Threatening Blindness in a Child With Typical Hemolytic Uremic Syndrome.

BACKGROUND: Hemolytic uremic syndrome (HUS) is the most common cause of acute kidney failure in children younger than five years. Central nervous system involvement occurs in 15% of patients, with clinical manifestations including confusion, coma, seizures, stroke, and cortical blindness. Ocular involvement in children with HUS is rare, but retinal and choroidal hemorrhages as well as ischemic retinopathy due to thrombotic microangiopathic lesions have been documented. PATIENT DESCRIPTION: We describe a 26-month-old girl with typical HUS who experienced severe visual loss likely resulting from cytotoxic injury of both lateral geniculate nuclei with bilateral damage to optic pathways coupled with macular thrombotic microangiopathic lesions. Her vision recovered completely within a month in conjunction with the normalization of her imaging studies. CONCLUSIONS: Although this child's vision was severely impaired, the prognosis for this mixed visual impairment of peripheral and central origin was excellent with a full recovery.

Safety, efficacy, and acceptability of ADV7103 during 24 months of treatment: an open-label study in pediatric and adult patients with distal renal tubular acidosis.

BACKGROUND: A new prolonged-release formulation of potassium citrate and potassium bicarbonate, ADV7103, has been shown to improve metabolic control, palatability, and gastrointestinal safety in patients with distal renal tubular acidosis (dRTA) when compared to standard of care (SoC) treatments. The present work evaluates safety and efficacy of ADV7103 during 24 months. METHODS: Thirty pediatric and adult patients were included in an open-label extension study after a phase II/III trial. Safety and tolerability were assessed. Plasma bicarbonate and potassium levels, as well as urine parameters, were evaluated over time. Acceptability, adherence, and quality of life were also assessed. The evolution of clinical consequences of dRTA in the cohort was explored. RESULTS: There were 104 adverse events (AEs) reported, but only 9 gastrointestinal events observed in five patients (17%) were considered to be related to ADV7103 treatment. There were no AEs leading to treatment discontinuation. Plasma bicarbonate and potassium levels were in the normal ranges at the different visits, respectively, in 69-86% and 83-93% of patients. Overall adherence rates were ≥ 75% throughout the whole study in 79% patients. An average improvement of quality of life of 89% was reported at 24 months of study. CONCLUSIONS: Common AEs concerned metabolism and gastrointestinal disorders; the former being related to the disease. Less than half of the gastrointestinal AEs were related to ADV7103 treatment and they were mostly mild in severity. Metabolic parameters were maintained in the normal ranges in most patients. Patient satisfaction was high and adherence to treatment was good and remained stable. TRIAL REGISTRATION NUMBER: Registered as EudraCT 2013-003828-36 on the 3rd of September 2013.

Dilatation of the aorta in children with advanced chronic kidney disease.

BACKGROUND: The peculiarity of the cardiovascular risk profile with increased arterial vulnerability is well known in adults with chronic kidney disease (CKD). It is explained by an increased incidence of traditional cardiovascular risk factors together with other comorbidities related to the uremic condition and cardiorenal syndrome (CRS). The present study aimed to determine the cardiovascular impact of the uremic condition in a pediatric population with advanced CKD. METHODS: From 2016 to 2018, 39 consecutive patients with advanced CKD who underwent echocardiographic evaluation were included. All echocardiographic examinations were performed by the same operator (FE). Demographic, clinical, biological, and echocardiographic data were collected. RESULTS: The mean age at echocardiographic exam was 9.7 ± 4.6 years. Twenty-four (61.5%) patients were on hemodialysis; 17 (43.6%) patients were in a peritoneal dialysis program of whom 11 switched at a later stage to hemodialysis. Eight (20.5%) patients had an arteriovenous fistula (AVF). Hypertension was present in 30 (76.9%) patients while left ventricular hypertrophy (LVH) was described in 13 (33.3%) patients. Dilatation of the ascending aorta (Z-score > 2) was found in 15 (38.4%) patients and was statistically (in univariate analysis) related to gender, hypertension, the presence of an AVF, and the use of hemodialysis after peritoneal dialysis (p = 0.024, p = 0.016, p = 0.006, p = 0.009, respectively). CONCLUSION: In addition to classical and predictable abnormalities related to CKD, we found a high prevalence of dilatation of the ascending aorta in children with advanced CKD. Hypertension, AVF, and hemodialysis were associated factors.

