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Biomedical subjects

Pierre Cochat

Publications and source records attributed to Pierre Cochat.

At least 19 recordsLinked to original sources
PubMed2007

Schimke immunoosseous dysplasia: suggestions of genetic diversity.

Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCAL1 mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.

Algorithms↗
PubMed2006

Hypertensive crisis, hepatitis B virus and polyarteritis nodosa in a child.

We report on a case of hepatitis B virus-related polyarteritis nodosa (PAN) in a 4-year-old Turkish boy who was first admitted because of severe arterial hypertension. The diagnosis of PAN was provided by conventional renal arteriography and the child was successfully treated with intensive sequential therapy combining short-term prednisone, plasma exchange and interferon-alpha-2b. Nine years later, he had no sign of PAN, normal blood pressure and normal renal function in the absence of any treatment.

Angiography↗
PubMed2006

The challenge of renal function in heart transplant children.

Renal dysfunction may occur after pediatric heart transplantation and impacts on long-term prognosis. This study aims to review the incidence and mechanisms of chronic nephropathy following heart transplantation, and suggest therapeutic directions. The proportion of pediatric heart-transplant recipients with impaired renal function varies from 22 to 57%, and end-stage renal failure from 3 to 10%, depending on the method used for estimating the glomerular filtration rate. The pathophysiology of renal dysfunction is in part due to calcineurin inhibitor-induced renal vasoconstriction, through activation of the intrarenal renin-angiotensin system, TGF-beta1 upregulation and TGF-beta1 gene polymorphisms. Overproduction of angiotensin II, associated with angiotensin-converting-enzyme genotype, might be associated with poor prognosis and pharmacological factor gene polymorphisms, and may contribute to variation of calcineurine inhibitor exposure in the kidney. Strategies to prevent renal dysfunction include reducing calcineurine inhibitor exposure or delaying calcineurine inhibitor administration from the early post-transplant period. Calcium channel blockers and angiotensin-converting-enzyme inhibitors, blockade of angiotensin II, or anti-TGF-beta1 antibodies might limit nephrotoxicity. No accurate marker can predict the potential of renal lesions to develop. Lowering calcineurine inhibitors levels with immunosuppressive agents that are either less nephrotoxic or non-nephrotoxic should be formally studied. Of high interest is the impact of genetic polymorphism on the development of renal dysfunction.

Calcineurin Inhibitors↗
PubMed2006

Body growth after combined liver-kidney transplantation in children with primary hyperoxaluria type 1.

BACKGROUND: Children with primary hyperoxaluria type 1 (PH1) often develop severe growth failure, which is related to metabolic and endocrine consequences of chronic renal failure, and/or oxalate deposition in bone and cartilage. Combined liver and kidney transplantation (LKT) corrects the underlying metabolic defect and restores renal function in these children. METHODS: We therefore analyzed longitudinal growth of 24 children with PH1 who underwent LKT at nine European centers. Mean age at LKT was 8.9 years, and mean duration of follow-up was 5.7 years. RESULTS: After LKT mean standardized height tended to increase from -1.79 SD to -1.47 SD until last observation. Mean adult height amounted to 167 cm and 158 cm in boys and girls, respectively. At last observation, seven out of 24 patients were stunted. Within the whole study population, the degree of catch-up growth after LKT was positively associated with degree of stunting at the time of LKT and negatively associated with prednisolone dosage explaining together 39% of the overall variability. CONCLUSIONS: Combined LKT does not induce true catch-up growth in the majority of children with PH1. Due to the preexisting growth retardation at the time of LKT, one third of patients end up with a reduced final height.

Body Height↗
PubMed2006

Primary hyperoxaluria type 1: still challenging!

