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Biomedical subjects

C Loirat

Publications and source records attributed to C Loirat.

At least 19 recordsLinked to original sources
PubMed2000

Pharmacokinetics and tolerance of mycophenolate mofetil in renal transplant children.

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

Abdominal Pain↗
PubMed2000

Haemolytic uraemic syndrome and Shiga toxin-producing Escherichia coli infection in children in France. The Société de Néphrologie Pédiatrique.

We conducted a study to determine the incidence of haemolytic uraemic syndrome (HUS) in children in France and to assess the role of Shiga-toxin-producing Escherichia coli (STEC) infection in the aetiology of HUS. In collaboration with the Société de Néphrologie Pédiatrique we undertook a retrospective review of all cases of HUS hospitalized from January 1993 to March 1995 and a 1-year prospective study (April 1995-March 1996) of epidemiological and microbiological features of cases of HUS. The polymerase chain reaction (PCR) procedure was used to detect stx, eae, e-hlyA genes directly from case stool samples. Serum samples from cases were examined for antibodies to lipopolysaccharide (LPS) of 26 major STEC serogroups. Two hundred and eighty-six cases were reported. The average incidence per year was 0.7/10(5) children < 15 years and 1.8/10(5) children < 5 years. During the prospective study, 122/130 cases were examined for evidence of STEC infection using PCR and/or serological assays and 105 (86%) had evidence of STEC infection. Serum antibodies to E. coli O157 LPS were detected in 79 (67%) cases tested. In conclusion, this study showed that STEC infection is an important cause of HUS in children in France, with a high proportion related to the O157 serogroup.

Adhesins, Bacterial↗
PubMed2000

WT1 splice-site mutations are rarely associated with primary steroid-resistant focal and segmental glomerulosclerosis.

BACKGROUND: Donor splice-site de novo heterozygous mutations in intron 9 of the Wilms' tumor gene (WT1) have been reported in Frasier syndrome, which is defined by the association of focal and segmental glomerulosclerosis (FSGS), male pseudohermaphroditism, and gonadoblastoma. These splice-site mutations alter the WT1 alternative splicing leading to two WT1 isoforms, with (+) or without (-) three amino acids, lysine-threonine-serine (KTS), between zinc fingers 3 and 4. The aim of this work was to investigate the possibility that some cases of primary steroid-resistant nephrotic syndrome associated with FSGS may be caused by WT1 splice-site mutations. METHODS: We analyzed WT1 exons 8 and 9 and the surrounding exon/intron boundary DNA sequences in 37 children with nonfamilial primary steroid-resistant nephrotic syndrome. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the relative ratio of +KTS/-KTS transcripts from immortalized lymphocyte RNA. RESULTS: One boy with FSGS and associated pathologies (diaphragmatic hernia, proximal hypospadias, and unilateral testicular ectopia) was found to carry the heterozygous 1228 +4 C-->T splice-site mutation. RT-PCR quantitation of the +KTS/-KTS transcripts from immortalized lymphocyte RNA of this patient showed a diminution of the +KTS/-KTS isoform ratio (0.43), which is identical to that reported in patients with Frasier syndrome. Using the same approach, healthy control subjects have +KTS/-KTS ratios ranging from 1.50 to 2.00. CONCLUSIONS: This study expands the range of the phenotypic presentation of the intron 9 splice-site WT1 mutations and adds to the already reported heterogeneity of primary steroid-resistant nephrotic syndromes. We suggest that these mutations are not likely to be a common cause of isolated steroid-resistant nephrotic syndrome, and recommend a WT1 exon 9/intron 9 splice-site study in children with primary steroid-resistant nephrotic syndrome if genital or diaphragmatic anomalies are associated. The identification of such WT1 mutations has practical implications for the management of these patients.

Adolescent↗
PubMed2000

Effect of individual plasma lipoprotein(a) variations in vivo on its competition with plasminogen for fibrin and cell binding: An in vitro study using plasma from children with idiopathic nephrotic syndrome.