Correction to: Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments.

The published version of the article unfortunately contained a mistake.

Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments.

BACKGROUND: Distal renal tubular acidosis (dRTA), due to impaired acid secretion in the urine, can lead to severe long-term consequences. Standard of care (SoC) oral alkalizers, requiring several daily intakes, are currently used to restore normal plasma bicarbonate levels. A new prolonged-release formulation, ADV7103, has been developed to achieve a sustained effect with an improved dosing scheme. METHODS: In a multicenter, open-label, non-inferiority trial (n = 37), patients with dRTA were switched from SoC to ADV7103. Mean plasma bicarbonate values and proportion of responders during steady state therapy with both treatments were compared, as were other blood and urine parameters, as well as acceptability, tolerability, and safety. RESULTS: When switching from SoC to ADV7103, the number of daily intakes was reduced from a median of three to twice daily. Mean plasma bicarbonate was increased and non-inferiority of ADV7103 was demonstrated (p < 0.0001, per protocol), as was statistical superiority (p = 0.0008, intention to treat [ITT]), and the response rate increased from 43 to 90% with ADV7103 (p < 0.001, ITT). Urine calcium/citrate ratio was reduced below the threshold for risk of lithogenesis with ADV7103 in 56% of previously non-responders with SoC (p = 0.021, ITT). Palatability was improved (difference [95% CI] of 25 [10.7, 39.2] mm) and gastrointestinal discomfort was reduced (difference [95% CI] of - 14.2 [- 25.9, - 2.6] mm) with ADV7103. CONCLUSIONS: Plasma bicarbonate levels and response rate were significantly higher with ADV7103 than with SoC. Urine calcium/citrate ratio, palatability, and gastrointestinal safety were significantly improved, supporting the use of ADV7103 as first-line treatment for dRTA. TRIAL REGISTRATION: Registered as EudraCT 2013-002988-25 on the 1st July 2013 Graphical abstract.

Complement Gene Variants and Shiga Toxin-Producing Escherichia coli-Associated Hemolytic Uremic Syndrome: Retrospective Genetic and Clinical Study.

BACKGROUND AND OBJECTIVES: Inherited complement hyperactivation is critical for the pathogenesis of atypical hemolytic uremic syndrome (HUS) but undetermined in postdiarrheal HUS. Our aim was to investigate complement activation and variants of complement genes, and their association with disease severity in children with Shiga toxin-associated HUS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Determination of complement biomarkers levels and next-generation sequencing for the six susceptibility genes for atypical HUS were performed in 108 children with a clinical diagnosis of post-diarrheal HUS (75 Shiga toxin-positive, and 33 Shiga toxin-negative) and 80 French controls. As an independent control cohort, we analyzed the genotypes in 503 European individuals from the 1000 Genomes Project. RESULTS: During the acute phase of HUS, plasma levels of C3 and sC5b-9 were increased, and half of patients had decreased membrane cofactor protein expression, which normalized after 2 weeks. Variants with minor allele frequency <1% were identified in 12 Shiga toxin-positive patients with HUS (12 out of 75, 16%), including pathogenic variants in four (four out of 75, 5%), with no significant differences compared with Shiga toxin-negative patients with HUS and controls. Pathogenic variants with minor allele frequency <0.1% were found in three Shiga toxin-positive patients with HUS (three out of 75, 4%) versus only four European controls (four out of 503, 0.8%) (odds ratio, 5.2; 95% confidence interval, 1.1 to 24; P=0.03). The genetic background did not significantly affect dialysis requirement, neurologic manifestations, and sC5b-9 level during the acute phase, and incident CKD during follow-up. However, the only patient who progressed to ESKD within 3 years carried a factor H pathogenic variant. CONCLUSIONS: Rare variants and complement activation biomarkers were not associated with severity of Shiga toxin-associated HUS. Only pathogenic variants with minor allele frequency <0.1% are more frequent in Shiga toxin-positive patients with HUS than in controls.

