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.

[Diagnosis and management of chronic kidney disease in children: Guidelines of the French Society of Pediatric Nephrology]. / Diagnostic et prise en charge de la maladie rénale chronique de l'enfant : recommandations de la Société de néphrologie pédiatrique (SNP).

These guidelines are intended to assist physicians in the care of children with chronic kidney disease (CKD), defined in children as in adults, regardless of its cause. Often silent for a long time, CKD can evolve to chronic renal failure or end-stage renal disease. Its management aims at slowing disease progression and treating CKD complications as soon as they appear. The different aspects of pediatric CKD care are addressed in these guidelines (screening, treatment, monitoring, diet, quality of life) as proposed by the French Society of Pediatric Nephrology. Highly specialized care provided in the hospital setting by pediatric nephrologists is not detailed.

Toll-like receptor 3 expression and function in childhood idiopathic nephrotic syndrome.

The efficacy of steroids and immunosuppressive treatments in idiopathic nephrotic syndrome (INS) hints at the implication of immune cells in the pathophysiology of the disease. Toll-like receptor (TLR) dysfunctions are involved in many kidney diseases of immune origin, but remain little described in INS. We investigated the expression and function of TLRs in peripheral blood mononuclear cells (PBMC) of INS children, including 28 in relapse, 23 in remission and 40 controls. No child had any sign of infection, but a higher Epstein-Barr virus viral load was measured in the PBMC of relapsing patients. TLR-3 expression was increased in B cells only during INS remission. There was a negative correlation between proteinuria and TLR-3 expression in total and the main subsets of PBMC from INS patients. The expression of TLR-8 was also increased in both CD4(+) T cells and B cells in INS remission. There was a negative correlation between proteinuria and TLR-8 expression in total PBMC, CD4(+) T cells and B cells of INS patients. Nevertheless, TLR-3 and TLR-8 expression was normalized in all PBMC subsets in an additional group of 15 INS patients in remission with B cell repletion after rituximab therapy. Paradoxically, interferon (IFN) regulatory factor 3 transactivation was increased in PBMC of all INS patients. In-vitro secretion of IFN-α and interleukin 6 were increased spontaneously in PBMC of INS remission patients, whereas PBMC from all INS patients displayed an impaired IFN-α secretion after TLR-3 stimulation. Thus, TLR-3 pathway dysfunctions may be closely involved in INS pathogenesis.

CYP24A1 Mutations in a Cohort of Hypercalcemic Patients: Evidence for a Recessive Trait.

CONTEXT: Loss-of-function mutations of CYP24A1 (which encodes the 25-OH-D3-24-hydroxylase) have recently been reported to cause hypercalcemia. OBJECTIVES: The aims of this study were: 1) to evaluate the frequency of CYP24A1 mutations in patients with medical history of hypercalcemia; 2) to show the clinical utility of a simultaneous assay of serum 25-hydroxyvitamin D3 (25-OH-D3) and 24,25-dihydroxyvitamin D3 (24,25-[OH]2D3) by liquid chromatography tandem mass spectrometry (LC-MS/MS); and 3) to investigate biochemical parameters in heterozygous gene carriers with CYP24A1 mutations. PATIENTS AND METHODS: We screened for CYP24A1 mutations in 72 patients with serum calcium levels > 2.6 mmol/L and PTH levels < 20 pg/mL and recruited 24 relatives after genetic counseling for subsequent investigations. Vitamin D metabolite concentrations were assessed in a subset of patients by LC-MS/MS and results expressed as a ratio (R) of 25-OH-D3:24,25-(OH)2D3. RESULTS: Twenty-five patients with hypercalcemia (35%) harbored CYP24A1 variations. Twenty (28%) had biallelic variations, mostly found in subjects with nephrocalcinosis or renal stones (19/20). Five patients, all neonates, were heterozygous, without renal disease. We describe 15 new variations leading to loss-of-function according to pathogenicity prediction programs, and we functionally characterized 5 of them in vitro. A dramatic increase of R, usually >80, was found in patients harboring biallelic mutations providing evidence in vivo for the loss of CYP24A1 activity. In contrast, R value remains <25 in patients without CYP24A1 mutations. Subjects carrying one mutant allele, hypercalcemic individuals, as well as gene-carrier relatives, had a detectable 24,25-(OH)2D3 level and R < 25, indicating normal 24-hydroxylase activity. CONCLUSION: CYP24A1 biallelic mutations are frequently found in patients presenting with hypercalcemia, low PTH, and renal disease. We confirm the accuracy and effectiveness of a novel blood test estimating the ratio between relevant vitamin D metabolites as a useful screening tool for CYP24A1 mutations. Haploinsufficiency is not associated with CYP24A1 deficiency.

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.

Evolution and prognosis value of intrarenal reflux.

PURPOSE: The aim of this study was to evaluate the prognostic significance of intrarenal reflux (IRR) regarding urinary tract infection (UTI), renal scarring and spontaneous resolution after 3 years of follow up. PATIENTS AND METHODS: 33 patients (42 refluxing units) with IRR were compared to 27 children (44 refluxing units) with high-grade vesicoureteral reflux (VUR) without IRR (controls) matched for gender, age and VUR grade. All patients received antibiotic prophylaxis during observation and antireflux surgery was performed in children with recurrent UTI. DMSA scan was performed at study entry, and 18 and 36 months. RESULTS: DMSA scores at entry showed a higher proportion of moderate and severe damage in the IRR group (25/42) compared to the control group (16/44) (Chi squared, P < 0.03). During follow up the incidence of UTI was similar in the two groups, as well as the stability of DMSA scintigraphy and the rate of spontaneous disappearance of the reflux. A similar proportion of patients underwent surgery (18/33 patients with IRR and 13/27 control patients; Chi squared, not significant). CONCLUSIONS: Under medical management, the prognosis for IRR is not different from high-grade VUR without IRR. The presence of IRR does not justify more aggressive management than a high-grade VUR without IRR.

