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1.
Mol Genet Metab ; 110(1-2): 106-10, 2013.
Article in English | MEDLINE | ID: mdl-23751327

ABSTRACT

INTRODUCTION: Patients with methylmalonic acidemia (MMA) may develop many complications despite medical treatment, in particular, severe central nervous system damage and chronic kidney disease (CKD). A kidney transplant may partially correct the metabolic dysfunctions. Liver, kidney and combined liver-kidney transplantations have been advocated but no guidelines are available to identify the most suitable organ to transplant. PATIENTS AND METHODS: Four patients with MMA (mut° phenotype) received a kidney graft because of repeated metabolic decompensations, with progression to CKD in 3 patients (end-stage kidney disease in two patients and CKD stage III in one patient with an estimated glomerular filtration rate [eGFR] of 40ml/min/1.73m(2)) but normal renal function in one (eGFR of 93ml/min/1.73m(2)) before transplantation. RESULTS: The medium age at transplantation was 7.9y (5-10.2) and the median follow-up was 2.8years (1.8-4.6). Renal transplantation improved the relevant metabolic parameters in 4/4 patients and renal function in the patients with CKD. Plasma and urinary MMA levels immediately decreased and remained normal or subnormal (mean values of plasma MMA before transplantation 1530µmol/L versus 240µmol/L after transplantation, and mean values of urine MMA before transplantation 4700mmol/mol creatinine versus 2300mmol/mol creatinine after transplantation). No further acute metabolic decompensation was observed and protein-intake was increased from 0.60 to 0.83g/Kg/day. One patient transplanted at age 9.7years developed a hepatoblastoma at age 11years with subsequent neurological complications and eventually died. The three other patients are alive. Two of them remained neurologically stable. The 3rd patient who displayed choreoathetosis transiently improved his neurological condition immediately after transplantation and then remained stable. CONCLUSION: Kidney transplantation represents an interesting alternative therapeutic option in methylmalonic aciduria, for renal complications but also as a "cellular therapy" that may significantly reduce metabolic decompensations and hospitalizations. However, further neurological impairment remains possible.


Subject(s)
Amino Acid Metabolism, Inborn Errors/therapy , Kidney Transplantation , Liver Transplantation , Metabolic Diseases/therapy , Renal Insufficiency, Chronic/therapy , Amino Acid Metabolism, Inborn Errors/blood , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/pathology , Amino Acid Metabolism, Inborn Errors/urine , Cell- and Tissue-Based Therapy , Child , Disease Progression , Female , Glomerular Filtration Rate , Humans , Male , Metabolic Diseases/genetics , Methylmalonic Acid/blood , Methylmalonic Acid/urine , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/pathology
3.
Am J Transplant ; 12(12): 3337-54, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22958221

ABSTRACT

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.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Hemolytic-Uremic Syndrome/drug therapy , Kidney Transplantation/adverse effects , Postoperative Complications , Secondary Prevention , Adolescent , Adult , Atypical Hemolytic Uremic Syndrome , Child , Child, Preschool , Complement C5/antagonists & inhibitors , Complement C5/immunology , Female , Hemolytic-Uremic Syndrome/etiology , Humans , Infant , Male , Prognosis , Retrospective Studies , Young Adult
4.
Am J Transplant ; 12(7): 1938-44, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22494769

ABSTRACT

We report the first observation of successful kidney transplantation under pre-emptive eculizumab treatment in a 7-year-old boy with atypical hemolytic uremic syndrome (aHUS) and a known hybrid CFH/CFHR1 gene, who was dependent on plasma therapy during the 3-year dialysis period. The hybrid CFH/CFHR1 protein has an altered C3b/C3d binding, is incapable to protect cells from complement attack and is directly implicated in aHUS pathogenesis. There was no evidence of recurrence during the first 16-month follow-up period. We conclude that eculizumab alone, without plasma therapy (plasma infusion and/or plasma exchange), is sufficient to prevent recurrence of aHUS and to maintain long-term graft function.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Complement C3b Inactivator Proteins/genetics , Hemolytic-Uremic Syndrome/surgery , Kidney Transplantation , Child , Child, Preschool , Complement Factor H/genetics , Hemolytic-Uremic Syndrome/genetics , Humans , Male
5.
Clin Pharmacol Ther ; 86(6): 609-18, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19865079

ABSTRACT

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.