Patterns of Clinical Response to Eculizumab in Patients With C3 Glomerulopathy.

BACKGROUND: Cases reports and small series of patients with C3 glomerulopathy have reported variable efficacy of eculizumab. STUDY DESIGN: Case series of C3 glomerulopathy. SETTING & PARTICIPANTS: Pediatric and adult patients with C3 glomerulopathy treated with eculizumab between 2010 and 2016 were identified through the C3 glomerulopathy French registry database, and a questionnaire was sent to participating French pediatric and adult nephrology centers, as well as one pediatric referral center in Québec, Canada. OUTCOMES: Global or partial clinical renal response. MEASUREMENTS: Evolution of serum creatinine and proteinuria values. RESULTS: 26 patients (13 children/adolescents) were included. 22 (85%) patients had received steroids, plasma exchange, or immunosuppressive therapy before eculizumab, and 3 of them had rapid progression of their kidney disease despite treatment. At the initiation of eculizumab therapy, 11 (42%) patients had chronic kidney disease, 7 (27%) had rapidly progressive disease, and 3 (12%) required dialysis. After eculizumab treatment (median duration, 14 months), 6 (23%) patients had a global clinical response; 6 (23%), a partial clinical response; and 14 (54%), no response. Compared with those who had a partial clinical or no response, patients who had a global clinical response had lower estimated glomerular filtration rates, a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy. Age, extent of renal fibrosis, frequency of nephrotic syndrome, low serum C3 and C3 nephritic factor and elevated soluble C5b-9 concentrations, or complement gene variants did not differ between responders and nonresponders. LIMITATIONS: Retrospective design without a control group, relatively small number of cases, inclusion of pediatric and adult cases. CONCLUSIONS: Eculizumab appears to be a potential treatment for patients with crescentic rapidly progressive C3 glomerulopathy. Its benefit in patients with non-rapidly progressing forms seems to be limited.

C5 nephritic factors drive the biological phenotype of C3 glomerulopathies.

C3 Glomerulopathies, which include Dense Deposit Disease and C3 Glomerulonephritis, are associated with genetic and acquired dysregulation of the C3 convertase alternative pathway of complement. The potential role of the activation of the C5 convertase has not been studied extensively. Here we analyzed IgG samples from patients with C3 Glomerulopathies to identify circulating autoantibodies that stabilize the C3 alternative pathway (C3 Nephritic Factors) as well as C5 convertases (C5 Nephritic Factors), thus preventing decay of these enzyme complexes. Rare variants in alternative pathway genes were found in 28 of 120 tested patients. C3 and C5 Nephritic Factors were found in 76 of 101 (75%) and 29 of 59 (49%) of the patients, respectively. Therefore, we compared the results of the assays for the C3 and C5 nephritic factors functional activity: 29% were positive for C3 Nephritic Factors alone, 39% were positive for both C3 and C5 Nephritic Factors, and 10% were positive for C5 Nephritic Factors alone. We found that the addition of properdin-enhanced stabilization of C3 convertase in the presence of IgG doubly positive for both Nephritic Factors, while it did not modify the stabilization mediated by IgG solely positive for C3 Nephritic Factors. Both C3 and C5 Nephritic Factors correlated with C3 consumption, while only C5 Nephritic Factors correlated with sC5b9 levels. C5 Nephritic Factors-positive patients were more likely to have C3 Glomerulonephritis than Dense Deposit Disease. Thus, dysregulation of the C5 convertase contributes to C3 Glomerulopathies inter-disease differences and may have direct therapeutic implications.

Clinical and Genetic Spectrum of Bartter Syndrome Type 3.