Primary hyperoxaluria type 1, the most common form of primary hyperoxaluria, is an autosomal recessive disorder caused by a deficiency of the liver-specific enzyme alanine: glyoxylate aminotransferase (AGT). This results in increased synthesis and subsequent urinary excretion of the metabolic end product oxalate and the deposition of insoluble calcium oxalate in the kidney and urinary tract. As glomerular filtration rate (GFR) decreases due to progressive renal involvement, oxalate accumulates and results in systemic oxalosis. Diagnosis is still often delayed. It may be established on the basis of clinical and sonographic findings, urinary oxalate +/- glycolate assessment, DNA analysis and, sometimes, direct AGT activity measurement in liver biopsy tissue. The initiation of conservative measures, based on hydration, citrate and/or phosphate, and pyridoxine, in responsive cases at an early stage to minimize oxalate crystal formation will help to maintain renal function in compliant subjects. Patients with established urolithiasis may benefit from extracorporeal shock-wave lithotripsy and/or JJ stent insertion. Correction of the enzyme defect by liver transplantation should be planned, before systemic oxalosis develops, to optimize outcomes and may be either sequential (biochemical benefit) or simultaneous (immunological benefit) liver-kidney transplantation, depending on facilities and access to cadaveric or living donors. Aggressive dialysis therapies are required to avoid progressive oxalate deposition in established end-stage renal disease (ESRD), and minimization of the time on dialysis will improve both the patient's quality of life and survival.

Child↗
PubMed2006

Longitudinal growth in children following kidney transplantation: from conservative to pharmacological strategies.

Impairment of longitudinal growth in children with chronic renal failure (CRF) is multifactorial. It is mainly due to disturbances in the growth hormone (GH)/insulin-like growth factor (IGF)/IGF-binding protein axis. Growth failure can be managed by optimizing nutrition and fluid/electrolyte homeostasis, and overcoming the growth-inhibiting effects of uremia by high-dose recombinant human (rh) GH treatment. A sufficient catch-up growth is one of the determining issues for the overall success of pediatric kidney transplantation (Tx). However, despite satisfactory renal function, spontaneous catch-up growth is often insufficient as glucocorticoid treatment is the main inhibiting factor for longitudinal growth after Tx. In addition, longitudinal growth may be jeopardized by low glomerular filtration rate (GFR) and African American or Hispanic background. Supraphysiological doses of GH and/or IGF-I in vitro and in vivo can partially overcome the growth-inhibiting effects of glucocorticoid treatment. GH-associated increase of leukocyte proliferation and cytotoxicity with stimulated interferon synthesis have been demonstrated. However, it is not clear whether such stimulatory effects on leukocyte function are a transitory or a constant risk factor after organ Tx. Clinical trials of GH in children after renal Tx have suggested a rather moderate or transient effect of rhGH on the immune system, and corticosteroids induce a hyporesponsiveness to the action of GH. As long as corticosteroids are believed to be essential after renal Tx, rhGH should be considered to optimize longitudinal growth in children.

Child↗
PubMed2006

Four-year follow-up of oral health surveillance in renal transplant children.

To outline the specific oral surveillance needs of renal transplant children, we report the 4-year follow-up data of 106 children examined routinely on a 6-month basis and upon request from the medical team or the parents in the interval. Data were recorded for hard and soft dental tissues, including enamel defects carious lesions, gingival status, orthodontic treatment needs, and wisdom teeth eruption. Hard-tissue lesions were noted in 34.9% of the children, caries lesions on the permanent teeth were seen in 15.0% of cases, 18.86% of the patients had orthodontic treatment. Spontaneous examination, upon request for medical reasons, was given for 26 children. Twenty-one demands originated from the parents. Over a 4-year period the attendance of a dental specialist resulted in a significant improvement in the oral health of the renal transplant children.

Adolescent↗
PubMed2006

Genetic investigation of autosomal recessive distal renal tubular acidosis: evidence for early sensorineural hearing loss associated with mutations in the ATP6V0A4 gene.

Mutations in the ATP6V1B1 and ATP6V0A4 genes, encoding subunits B1 and 4 of apical H(+) ATPase, cause recessive forms of distal renal tubular acidosis (dRTA). ATP6V1B mutations have been associated with early sensorineural hearing loss (SNHL), whereas ATP6V0A4 mutations are classically associated with either late-onset SNHL or normal hearing. The phenotype and genotype of 39 new kindreds with recessive dRTA, 18 of whom were consanguineous, were assessed. Novel and known loss-of-function mutations were identified in 31 kindreds. Fourteen new and five recurrent mutations of the ATP6V0A4 gene were identified in 21 families. For the ATP6V1B1 gene, two new and two previously described mutations were identified in 10 families. Surprisingly, seven probands with ATP6V0A4 gene mutations developed severe early SNHL between the ages of 2 mo and 10 yr. No mutation was detected in eight families. These data extend the spectrum of disease-causing mutations and provide evidence for genetic heterogeneity in SNHL. The data also demonstrate that mutations in either of these genes may cause early deafness, and they highlight the importance of genetic screening for recessive forms of dRTA independent of hearing status.

