFI) gene mutation (31.8%, p<0.001 vs controls). The CFHR1 deletion was not significantly more frequent in the cohort of aHUS patients when patients with anti-FH IgG or CFI mutation were excluded. CONCLUSIONS: The high frequency of CFHR1 deletion in aHUS patients is restricted to the subgroups of patients presenting with anti-FH autoantibodies or, to a lesser degree, CFI mutation. These results suggest that the CFHR1 deletion plays a secondary role in susceptibility to aHUS.

Gastrointestinal complications of post-diarrheal hemolytic uremic syndrome.

PURPOSE: Whereas gastrointestinal symptoms such as vomiting, diarrhea and abdominal pain are common in children suffering from the so-called post-diarrheal form (D+) of hemolytic uremic syndrome (HUS), more serious gastrointestinal complications are rare. We tried to define factors predictive of the severity of gastrointestinal complications post D+ HUS. METHODS: We reviewed the files of all children admitted to our hospital for D+ HUS between 1988 and 2000. We retained those cases with gastrointestinal complications and analyzed the consequences of these complications on the evolution of the children's conditions. RESULTS: Sixty-five children with D+ HUS were admitted to our hospital during this period. Sixteen children developed gastrointestinal complications involving one or more digestive organs: necrosis of the colon or ileum, hemorrhagic colitis, pancreatitis, transient diabetes, hepatic cytolysis and cholestasis, peritonitis and prolapse of the rectum. One child died. CONCLUSION: Gastrointestinal complications of D+ HUS are rare, but they can be lethal, and early surgery may sometimes prove necessary. However, we were not able to demonstrate a correlation between the severity of the gastrointestinal manifestations and the clinical or biological signs accompanying D+ HUS.

Phylogenetic groups and virulence factors of Escherichia coli strains causing pyelonephritis in children with and without urinary tract abnormalities.

Escherichia coli isolates causing acute pyelonephritis in 93 children (25% with urinary tract abnormalities) were tested for nine virulence factors (papC, papGII, papGIII, sfa/foc, hlyC, cnf1, iucC, fyuA and iroN) and their phylogenetic groups were determined. Isolates lacking papGII were more frequent among patients with urinary tract abnormalities (58% vs. 10%, p 0.0003), as were non-virulent phylogenetic group A isolates (25% vs. 5%, p 0.043). Pyelonephritis caused by less virulent E. coli strains was more frequent among patients with significant urinary tract abnormalities. Further studies are required to determine whether screening for E. coli virulence factors may help to identify children warranting anatomical investigations.

Abdominal manifestations in childhood-onset systemic lupus erythematosus.

BACKGROUND: Childhood-onset lupus erythematosus is a rare disorder of unknown origin. OBJECTIVES: To describe the frequency of gastrointestinal manifestations at presentation of systemic lupus erythematosus SLE and at follow-up, and discuss the specific causes of these manifestations. METHODS: Medical records of 201 patients with childhood-onset SLE followed up in French paediatric nephrological, haematological and rheumatological centres were reviewed and abstracted for gastrointestinal manifestations. RESULTS: Gastrointestinal involvement was recorded in 39 (19%) children. The median (range) age at the time of initial gastrointestinal manifestations was 11.3 (4.5-16) years. Gastrointestinal symptoms were present at or occurred within 1 month after diagnosis in 32% patients. Abdominal pain was the most frequent symptom, present in 34 (87%) patients. It was mostly related to lupus involvement, especially ascites (n = 14) and pancreatitis (n = 12), more rarely to treatment-induced events (n = 1) or infection (n = 1) and never to events unrelated to SLE. Three children with surgical abdomen underwent a laparotomy before SLE was diagnosed, with a final diagnosis of lupus peritonitis and lupus acalculous cholecystitis. C reactive protein values were <40 mg/l in all but two patients who had surgical abdomen. Abdominal ultrasonography and computed tomography scans were abnormal in 58% and 83% of the evaluated patients, respectively. Corticosteroids, associated with intravenous cyclophospamide in eight patients, led to complete remission of gastrointestinal involvement in 30 of 31 treated patients. CONCLUSION: Gastrointestinal involvement is common in children with SLE, and is mainly due to primary lupus involvement. Corticoidsteroid treatment should be promptly considered in children with lupus presenting with abdominal pain after infectious disease; side effects of treatment and intestinal perforation have been excluded.