Bartter syndrome type 3 is a clinically heterogeneous hereditary salt-losing tubulopathy caused by mutations of the chloride voltage-gated channel Kb gene (CLCNKB), which encodes the ClC-Kb chloride channel involved in NaCl reabsorption in the renal tubule. To study phenotype/genotype correlations, we performed genetic analyses by direct sequencing and multiplex ligation-dependent probe amplification and retrospectively analyzed medical charts for 115 patients with CLCNKB mutations. Functional analyses were performed in Xenopus laevis oocytes for eight missense and two nonsense mutations. We detected 60 mutations, including 27 previously unreported mutations. Among patients, 29.5% had a phenotype of ante/neonatal Bartter syndrome (polyhydramnios or diagnosis in the first month of life), 44.5% had classic Bartter syndrome (diagnosis during childhood, hypercalciuria, and/or polyuria), and 26.0% had Gitelman-like syndrome (fortuitous discovery of hypokalemia with hypomagnesemia and/or hypocalciuria in childhood or adulthood). Nine of the ten mutations expressed in vitro decreased or abolished chloride conductance. Severe (large deletions, frameshift, nonsense, and essential splicing) and missense mutations resulting in poor residual conductance were associated with younger age at diagnosis. Electrolyte supplements and indomethacin were used frequently to induce catch-up growth, with few adverse effects. After a median follow-up of 8 (range, 1-41) years in 77 patients, chronic renal failure was detected in 19 patients (25%): one required hemodialysis and four underwent renal transplant. In summary, we report a genotype/phenotype correlation for Bartter syndrome type 3: complete loss-of-function mutations associated with younger age at diagnosis, and CKD was observed in all phenotypes.

Pathogenic Variants in Complement Genes and Risk of Atypical Hemolytic Uremic Syndrome Relapse after Eculizumab Discontinuation.

BACKGROUND AND OBJECTIVES: The complement inhibitor eculizumab has dramatically improved the outcome of atypical hemolytic uremic syndrome. However, the optimal duration of eculizumab treatment in atypical hemolytic uremic syndrome remains debated. We report on the French atypical hemolytic uremic syndrome working group's first 2-year experience with eculizumab discontinuation in patients with atypical hemolytic uremic syndrome. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Using the French atypical hemolytic uremic syndrome registry database, we retrospectively identified all dialysis-free patients with atypical hemolytic uremic syndrome who discontinued eculizumab between 2010 and 2014 and reviewed their relevant clinical and biologic data. The decision to discontinue eculizumab was made by the clinician in charge of the patient. All patients were closely monitored by regular urine dipsticks and blood tests. Eculizumab was rapidly (24-48 hours) restarted in case of relapse. RESULTS: Among 108 patients treated with eculizumab, 38 patients (nine children and 29 adults) discontinued eculizumab (median treatment duration of 17.5 months). Twenty-one patients (55%) carried novel or rare complement genes variants. Renal recovery under eculizumab was equally good in patients with and those without complement gene variants detected. After a median follow-up of 22 months, 12 patients (31%) experienced atypical hemolytic uremic syndrome relapse. Eight of 11 patients (72%) with complement factor H variants, four of eight patients (50%) with membrane cofactor protein variants, and zero of 16 patients with no rare variant detected relapsed. In relapsing patients, early reintroduction (≤48 hours) of eculizumab led to rapid (<7 days) hematologic remission and a return of serum creatinine to baseline level in a median time of 26 days. At last follow-up, renal function remained unchanged in nonrelapsing and relapsing patients compared with baseline values before eculizumab discontinuation. CONCLUSIONS: Pathogenic variants in complement genes were associated with higher risk of atypical hemolytic uremic syndrome relapse after eculizumab discontinuation. Prospective studies are needed to identify biomarkers predictive of relapse and determine the best strategy of retreatment in relapsing patients.

Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1.

Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.

Rituximab fails where eculizumab restores renal function in C3nef-related DDD.