Subject(s)
Cytochrome P-450 CYP3A/genetics , Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation , Models, Biological , Polymorphism, Genetic , Tacrolimus/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adolescent , Age Factors , Body Weight , Child , Child, Preschool , Cytochrome P-450 CYP3A/metabolism , Drug Dosage Calculations , Drug Monitoring , Drug Therapy, Combination , Female , France , Hematocrit , Humans , Immunosuppressive Agents/administration & dosage , Male , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Reproducibility of Results , Tacrolimus/administration & dosage , Treatment Outcome
7.
Am J Transplant ; 9(5): 1223-9, 2009 May.
Article in English | MEDLINE | ID: mdl-19422347

ABSTRACT

Hemolytic uremic syndrome (HUS) associated with anti-Factor H (anti-FH) autoantibodies is a recently described pathophysiological entity. Monitoring of anti-FH IgG titer may be a sensitive marker of disease activity and guide treatment to eliminate circulating anti-FH antibodies. We report here a case of atypical HUS (aHUS) in which anti-FH autoantibodies were detected during the course of a fifth kidney transplant, 30 years after the first flare of aHUS. This exceptional case suggests that early, specific management based on immunosuppressive therapy and plasma exchanges monitored by anti-FH IgG titer may result in long-term graft survival.


Subject(s)
Autoantibodies/blood , Complement Factor H/immunology , Hemolytic-Uremic Syndrome/surgery , Kidney Transplantation/immunology , Blood Proteins/genetics , Child , Complement C3b Inactivator Proteins/genetics , Complement Factor B/immunology , Female , Gene Deletion , Hemolytic-Uremic Syndrome/classification , Hemolytic-Uremic Syndrome/immunology , Humans , Recurrence , Reoperation/statistics & numerical data
8.
Mol Genet Metab ; 97(3): 172-8, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19375370

ABSTRACT

OBJECTIVE: To better delineate the natural history of patients with methylmalonic aciduria (MMA). STUDY DESIGN: Thirty patients with vitamin-B12-unresponsive MMA (25 aged 1.5 to 22.0 years (y) at the end of the study and 5 who died during a metabolic crisis) were managed following standardized guidelines and studied retrospectively. The median follow-up was 8.3 y (range: 1.4-19.5). Patients were investigated with neuropsychological testing, brain MRIs, inulin clearances, biochemical and genetic studies. RESULTS: Fifteen patients had a neonatal onset. Thirteen patients (43%) had significant neurological impairment. Chronic renal disease (CRD) occurred in 14 patients (47%) with a median age of onset of 6.5 y (range 1.5-18.6). Renal function further deteriorated in 4 patients within a median period of 5.8 y (range 2-7.4). Of 25 patients investigated at the enzymatic level, 17 were classified mut(o), 3 mut- and 5 cblA. Mortality, number of acute decompensations (p=0.031), median MMA urinary excretion (p=0.006) and neurological impairment (p<0.0001) were higher in mut degrees patients compared to mut-/cblA patients. Concerning the CRD, no difference incidence was found although the onset of CRD occurred earlier in mut(o) patients and was more severe. CONCLUSIONS: Our study provides unique data concerning the progression of renal disease in MMA. Patients with mut(o) phenotype have a more severe phenotype and probably an earlier and more severe CRD than patients with mut-/cblA phenotype.


Subject(s)
Amino Acid Metabolism, Inborn Errors/therapy , White People , Adolescent , Adult , Amino Acid Metabolism, Inborn Errors/complications , Amino Acid Metabolism, Inborn Errors/urine , Child , Child, Preschool , Disease Progression , Female , France , Humans , Infant , Kidney/pathology , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/pathology , Male , Methylmalonic Acid/urine , Nervous System Diseases/complications , Phenotype , Time Factors , Treatment Outcome
9.
Mol Genet Metab ; 95(1-2): 107-9, 2008.
Article in English | MEDLINE | ID: mdl-18676166

ABSTRACT

A boy who was diagnosed with methylmalonic aciduria (MMA) at the age of 10 days developed persistent hepatomegaly and raised transaminases from the age of 4 years. He was subsequently diagnosed with Leigh syndrome and required a kidney transplantation for end-stage renal failure. A massive hepatoblastoma led to his death by the age of 11 years. Methylmalonyl-CoA mutase activity was undetectable on both cultured skin fibroblasts and kidney biopsy and multiple respiratory chain deficiency was demonstrated in the kidney. Mitochondrial dysfunction and/or post-transplant immunosuppressive therapy should be considered as a possible cause of liver cancer in this patient.