Simultaneous natural changes in lipoprotein(a) [Lp(a)] and plasminogen occur in the nephrotic syndrome and offer a unique opportunity to investigate their effects on plasminogen activation under conditions fashioned in vivo. Plasminogen, Lp(a), and apolipoprotein(a) in plasma were characterized, and their competitive binding to carboxy-terminal lysine residues of fibrin and cell membrane proteins was determined in nephrotic children during a flare-up of the disease (61 cases) and after 6 weeks (33 cases) and 6 months (42 cases) of remission. Low plasminogen concentrations (median 1.34 micromol/L, range 0.39 to 1.96 micromol/L) and high Lp(a) levels (median 0.27 g/L, range 0.07 to 2. 57 g/L) were detected at flare-up. These changes were associated with an increased Lp(a) binding ratio onto fibrin (3.13+/-0.48) and cells (1.53+/-0.24) compared with binding ratios of control children (1.31+/-0.19 and 1.05+/-0.07, respectively) with normal plasminogen and low Lp(a) (median 0.071 g/L). After 6 weeks and 6 months of remission, the values for net decrease in Lp(a) binding to fibrin were 1.7+/-0.22 (after 6 weeks) and 1.88+/-0.38 (after 6 months) and were correlated with low Lp(a) concentrations (median 0.2 g/L, range 0.07 to 0.8 g/L; and median 0.12 g/L, range 0.07 to 1.34 g/L) and inversely associated with increased plasminogen levels (median 1.82 micromol/L, range 1.4 to 2.1 micromol/L; and median 1.58 micromol/L, range 1.1 to 2.1 micromol/L). These studies provide the first quantitative evidence that binding of Lp(a) to lysine residues of fibrin and cell surfaces is directly related to circulating levels of both plasminogen and Lp(a) and that these glycoproteins may interact as competitive ligands for these biological surfaces in vivo. This mechanism may be of relevance to the atherothrombotic role of Lp(a), particularly in nephrotic patients.

Adolescent↗
PubMed1999

Human herpes virus-8 and other risk factors for Kaposi's sarcoma in kidney transplant recipients. Groupe Cooperatif de Transplantation d' Ile de France (GCIF).

BACKGROUND: The exact reasons for the high incidence of Kaposi's sarcoma (KS) after kidney transplantation are still unknown. Immunosuppression is classically considered as the main risk factor, but the relative risk contributed by the patient's geographic origin and by human herpes virus (HHV)-8 infection still has to be determined. METHODS: We carried out a retrospective and a prospective study among kidney transplant recipients (TP) to identify the risk factors for posttransplantation KS. Each of 30 KS patients was matched with two controls to investigate the association with geographic origin, immunosuppressive regimen, HHV-8 antibodies before and after transplantation, and other infections. Among TP with new onset of KS, we prospectively evaluated HHV-8 serology and viremia in response to decreased immunosuppression. RESULTS: African and Middle East origins, past infection with hepatitis B, hemoglobin level <12 g/dl, lymphocyte count <750/mm3 at the time of diagnosis and initial use of polyclonal antilymphocyte sera were risk factors for KS. After multivariate analysis, origin in Africa or Middle East and use of antilymphocyte sera for induction remained as independent risk factors. Sixty-eight percent (17/25) of TP with HHV-8 antibodies before or after transplantation developed KS compared with 3% (1/33) of seronegative TP (P<0.00001). HHV-8 DNA was detectable in seven of nine peripheral blood mononuclear cells (PBMC) and in six of six KS lesions at diagnosis; it became negative in PBMC in three of five patients in parallel with tumor regression. CONCLUSION: African and Middle East geographic origins, HHV-8 infection before and after kidney transplantation, and initial use of polyclonal antilymphocyte sera were independent risk factors for KS. The presence of HHV-8 antibodies before or after transplantation was highly predictive of the emergence of posttransplantation KS and conferred a 28-fold increased risk of KS (odds ratio=28.4; 95% confidence interval: 4.9-279). Detection of HHV-8 DNA within PBMC and KS lesions seems related to tumor burden and evolution.

Adult↗
PubMed1999

Renal granulomatous sarcoidosis in childhood: a report of 11 cases and a review of the literature.

UNLABELLED: We analysed retrospectively 11 children with renal granulomatous sarcoidosis confirmed by renal histology in order to describe the course and prognosis of the disease. Symptomatic sarcoidosis was diagnosed at a mean age of 10.1 years. Nine children had renal involvement at the time of diagnosis. In the course of the disease, nine patients developed renal failure and mild proteinuria, seven had transient sterile leukocyturia, four showed microscopic haematuria, seven had a urinary concentrating defect, and enlarged kidneys were seen in three patients. One child had hypercalcaemia and hypercalciuria, none had hypertension. Light microscopy of the kidney showed interstitial infiltration by mononuclear cells in all children, interstitial fibrosis in nine patients, epithelioid granulomas in seven, tubular involvement in eight, and mild glomerular involvement in seven patients. Renal immunofluorescence was negative. Ten children received prednisone for 1-11 years. After a mean follow up of 5.5 years, three patients had entered end-stage renal failure and one had chronic insufficiency after interruption of medical supervision and prednisone therapy. CONCLUSION: Renal failure, proteinuria, leukocyturia, haematuria, and concentration defect are the prominent features of renal granulomatous sarcoidosis in children. Steroid therapy, adjusted according to disease activity, may prevent end-stage renal failure.

Adolescent↗
PubMed1999

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

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

Age Factors↗
PubMed1999

[Passage from sandimmun to neoral in kidney transplantation in children].

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

Age Factors↗
PubMed1999

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

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

Antimetabolites↗
PubMed1999

Mother-to-child transmitted WT1 splice-site mutation is responsible for distinct glomerular diseases.