Rituximab therapy for childhood-onset systemic lupus erythematosus.

OBJECTIVE: To describe the safety and efficacy of rituximab in the treatment of childhood-onset systemic lupus erythematosus (SLE). STUDY DESIGN: We conducted a French multicenter retrospective study of childhood-onset SLE treated with rituximab. RESULTS: Eleven girls with severe SLE, including 8 girls with class IV or V lupus nephritis, 2 girls with severe autoimmune cytopenia, and 1 girl with antiprothrombin antibody with severe hemorrhage, were treated with rituximab. The mean age at onset of rituximab treatment was 13.9 years. Patients received 2 to 12 intravenous infusions of rituximab (350-450 mg/m2/infusion), with corticosteroids. Six patients also received different standard immunosuppressive agents, including Cyclophosphamide (2 patients). Remission was achieved in 6 of 8 patients with lupus nephritis and in the 2 patients with autoimmune cytopenia. Steroid therapy was tapered in 5 patients who responded to treatment, and low-dose prednisone treatment was maintained in 1 patient. The mean follow-up period was 13.2 months (range, 6-26 months), and remission lasted in all who patients who responded to treatment, except 1 patient who was successfully retreated with a second course of rituximab. Anti-double-stranded DNA antibody levels decreased in 6 of 11 patients, and anticardiolipin antibody levels decreased in 3 of 4 patients. Severe adverse events developed in 5 patients. Effective depletion of peripheral blood B cells was observed in 7 of 8 patients who were examined, and this paralleled the remission. CONCLUSION: Rituximab may be an effective co-therapy; however, further investigations are required because severe adverse events occurred in 45% of the patients in this study.

A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders.

The diagnostic terms hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are based on historical and overlapping clinical descriptions. Advances in understanding some of the causes of the syndrome now permit many patients to be classified according to etiology. The increased precision of a diagnosis based on causation is important for considering logical approaches to treatment and prognosis. It is also essential for research. We propose a classification that accommodates both a current understanding of causation (level 1) and clinical association in cases for whom cause of disease is unclear (level 2). We tested the classification in a pediatric disease registry of HUS. The revised classification is a stimulus to comprehensive investigation of all cases of HUS and TTP and is expected to increase the proportion of cases in whom a level 1 etiological diagnosis is confirmed.

Initial presentation of childhood-onset systemic lupus erythematosus: a French multicenter study.

OBJECTIVE: To describe the clinical and laboratory manifestations of childhood-onset systemic lupus erythematosus (SLE) at presentation. STUDY DESIGN: This retrospective French multicenter study involved 155 patients in whom SLE developed before the age of 16 years. Mean patient age at onset was 11.5 +/- 2.5 years (range, 1.5-16 years). The female to male ratio was 4.5. RESULTS: The most common initial manifestations were hematologic (72%), cutaneous (70%), musculoskeletal (64%), renal (50%), and fever (58%). Thirty-two percent of children had atypical symptoms, mainly including abdominal involvement in 26 patients, which lead to negative laparotomy results for presumed appendicitis. Severe renal, neurologic, hematologic, abdominal, cardiac, pulmonary, thrombotic, and/or cutaneous manifestations occurred within the first month after the diagnosis in 40% of patients. The mean erythrocyte sedimentation rate was 72 +/- 29 mm/h, and the mean C-reactive protein value 22 +/- 21 mg/L. Antinuclear antibodies an, anti-double stranded DNA antibodies, and low C3 or C4 level were retrieved in 97%, 93%, and 78 % of patients, respectively. CONCLUSION: Initial manifestations of childhood-onset SLE are diverse and often severe. The diagnosis of SLE should be promptly considered in any febrile adolescent with unexplained organ involvement, especially when associated with an increased erythrocyte sedimentation rate.

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.