Subject(s)
Hepatoblastoma/enzymology , Lipid Metabolism, Inborn Errors/complications , Lipid Metabolism, Inborn Errors/enzymology , Methylmalonyl-CoA Mutase/metabolism , Cells, Cultured , Child , Electron Transport , Fatal Outcome , Fibroblasts/enzymology , Follow-Up Studies , Hepatoblastoma/etiology , Hepatoblastoma/genetics , Hepatoblastoma/therapy , Humans , Immunosuppressive Agents/adverse effects , Kidney/enzymology , Kidney/metabolism , Kidney Transplantation/adverse effects , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/therapy , Male , Methylmalonic Acid/metabolism , Methylmalonyl-CoA Mutase/genetics , Mutation
10.
J Pediatr ; 148(5): 623-627, 2006 May.
Article in English | MEDLINE | ID: mdl-16737873

ABSTRACT

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.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Immunologic Factors/therapeutic use , Lupus Erythematosus, Systemic/drug therapy , Adolescent , Adult , Age Factors , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Murine-Derived , Child , Cross-Sectional Studies , Female , France , Humans , Immunologic Factors/adverse effects , Kidney Function Tests , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/immunology , Lymphocyte Count , Retrospective Studies , Rituximab , Treatment Outcome
12.
J Pediatr ; 146(5): 648-53, 2005 May.
Article in English | MEDLINE | ID: mdl-15870669

ABSTRACT

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.


Subject(s)
Lupus Erythematosus, Systemic/physiopathology , Child , Child, Preschool , Cross-Sectional Studies , Female , France , Humans , Infant , Lupus Erythematosus, Systemic/diagnosis , Male , Multicenter Studies as Topic , Retrospective Studies , Sex Distribution
13.
Arch Pediatr ; 11(8): 941-4, 2004 Aug.
Article in French | MEDLINE | ID: mdl-15288087

ABSTRACT

Childhood-onset systemic lupus erythematosus (SLE) is often severe and has a serious long-term morbidity. Pediatric guidelines about its management do not exist. The French study group of childhood-onset SLE proposes recommendations about the investigation which are needed at diagnosis and during follow-up of SLE, in order to adjust the treatment according to the severity of the disease and to avoid unnecessary investigations.


Subject(s)
Aftercare/methods , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/therapy , Pediatrics/methods , Aftercare/standards , Anti-Inflammatory Agents/therapeutic use , Child , Diagnosis, Differential , Drug Monitoring/methods , Drug Monitoring/standards , Humans , Immunosuppressive Agents/therapeutic use , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/immunology , Pediatrics/standards , Treatment Outcome
16.
Nat Genet ; 29(1): 57-60, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11528392

ABSTRACT

Complex III (CIII; ubiquinol cytochrome c reductase of the mitochondrial respiratory chain) catalyzes electron transfer from succinate and nicotinamide adenine dinucleotide-linked dehydrogenases to cytochrome c. CIII is made up of 11 subunits, of which all but one (cytochrome b) are encoded by nuclear DNA. CIII deficiencies are rare and manifest heterogeneous clinical presentations. Although pathogenic mutations in the gene encoding mitochondrial cytochrome b have been described, mutations in the nuclear-DNA-encoded subunits have not been reported. Involvement of various genes has been indicated in assembly of yeast CIII (refs. 8-11). So far only one such gene, BCS1L, has been identified in human. BCS1L represents, therefore, an obvious candidate gene in CIII deficiency. Here, we report BCS1L mutations in six patients, from four unrelated families and presenting neonatal proximal tubulopathy, hepatic involvement and encephalopathy. Complementation study in yeast confirmed the deleterious effect of these mutations. Mutation of BCS1L would seem to be a frequent cause of CIII deficiency, as one-third of our patients have BCS1L mutations.