BACKGROUND: Dense deposit disease (DDD), a C3 glomerulopathy (C3G), is a rare disease with unfavorable progression towards end-stage kidney disease. The pathogenesis of DDD is due to cytotoxic effects related to acquired or genetic dysregulation of the complement alternative pathway, which is at times accompanied by the production of C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase. Available treatments include plasma exchange, CD20-targeted antibodies, and a terminal complement blockade via the anti-C5 monoclonal antibody eculizumab. CASE-DIAGNOSIS/TREATMENT: We report here the case of an 8-year-old child with C3NeF and refractory DDD who presented with a nephritic syndrome. She tested positive for C3NeF activity; C3 was undetectable. Genetic analyses of the alternative complement pathway were normal. Methylprednisolone pulses and mycophenolate mofetil treatment resulted in complete recovery of renal function and a reduction in proteinuria. Corticosteroids were tapered and then withdrawn. Four months after corticosteroid discontinuation, hematuria and proteinuria recurred, and a renal biopsy confirmed an active DDD with a majority of extracapillary crescents. Despite an increase in immunosuppressive drugs, including methylprednisolone pulses and rituximab therapy, the patient suffered acute renal failure within 3 weeks, requiring dialysis. Eculizumab treatment resulted in a quick and impressive response. Hematuria very quickly resolved, kidney function improved, and no further dialysis was required. The patient received bimonthly eculizumab injections of 600 mg, allowing for normalization of renal function and reduction of proteinuria to <0.5 g per day. Since then, she continues to receive eculizumab. CONCLUSION: Complement regulation pathway-targeted therapy may be a specific and useful treatment for rapidly progressing DDD prior to the development of glomerulosclerosis. Our data provide evidence supporting the pivotal role of complement alternative pathway abnormalities in C3G with DDD.

Diagnosis of Streptococcus pneumoniae-associated hemolytic uremic syndrome.

BACKGROUND: Hemolytic uremic syndrome related to pneumococcal infection (P+HUS) can be difficult to diagnose due to the lack of a specific test and the absence of a consensus for definite diagnostic criteria. METHODS: A retrospective study was conducted on the cases that have been considered as P+HUS in the participating centers during the past 10 years. Diagnostic strategy and criteria used for the diagnosis of P+HUS were evaluated and compared with a review of literature data. RESULTS: A total of 17 children were studied. Tests ruling out other causes of HUS were performed in 94% of cases. Direct confirmatory tests for P+HUS were done in a minority of cases as Thomsen-Friedenreich antigen testing using lectin assay were done in only 2 patients (11%). Retrospectively, the diagnosis of P+HUS was confirmed in 28% to 89% of cases depending on the already published criteria used. A literature review focused on the last 15 years confirmed these diagnostic difficulties due to variable definition criteria and bring a new light on the potential usefulness of tests used to reveal T activation in this setting. CONCLUSION: To date, in a context of suspicion of P+HUS, no precise, practical and consensual strategy exists for T-antigen exposure diagnosis. The T-antigen activation test using peanut lectin might be the most appropriate test for a direct diagnosis of P+HUS. A large prospective study is required to confirm this hypothesis. However, before such data are available, its use could be of help when a suspicion of P+HUS is present given the therapeutic impact of such a diagnosis.

Long-term outcome of children treated with rituximab for idiopathic nephrotic syndrome.

BACKGROUND: Rituximab (RTX) has recently showed promising results in the treatment of steroid-dependent idiopathic nephrotic syndrome (SDNS). METHODS: This was a retrospective multicenter study of 18 children treated with RTX for SDNS, with a mean follow-up of 3.2 years. RTX was introduced because of side effects or relapses during therapy with immunosuppressive agents. The children received one to four infusions of RTX during the first course of treatment, and subsequent infusions were given due to CD19-cell recovery (CD19 >1 %; 54 % of children) or relapse (41 %), as well as systematically (5 %). RESULTS: Treatment with RTX maintained sustained remission without relapse in 22 % of patients and increased the duration of remission in all other patients. The time between two successive relapses was 9 months in the absence of re-treatment and 24.5 months when infusions were performed at the time of CD19-cell recovery. At the last follow-up, 44.5 % of patients were free of oral drug therapy. Of those still receiving oral drugs, all doses had been decreased. No serious adverse events occurred. CONCLUSION: The results of this retrospective study confirm the efficacy and very good safety of RTX in the treatment of SDNS. The optimal therapeutic protocol seems to be a repeated single infusion at the time of CD19-cell recovery.