Acidosis, Renal Tubular↗
PubMed2005

Recurrence of nephrotic syndrome after renal transplantation: influence of increased immunosuppression.

Recurrence of nephrotic syndrome after renal transplantation leads to graft loss within 1 year in 50-80% of patients who do not receive any specific treatment. Several treatment protocols have been proposed leading to long-term remission in 50-80% of patients. The aim of our study was to evaluate the efficiency of intensified immunosuppression, simultaneously including methylprednisolone pulses, cyclophosphamide, high-dose cyclosporine and plasma exchanges. Fourteen patients with early recurrence were treated with a protracted high-dose prednisone or IV methylprednisolone, oral cyclophosphamide, high-dose oral or IV cyclosporine, and plasma exchanges. By the end of cyclophosphamide therapy and plasma-exchange program, six out of 14 patients had no proteinuria; five had residual proteinuria without nephrotic syndrome and three experienced ongoing gross proteinuria with nephrotic syndrome. By the end of follow-up, four out of the 14 patients had lost their graft: one out of six with complete remission, one out of five with residual proteinuria and two out of three with persistent nephrotic syndrome. We conclude that multiple reinforcement of immunosuppression in patients with recurrent nephrotic syndrome following renal transplantation as performed in our patients is not more efficient than the single use of cyclophosphamide or plasma exchange or high-dose cyclosporine as reported in the literature.

Adolescent↗
PubMed2005

Decision making concerning life-sustaining treatment in paediatric nephrology: professionals' experiences and values.

BACKGROUND: In a previous article, we studied decisions to withhold or withdraw life-sustaining treatment (LST) taken between 1995 and 2001 in 31 French-speaking paediatric nephrology centres. Files were available for 18 of the 31 centres. A grid was used to analyse the criteria on which decisions were based, and the results were enriched by an analysis of interviews with the doctors at these centres (31 interviews with doctors from the 18 centres). The goal was to describe in detail and to specify the criteria on which decisions to withhold or withdraw LST were based, in cases extracted from the files. The second paper deals exclusively with the interviews with doctors and analyses their lifetime's experience and perception. METHODS: We carried out semi-directed interviews with nephrologists from all the paediatric nephrology centres in France and the French-speaking regions of Switzerland and Belgium. RESULTS: We interviewed 46 paediatric nephrologists. Most were aware that decisions relating to LST are necessary and based on the assessment of the child's quality of life. According to them, decisions are not based on scientific criteria, but on the capacity to accept handicap, the family's past experiences and the doctor's own projections. They report that their task is particularly difficult when their action may contribute to death (withdrawal of treatment or acceleration of the process). They feel that their duty is to help the families in the acceptance of the doctors' decision rather than to encourage their participation in the decision-making process (DMP). CONCLUSIONS: This article shows that paediatric nephrologists differ in their opinions, mostly due to their own ethical convictions. This observation highlights the need to establish common rules taking into account the views held by doctors. This is the only way to establish an ethical code shared by professionals.

Adult↗
PubMed2005

Neonatal hemolytic uremic syndrome after mother-to-child transmission of Escherichia coli O157.

About 90% of cases of hemorrhagic uremic syndrome (HUS) occur in early childhood and most frequently are preceded by bloody diarrhea due to shiga-like toxin (SLT) producing Escherichia coli. We report a case of a newborn girl presenting with bloody diarrhea on her 7th day of life. Acute renal failure, severe arterial hypertension and hemolytic anemia were detected and prompt peritoneal dialysis and antihypertensive therapy were required. The girl had several episodes of seizures, necessitating intravenous phenobarbital. Transfontanel ultrasonography 48 h after disease onset was normal, whereas, MRI investigation 10 days later revealed severe ischemic lesions with beginning cystic encephalopathy. Renal function recovered and only very moderate tubular dysfunction remained. Serum analysis of factor H, von Willebrand factor protease, homocystinemia, proteins C and S, and antithrombin III were all normal. Mutation analysis of factor V Leiden, factor II, and methyltetrahydrofolate-reductase were normal. E. coli 0157:H7 and SLT 2 were detected in the stool. SLT 2 was also found in the mother's stool. This is the first report of mother-to-child transmission of SLT-producing E. coli.