Mutations in the Wilms' tumor suppressor gene (WT1) are linked with Denys-Drash syndrome (DDS), a rare childhood disease characterized by diffuse mesangial sclerosis and renal failure of early onset, XY pseudohermaphroditism, and high risk of Wilms' tumor. KTS (lysine-threonine-serine) splice site mutations in WT1 intron 9 have been described in patients with Frasier syndrome, another rare syndrome defined by focal and segmental glomerulosclerosis (FSGS), XY pseudohermaphroditism, and frequent occurrence of gonadoblastoma. Cases of Frasier syndrome raise the question whether splice site mutations may also be found in XX females with isolated FSGS. A girl (index case) presented with the nephrotic syndrome at 9 mo of age. The diagnosis of DDS was based on the finding of diffuse mesangial sclerosis in the kidney biopsy and of a XY karyotype. The index case's mother had had proteinuria since she was 6 years of age. A renal biopsy was performed when she was 28 and disclosed FSGS. The same splice site mutation in intron 9 (WT1 1228+5 G-->A) involving one allele was found in the child and in her mother, but not in other members of the kindred (including the parents, the two brothers, and the two sisters of the index case's mother) who were free of renal symptoms. Quantification of WT1 +KTS/-KTS isoforms in the index case's father and one index case's maternal uncle showed a normal +KTS/-KTS ratio of 1.50. In contrast, the index case and her mother had a low ratio (0.40 and 0.34, respectively), within the range reported in Frasier syndrome. In conclusion, this study shows that the KTS splice site mutation is not specific for Frasier syndrome, but that it can also be found in DDS and in a normal female (XX) with FSGS, a woman who achieved normal pregnancy. It is suggested that WT1 splice site mutations should be sought in phenotypically normal females who present with FSGS or with related glomerulopathies of early onset.

Adult↗
PubMed1999

Evidence that modifications of Lp(a) in vivo inhibit plasmin formation on fibrin--a study with individual plasmas presenting natural variations of Lp(a).

In the present study we have investigated the effect of individual variations in the concentration of Lp(a) on plasmin formation at the surface of fibrin. The plasma Lp(a) concentrations from 20 nephrotic children were high at flare-up of the disease (0.43+/-0.45 g/l) and decreased progressively with remission at both 6 weeks (0.28+/-0.24 g/l) and 6 months (0.24+/-0.288 g/l). In contrast, the concentration of plasminogen showed an inverse variation, with low values at flare-up (1.27+/-0.34 microM) and normal values at remission (1.66+/-0.17 microM at 6 weeks and 1.99+/-0.21 microM at 6 months). An increase in plasmin formation (from 0.62+/-0.49 to 0.73+/-0.61, and 0.84+/-0.75 pmol/well) and a decrease in apo(a) binding (from 5.45+/-2.42 to 4.54+/-2.12, and 3.93+/-1.51 fmol/well) on the surface of fibrin, were concomitantly observed from flare-up to remission at 6 weeks and at 6 months, respectively. Values for plasmin formation parallel the amount of plasminogen bound. The low concentration of plasminogen found at flare-up may also have contributed to the increased binding of Lp(a) as indicated by a decrease in the maximal amount of Lp(a) bound (Bmax) to fibrin as a function of plasma plasminogen concentrations. Bmax was 1.51 fmol in the absence of plasminogen and decreased to 1.1 fmol and 0.93 fmol at respectively 1 and 2 microM of plasminogen. Altogether, these data constitute the first quantitative evidence indicating that plasmin formed at the surface of fibrin may vary with modifications of the concentration of Lp(a) in vivo.

Adolescent↗
PubMed1998

Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.

Constitutional mutations of the WT1 gene, encoding a zinc-finger transcription factor involved in renal and gonadal development, are found in most patients with Denys-Drash syndrome (DDS), or diffuse mesangial sclerosis (DMS) associated with pseudohermaphroditism and/or Wilms tumor (WT). Most mutations in DDS patients lie in exon 8 or exon 9, encoding zinc finger 2 or zinc finger 3, respectively, with a hot spot (R394W) in exon 9. We analyzed a series of 24 patients, 10 with isolated DMS (IDMS), 10 with DDS, and 4 with urogenital abnormalities and/or WT. We report WT1 heterozygous mutations in 16 patients, 4 of whom presented with IDMS. One male and two female IDMS patients with WT1 mutations underwent normal puberty. Two mutations associated with IDMS are different from those described in DDS patients. No WT1 mutations were detected in the six other IDMS patients, suggesting genetic heterogeneity of this disease. We analyzed genotype/phenotype correlations, on the basis of the constitution of a WT1 mutation database of 84 germ-line mutations, to compare the distribution and type of mutations, according to the different symptoms. This demonstrated (1) the association between mutations in exons 8 and 9 and DMS; (2) among patients with DMS, a higher frequency of exon 8 mutations among 46, XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype; and (3) statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions.

Amino Acid Sequence↗