In vivo reflectance confocal microscopy of the skin: a noninvasive means of assessing body cystine accumulation in infantile cystinosis.

BACKGROUND: Patients with infantile nephropathic cystinosis have progressive accumulation of cystine in tissues leading to delayed extrarenal complications. No simple tool is available to evaluate the level of body cystine accumulation. OBJECTIVE: We sought to determine the value of in vivo reflectance confocal microscopy of the skin in patients with infantile nephrogenic cystinosis. METHODS: Nine patients and control subjects were recruited for this study. Images were acquired by means of a near-infrared reflectance confocal laser scanning microscope. RESULTS: Scattered bright particles within the papillary dermis were observed in all patients but not in control subjects. The density of particles ranged from numerous (+++) to very few (+/-) and their distribution was heterogeneous. Electron microscopy confirmed that these particles corresponded to cystine crystal deposits within dermal fibroblasts. The density of cystine crystals within the dermis was greater in older patients, in patients with a high leukocyte cystine concentration, and with delayed cysteamine therapy. There was no correlation between the density of cystine deposits and renal disease or hypopigmentation but high levels of deposition occurred in association with extrarenal manifestations. LIMITATIONS: This is a preliminary study on a small sample of patients. Repeated examination and longer follow-up is necessary. CONCLUSION: In vivo reflectance confocal microscopy of the skin appears to be a noninvasive means of assessing body cystine accumulation in infantile cystinosis and could be used as a complementary marker of treatment response in addition to leukocyte cystine measurement.

Cystinosin is a melanosomal protein that regulates melanin synthesis.

Cystinosis is a rare autosomal recessive disease characterized by cystine crystal accumulation leading to multiorgan dysfunctions and caused by mutation in CTNS. CTNS encodes cystinosin, a cystine/H(+) symporter that exports cystine out of the lysosomes. Patients with cystinosis frequently exhibit blond hair and fair complexion, suggesting an alteration in melanogenesis. However, the pigmentation singularities of these patients have not been studied, and the role of cystinosin in melanogenesis has remained unknown. In our study, a clinical evaluation of 27 patients with cystinosis showed that 44% had a cutaneous pigmentation dilution compared to their relatives. Analysis of the hair melanin content in these patients by HPLC demonstrated a 50% decrease in eumelanin (4360 vs. 9360 ng/mg), and a 2-fold increase in pheomelanin (53 vs. 20 ng/mg), the yellow/red pigments. Cystinosin-deficient mice also showed a 4-fold increase in hair pheomelanin content. In vitro studies showed that cystinosin was located at melanosomes. CTNS silencing led to a 75% reduction of melanin synthesis that was caused by a degradation of tyrosinase by lysosomal proteases. Our results objectify the pigmentation defect in patients with cystinosis. We also identify the role of CTNS in melanogenesis and add a new gene to the list of the genes involved in the control of skin and hair pigmentation.

Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial.

Mycophenolate mofetil (MMF) has emerged as a new therapeutic option in steroid-dependent nephrotic syndrome (SDNS). We conducted a phase II Bayesian trial of MMF in children with SDNS. Phase II trials, usually single-arm studies, investigate the effect of new treatments. Standard Fleming's procedure relies on observed results (relapse rate during the trial), whereas Bayesian approach combines observed results with prior information (expected relapse rate according to prior studies and clinical experience). All patients were required to have received prior alkylating-agent treatment. Sixty-seven percent of them had also received levamisole. Patients received MMF (1,200 mg/m(2)/day) and prednisone according to a defined schedule [reduction of alternate-day (e.o.d) dose to 50% of pre-MMF dose at 3 months, 25% at 6 months]. Twenty-four children (median age 6.0 years, 2.8-14.4) entered the study and 23 completed it. Bayesian analysis showed that adding four patients would not change significance of results, allowing stopping inclusions. Four patients relapsed during the first 6 months (estimated probability 17.6%, 95% credibility interval: 5.4-35.0%) and two at months 8 and 11.5. In the 19 patients free of relapse during the first 6 months, median (Q1-Q3) prednisone maintenance dose decreased from 25 (10-44) to 9 (7.5-11.2) mg/m(2) e.o.d (p < 0.001) and cumulative dose from 459 (382-689) to 264 (196-306) mg/m(2)/month (p < 0.001) before and on MMF respectively. Pre-MMF patient characteristics and MMF pharmacokinetics did not differ between patients with or without relapse. MMF reduces relapse rate and steroid dose in children with SDNS and should be proposed before cyclosporine and cyclophosphamide.