Escherichia coli Infections↗
PubMed2005

Neurogenic bladder in an infant due to spinal arachnoid cyst.

The urinary bladder of patients with occult spinal defects may become dysfunctional, exposing the renal parenchyma to irreversible damage. However, during infancy clinical signs are often misdiagnosed. The treatment should be aimed at protecting kidneys from severe bladder dysfunction. We report a case of a female infant with an arachnoid cyst diagnosed at the age of 6 months, who suffered from intractable, repeated febrile urinary tract infections (UTI) for the previous 3 months. The images obtained by ultrasonography and voiding cystoureterography techniques were typical of a neurogenic bladder. The spinal cord was examined by magnetic resonance imaging (MRI), which revealed an arachnoid cyst that was surgically treated when the child was 8 months old. The postoperative results were excellent: spinal cord MRI was normal after 1 year, and the child experienced only one UTI episode in the next 2 years. Such an etiology of neurogenic bladder has never been reported in a 6-month-old child.

Arachnoid Cysts↗
PubMed2005

Triamcinolone acetonide: a new management of noncompliance in nephrotic children.

Noncompliance is frequent in children and adolescents with nephrotic syndrome. Once suspected, noncompliance is difficult to confirm and often impossible to avoid. The standard oral glucocorticoid treatment for children has been shown to be efficient and safe. However, a small number of children/parents are noncompliant to the steroid treatment, resulting in multiple relapses. For these patients the use of steroids with prolonged half-life such as triamcinolone acetonide (TA) can be helpful. We studied seven children (six boys, one girl; median age at diagnosis 8.6 years, range 1.8-10.7) receiving conventional steroid treatment for a median of 30 months (8-74) before starting intramuscular (IM) TA treatment. The standard prednisone treatment was replaced by 1 monthly IM injection of TA (1 mg/kg per day oral prednisone replaced by 1 mg/kg per month IM TA). The treatment was tapered off by a reduction of 10-20% of the initial dose per month over 6-8 months. After a mean observation period of 14 months (3-36) the results were evaluated in terms of number of relapses and treatment tolerance. Four children showed a clear decrease in number of relapses (1.8 to 0 per year); in the other three the number of relapses remained stable. Tolerance was excellent (no cataract, no arterial hypertension), and the cushingoid syndrome did not exceed the level experienced under conventional oral steroid therapy. However, growth velocity decreased during the TA treatment and returned to normal after discontinuation of TA. These preliminary results demonstrate that TA may be used in patients of suspected noncompliance in steroid-sensitive patients who respond with a complete remission during TA treatment over the observation period. Patients who do not benefit from the TA can be classified as very probably steroid-dependent. TA seems to be a useful therapeutic strategy in those patients for whom noncompliance is strongly suspected.

Child↗
PubMed2005

Switch from cyclosporine A to mycophenolate mofetil in nephrotic children.

Nephrotoxicity is a well-known adverse effect of cyclosporine A (CyA) treatment in children with steroid-dependent (SD) and steroid-resistant (SR) nephrotic syndrome (NS). We analyzed nine children (age: 3.3-15.7 years, two girls) with SD or SR NS who experienced a significant decrease in their GFR under CyA treatment as measured by inulin clearance (C(IN)). Mycophenolate mofetil (MMF) was introduced progressively until doses of 1 g/1.73 m(2) twice daily were reached. CyA treatment was stopped after introduction of MMF and oral steroids were reduced if possible. After a median follow up of 261 days, no adverse effects of MMF such as diarrhea or hematological anomalies occurred in our patients. After switching from CyA to MMF, those children with SD NS remained in remission without proteinuria and those with SR NS did not show any significant changes in their residual proteinuria. The serum protein level did not change significantly in any of the children analyzed. GFR increased from a mean of 76.9+/-4.8 to 119.9+/-5.9 mL/1.73 m(2) per min (P<0.001). Oral steroid treatment could be reduced from a median [range] prednisone dose of 0.85 [0.26-2.94] mg/kg/d pre-MMF to 0.29 [0-1.1] mg/kg per day (P=0.026), and blood pressure decreased moderately after CyA withdrawal, but the difference did not reach statistical significance. We conclude that a switch from CyA to MMF seems to be safe for children with SDNS and SRNS in terms of side effects as well as disease control, at least in the short term. Interruption of CyA treatment lead to rapid amelioration of kidney function in these children, often associated with steroid sparing, which may lead to additional benefit for growth velocity, blood pressure and physical appearance.