Successful anti-TNFalpha treatment in a child with posttransplant recurrent focal segmental glomerulosclerosis.

Posttransplant recurrence of focal and segmental glomulosclerosis (FSGS) occurs in approximately 30% of patients, and remains after uncontrolled despite increased immunosuppression and plasma exchanges (PE) in approximately 30% of cases. New immunosuppressive drugs might then be warranted. We report the case of a 15-year-old boy with FSGS leading to end-stage renal disease (ESRD) who presented with an early posttransplant recurrence of disease. Reinforced immunosuppression and PE resulted in partial and transient disease control, but proteinuria significantly decreased with anti-TNFalpha treatment (infliximab then etanercep). This is the first case report of successful anti-TNFalpha treatment despite a constant high activity of FSGS, as demonstrated by relapse after discontinuation of anti-TNFalpha agents.

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.

From humoral rejection to generalized thrombotic microangiopathy--role of acquired ADAMTS13 deficiency in a renal allograft recipient.

A 9-year-old renal transplant recipient presented with elevated serum creatinine levels 4 years post-transplant renal biopsy revealed humoral rejection including lesions suggestive for thrombotic microangiopathy (TMA). He received methylprednisolone pulses followed by a normalization of serum creatinine. Two more steroid responsive acute rejection episodes occurred. Two months later he presented rapidly progressive life threatening symptoms including bilateral pyramidal syndrome and hemoptysis. Serum haptoglobin became undetectable at this time and platelet count decreased (70000/microl), suggesting TMA. Cerebral MRI revealed generalized ischemic white matter lesions. ADAMTS13 activity decreased to < 5%. Daily plasma exchanges (PE) resulted in immediate improvement. All attempts to discontinue PE were unsuccessful. Transplantectomy resulted in normalization of generalized symptoms, hemolysis and ADAMTS13 activity (110%). Multi-organ involvement has never been reported in acquired ADAMTS13 deficiency post-transplant. Rapid resolution after transplantectomy might suggest that renal TMA was responsible for acquired ADAMTS13 deficiency and thereby triggered the generalization of TMA lesions.

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.

[Immunity and immunosuppression in childhood idiopathic nephrotic syndrome]. / Immunité cellulaire et traitement immunosuppresseur du syndrome néphrotique idiopathique corticosensible.

Steroid sensitive idiopathic nephrotic syndrome is a T-cell disorder characterized by a functional renal impairment. Concluding a still relevant demonstration involving cellular immunity in the pathogenesis of the disease, R. Shalhoub in 1974 suggested a "special role for the thymus" based on the efficiency of steroids and alkylating agents, dramatic recoveries following measles, sensibility to bacterial infection due to a lack of cooperation between T and B cell and association to Hodgkin disease. As a matter of fact, the selected drugs based on medical empirism somehow enhance thymocytes apoptosis and negative selection of T cell, except cyclosporin. Steroids have been the first historical treatment of idiopathic nephrotic syndrome and have steadily been the first-line treatment for 50 years. Their unavoidable ability to induce rapid recovery of proteinuria and long-lasting or definite remission are dependent to a strict compliance to treatment. Indications of steroids-sparing treatments are not that clearcut in patients with steroids intoxication. Objectively, efficiency of levamisole and cyclophosphamide are much more limited than previously reported and cyclosporin nephrotoxicity might severely impair renal function following long-lasting treatment as well as it may paradoxically increase the activity of the disease. An alternate strategy to those currently adopted would use cyclosporin as the first-line steroids-sparing treatment during a very limited period, awaiting favourable ageing of patients and natural dampening activity of the disease to a full efficiency of alkylating agents. Compared to cyclophosphamide and cyclosporin, the relative safety of levamisole is encouraging to a more frequent uses. Its association to a full dose of prednisone in the treatment of the inaugural episode should be investigated. According to the limitations of those therapies, emerging drugs as mycophenolate might be worthwhile in the treatment of nephrotic patients.

[Molecular mechanism of edema formation in nephrotic syndrome]. / Mécanismes physiologiques et moléculaires de la constitution des oedèmes au cours du syndrome néphrotique.

Nephrotic edema are the clinical feature of isolated interstitial expansion. Expanded interstitial compartment compensates sodium accumulation in the extracellular volume due to inappropriate renal sodium retention. Renal sodium retention is brought about by an activation of the molecular structures responsible for the reabsorption of sodium along the cortical collecting duct: amiloride-sensitive epithelial sodium channel at the apical face and sodium pump at the basolateral face of the principal cell. This activation is independent of aldosterone and vasopressin. The asymmetry of expansion between interstitium and plasma compartments is due to impaired Starling forces and increased fluid transfer through the capillary wall. The lack of significant changes in transcapillary oncotic and hydrostatic gradients suggests that increased hydraulic conductivity due to transconformation of endothelial intercellular junctions drives the leakage of fluid into the interstitium and allows to understand the mobility of nephrotic edema. Consistently with the site of renal sodium retention and the activation of the epithelial sodium channel, the association of amiloride and furosemide is efficient to increase urinary sodium excretion, to reverse sodium balance and to remove edema from patients with nephrotic syndrome.