Population pharmacokinetics and Bayesian estimator of mycophenolic acid in children with idiopathic nephrotic syndrome.

AIMS: To develop a population pharmacokinetic model for mycophenolic acid (MPA) in children with idiopathic nephrotic syndrome (INS) treated with mycophenolate mofetil (MMF), identify covariates that explain variability and determine the Bayesian estimator of the area under the concentration-time curve over 12 h (AUC(0-12)). METHODS: The pharmacokinetic model of MMF was described from 23 patients aged 7.4 +/- 3.9 years (range 2.9-14.9) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with lag-time and first-order absorption and elimination was developed. The final model was validated using visual predictive check. Bayesian estimator was validated using circular permutation method. RESULTS: The population pharmacokinetic parameters were apparent oral clearance 9.7 l h(-1), apparent central volume of distribution 22.3 l, apparent peripheral volume of distribution 250 l, inter-compartment clearance 18.8 l h(-1), absorption rate constant 5.16 h(-1), lag time 0.215 h. The covariate analysis identified body weight and serum albumin as individual factors influencing the apparent oral clearance. Accurate Bayesian estimation of AUC(0-12) was obtained using the combination of three MPA concentrations measured just before (T(0)), 1 and 4 h (T(1) and T(4)) after drug intake with a small error of 0.298 microg h(-1) ml(-1) between estimated and reference AUC(0-12). CONCLUSIONS: The population pharmacokinetic model of MPA was developed in children with INS. A three-point (T(0), T(1) and T(4)h) Bayesian estimator of AUC(0-12) was developed and might be used to investigate the relation between MPA pharmacokinetic and pharmacodynamics in children with INS and determine if there is any indication to monitor MPA exposure in order to improve patient outcome based on individual AUC-controlled MMF dosing.

Enteric-coated mycophenolate sodium in de novo pediatric renal transplant patients.

Data on the use of enteric-coated mycophenolic acid (EC-MPS) in pediatric transplantation cases are scarce. We undertook a 12-month, multicenter, open-label pilot study in which 16 de novo renal transplant patients aged 5-16 years received EC-MPS with cyclosporine A microemulsion (CsA-ME), steroids, and anti-interleukin-2 receptor antibody induction. The mean dose of EC-MPS was 916 +/- 93 mg/m(2) per day during weeks 1-2, 810 +/- 193 mg/m(2) per day during months 3-6, and 827 +/- 153 mg/m(2) per day during months 6-12. The mean CsA C(2) level exceeded target range up to month 6 post-transplant. Efficacy failure (biopsy-proven acute rejection, graft loss, death or loss to follow-up) occurred in two patients: one patient with primary non-function underwent nephrectomy, and one patient experienced biopsy-proven acute rejection (Grade 1B, day 344) following EC-MPS dose reduction. There were no deaths. Creatinine clearance (Schwartz) was 103 +/- 30 mL/min per 1.73 m(2) at month 6 and 100 +/- 16 mL/min per 1.73 m(2) at month 12. The majority of adverse events were mild or moderate (101/126, 80.2%). In this pilot study, EC-MPS 450 mg/m(2) administered twice daily with CsA, steroids, and interleukin-2 antibody induction resulted in a low rate of rejection with good renal function in a pediatric population. However, a larger, controlled trial is required to confirm these results.