Adolescent↗
PubMed2005

Maternal isodisomy of the telomeric end of chromosome 2 is responsible for a case of primary hyperoxaluria type 1.

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism, in which excessive oxalates are formed by the liver and excreted by the kidneys, causing a wide spectrum of disease, ranging from renal failure in infancy to mere renal stones in late adulthood. This disease is caused by a deficiency of alanine:glyoxylate aminotransferase (AGT), which is encoded by a single copy gene, AGXT, located in 2q37.3. We identified an apparently homozygous, loss-of-function, mutation in a patient; the gene defect was present in the heterozygous mother but not in the patient's father. We performed a microsatellite repeat analysis using 13 specific chromosome 2 markers and non-chromosome 2 minisatellites. Six specific chromosome 2 markers showed an apparently homozygous maternal inheritance while four showed a biparental transmission consistent with paternity (confirmed by minisatellite analysis). Quantitative PCR of AGXT exons 1 and 3 on the patient's and parents genomic DNA revealed the presence of two copies of the gene. This is the first case of PH1 caused by segmental maternal isodisomy of 2q37.3.

Alleles↗
PubMed2005

Fatal neurologic involvement in pediatric Wegener's granulomatosis.

Wegener's granulomatosis is a potentially life-threatening vasculitis with widely variable presentation. Only three pediatric cases with severe central nervous system involvement are reported in the literature. Early fatal outcome as described here is exceptional. This report describes a 13-year-old female with typical skin lesions, proteinuria, and renal failure initially misdiagnosed as a Schoenlein-Henoch purpura. A kidney biopsy revealed severe extracapillary proliferation in 70% of the analyzed glomeruli but no granuloma. In spite of methylprednisolone pulse therapy and oral high-dose prednisone, end-stage renal failure was reached 4 months later, necessitating peritoneal dialysis. Three months later she presented with pulmonary hemorrhage and positive antineutrophil cytoplasmic antibodies suggesting Wegener's granulomatosis. This episode was controlled by methylprednisolone pulses. Seven months later she presented generalized seizures and coma, suggesting central nervous system involvement confirmed by magnetic resonance imaging. Methylprednisolone pulses and intravenous immunoglobulins led to neurologic improvement. Oral methotrexate was then introduced for long-term disease control. Another severe relapse of central nervous system vasculitis did not respond to any applied therapies and led to death 16 months after initial symptoms. This case emphasizes the need for activity scores to identify patients at risk for progressive systemic vasculitis requiring early and long-term aggressive immunosuppressive therapy.

Adolescent↗
PubMed2005

[Renal transplantation techniques in children with impaired patency of the inferior vena cava or iliac vein].

INTRODUCTION: Congenital or acquired disorders of patency of the inferior vena cava (IVC) or iliac veins have been considered for a long time to be an almost insurmountable technical obstacle in paediatric renal transplantation. The authors report their experience based on 7 transplantations performed in children with a disorder of venous patency, in whom renal transplantation was able to be performed. More generally, they also discuss the available technical options based on a review of the literature. MATERIAL AND METHOD: From April 1987 to January 2002, renal transplantation was performed in 7 children with congenital or acquired abnormality of the iliac veins or IVC in our unit. All children underwent radiological assessment by venous Doppler ultrasound before transplantation. The contribution of radiological examinations to the diagnosis, the surgical technique performed, postoperative complications, patient survival and graft survival as well as long-term renal function were studied retrospectively. RESULTS: Four of the 7 transplanted children presented a congenital anomaly of the IVC and 3 had acquired thrombosis. In 5 out of 7 cases, the diagnosis was established before transplantation by Doppler ultrasound (completed by cavography in one case). The transplant renal vein was anastomosed to the iliocaval system in the majority of cases and the portal system had to be used in one case. With a mean follow-up of 94 months, all children have a functioning graft with a mean serum creatinine of 88 micromol/l. CONCLUSIONS: Disorders of patency of the IVC or iliac veins in children waiting for renal transplantation are rare, but these abnormalities can cause problems for the surgical team and compromise graft survival. Radiological assessment of patency of the venous network must help to demonstrated these abnormalities in order to optimally adapt the transplantation technique, which ensures very acceptable graft survival rates.

Adolescent↗