Subject(s)
Brain Diseases/genetics , Electron Transport Complex III/genetics , Electron Transport , Kidney Tubules, Proximal/pathology , Liver Failure/genetics , Mitochondria/genetics , Mutation , Proteins/genetics , ATPases Associated with Diverse Cellular Activities , Amino Acid Sequence , Animals , Base Sequence , Brain Diseases/pathology , Female , Humans , Infant, Newborn , Liver Failure/pathology , Male , Molecular Sequence Data , Proteins/chemistry , Sequence Homology, Amino Acid
17.
J Urol ; 166(3): 1046-8, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11490295

ABSTRACT

PURPOSE: Ureterovesical reimplantation is most often performed for renal transplantation in children. We reviewed our experience to evaluate the safety and efficacy of ureteroureteral reimplantation in pediatric renal transplantation. MATERIALS AND METHODS: We retrospectively evaluated the charts of 92 boys and 72 girls who underwent a total of 166 ureteroureteral anastomoses for renal transplantation from January 1990 to December 1999. Spatulated end-to-end anastomosis was performed between recipient and graft ureters without stenting and with a bladder catheter for at least 10 days. RESULTS: Mean patient age at transplantation was 11.2 years (range 1 to 21.5). There were 22 living related donor and 144 cadaveric grafts. Urological anomalies and nephropathy were the cause of end stage renal disease in 146 and 20 patients, respectively. Urological complications were noted in 14 of the 166 transplantations (8.4%) in 10 boys and 4 girls, including 12 initial and 2 repeat grafts from 2 living related and 12 cadaveric donors. Five of these patients had undergone previous urological surgery. The 2 children (1.2%) with acute ureteral obstruction underwent repeat intervention after stent failure. Anastomotic leakage in 7 cases (4.2%) was treated conservatively in 1 and with a Double-J stent (Medical Engineering Corp., New York, New York) only required in 3. Reoperation was required in 3 cases. One patient (0.6%) with late ureteral stenosis underwent repeat anastomosis, 1 (0.6%) required reimplantation for recurrent pyelonephritis due to vesicoureteral reflux in the graft, 1 (0.6%) with a valve bladder required bladder augmentation and ureteral reimplantation, and 1 (0.6%) with lymphocele and 1 (0.6%) with lithiasis were successfully treated conservatively. Complications were associated with acute rejection in 6 cases. Mean followup without graft loss in patients who presented with versus without complications was 58.3 months (range 1 to 112) versus 75 (range 1 to 118). In the former patients with a mean age of 16 years 9 months versus those without urological complications mean serum creatinine was 116 and 108 mol./l., respectively. Two grafts were lost in patients with urological complications, including 1 who died of pulmonary embolism and 1 with refractory chronic rejection. Seven patients were lost to followup after 54 months (range 12 to 113) of adequate graft function. CONCLUSIONS: Ureteroureteral anastomosis is a safe and effective technique for pediatric renal transplantation with a low complication rate, which may be due to better vascularization of the shorter ureteral end of the graft. Our results should encourage the use of this technique in pediatric renal transplantation. Efforts to preserve the recipient ureters should be made at nephrectomy.


Subject(s)
Kidney Transplantation/adverse effects , Ureter/surgery , Urologic Diseases/epidemiology , Adolescent , Adult , Anastomosis, Surgical/adverse effects , Child , Child, Preschool , Female , Humans , Infant , Male , Retrospective Studies , Urologic Diseases/etiology
20.
Pediatr Nephrol ; 16(2): 154-5, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11261685

ABSTRACT

Seven children with steroid-dependent nephrotic syndrome who were on stable remission under Sandimmun therapy were switched to Neoral at the same dosage. During the 4-month follow-up period, two patients relapsed, due to poor compliance in one of them. Serum creatinine remained stable in all patients. Pharmacokinetic profiles were performed at day 0 while on Sandimmun and 4 weeks after conversion to Neoral. Following conversion to Neoral, the peak concentration occurred earlier (2+/-1.4 h vs 3.9+/-2.4 h), and the maximum concentration (677+/-386 ng/ml vs 488+/-265 ng/ml) and the area under the curve (3,082+/-1,536 ng/ml/h vs 2,201+/889 ng/ml/h) were higher. We conclude that Neoral results in an increased bioavailability of cyclosporine (CsA) as compared to Sandimmun in patients with steroid-dependent nephrotic syndrome in remission.


Subject(s)
Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/therapeutic use , Cyclosporine/pharmacokinetics , Cyclosporine/therapeutic use , Nephrotic Syndrome/drug therapy , Adolescent , Area Under Curve , Child , Humans , Male , Steroids
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