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Biomedical subjects

Pierre Cochat

Publications and source records attributed to Pierre Cochat.

36 records · Page 2Linked to original sources
PubMed2004

Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities.

Congenital nephrotic syndrome (CNS) is clinically and genetically heterogeneous, with mutations in WT1, NPHS1 and NPHS2 accounting for part of cases. We recently delineated a new autosomal recessive entity comprising CNS with diffuse mesangial sclerosis and distinct ocular anomalies with microcoria as the leading clinical feature (Pierson syndrome). On the basis of homozygosity mapping to markers on chromosome 3p14-p22, we identified homozygous or compound heterozygous mutations of LAMB2 in patients from five unrelated families. Most disease-associated alleles were truncating mutations. Using immunohistochemistry and western blotting we could demonstrate that the respective LAMB2 mutations lead to loss of laminin beta2 expression in kidney and other tissues studied. Laminin beta2 is known to be abundantly expressed in the glomerular basement membrane (GBM) where it is thought to play a key role in anchoring as well as differentiation of podocyte foot processes. Lamb2 knockout mice were reported to exhibit congenital nephrosis in association with anomalies of retina and neuromuscular junctions. By studying ocular laminin beta2 expression in unaffected controls, we detected the strongest expression in the intraocular muscles corresponding well to the characteristic hypoplasia of ciliary and pupillary muscles observed in patients. Moreover, we present first clinical evidence of severe impairment of vision and neurodevelopment due to LAMB2 defects. Our current data suggest that human laminin beta2 deficiency is consistently and specifically associated with this particular oculorenal syndrome. In addition, components of the molecular interface between GBM and podocyte foot processes come in the focus as potential candidates for isolated and syndromic CNS.

Amino Acid Sequence↗
PubMed2004

Current management of infants with fetal renal pelvis dilation: a survey by French-speaking pediatric nephrologists and urologists.

To analyze the current management recommendations among French-speaking physicians treating infants with antenatal renal pelvis dilatation, we surveyed 83 pediatric nephrologists and 68 pediatric urologists by questionnaire. A total of 45 (54%) pediatric nephrologists and 38 (56%) pediatric urologists responded. The threshold for the diagnosis of abnormal fetal renal pelvis dilatation was significantly higher among pediatric urologists than nephrologists. All responders perform renal ultrasound examinations after birth. Postnatal renal pelvis dilatation was considered abnormal if the anteroposterior diameter was >/=11+/-1.9 mm by the pediatric urologists and >/=9+/-2.9 mm by the pediatric nephrologists ( P=0.003). Pediatric urologists were more likely than nephrologists to recommend routine voiding cystourethrography [41% versus 20% ( P=0.04)]. Mercaptoacetyl-triglycine renography was the most routinely used tool to achieve functional evaluation during follow-up among the responders. Pediatric urologists were more likely to recommend surgical treatment in dilated kidneys with initial function <40%. In conclusion, pediatric urologists had significantly higher thresholds for the detection of prenatal and neonatal renal pelvis dilatation. They also more frequently recommended routine voiding cystourethrography and surgical therapy of dilated kidneys with low function than pediatric nephrologists. The variability in attitudes is most probably due to the absence of clear guidelines based on prospective and controlled trials.

Dilatation, Pathologic↗
PubMed2004

Munchausen syndrome by proxy with massive proteinuria and gastrointestinal hemorrhage.

A 5-year-old boy presented with acute abdominal pain. Massive proteinuria of 10 g/1.73 m(2) per day was detected on standard urinalysis. There was no peripheral edema. Serum concentrations of total proteins, lipids, and creatinine and immunological investigations were normal. Two kidney biopsies revealed no abnormalities. Several weeks later he was admitted for intestinal hemorrhage with significant anemia. Endoscopy of the esophagus, stomach, colon, and small bowel (via laparotomy) were normal. Electrophoresis of urine proteins revealed the unusual finding of an albumin fraction of 99.4%. During a routine check-up in the outpatient clinic fresh urine samples were obtained while the boy's mother was absent. These were all negative for protein. The mother, who was a nurse, finally confessed to adding human albumin to the urine samples.

Child, Preschool↗
PubMed2004

Decisions concerning potentially life-sustaining treatments in paediatric nephrology: a multicentre study in French-speaking countries.

BACKGROUND: Few studies have looked at how decisions are made to withhold or to withdraw potentially life-sustaining treatments (LST) in paediatric nephrology. The aim of this work was to evaluate such practices in all nephrology centres in French-speaking European countries, so that guidelines could be discussed and drawn up by professionals. METHODS: We used semi-directed interviews to question health care professionals prospectively. We also retrospectively analysed the medical files of all children (n = 50) for whom a decision to withhold or to withdraw LST had been made in the last 5 years. The doctors (n = 31) who had been involved in the decision-making process were interviewed. RESULTS: All 31 of the French-speaking paediatric nephrology centres in Europe were included in this study. Of these, 18 had made decisions in the previous 5 years about withholding or withdrawing LST. Resultant quality of life, based on long-term living conditions, was the principal criterion used to make the decisions. Relational aspects of life and the child's prognosis were also considered. The decision-making processes were not always collective, even though interactions between doctors and the rest of the medical team seemed to be key elements to them. The parents' involvement in the decision-making process differed between centres. CONCLUSIONS: The criteria used to decide whether to withhold or to withdraw LST are not standardized, and no specific guidelines exist.

Child↗
PubMed2004

Bilateral urinary calculi after treatment with a silicate-containing milk thickener.

UNLABELLED: Nephrocalcinosis and/or urinary calculi are rare in infants. Furosemide treatment during the neonatal period, vitamin D intoxication, hereditary diseases such as hyperoxaluria or distal tubular acidosis are among the most common aetiologies. We report the case of a 6-month-old boy with an extra-hepatic biliary duct atresia treated by the Kasai procedure and a gastro-oesophageal reflux treated with a silicate containing milk thickener (Gelopectose, 5.5% colloidal silicate) since the neonatal period. He did not present any other endogenous risk factor for urinary stone formation (normal urinary calcium/creatinine ratio; normal urinary magnesium excretion). The nephrolithiasis was discovered as the boy presented painful episodes of macroscopic haematuria. Ultrasound examination revealed bilateral nephrocalcinosis and multiple bilateral calculi without infection or urinary obstruction. Infrared spectroscopy revealed silicate as the major component suggesting silicate absorption to be responsible for the described symptoms. After replacement of the silicate-containing agent by a silicate-free milk thickener, the lesions were completely reversible as confirmed by repeated renal ultrasound examinations over a 2-month period. CONCLUSION: Silicate-containing milk thickeners can be responsible for urinary calculi and/or nephrocalcinosis.

Gastroesophageal Reflux↗
PubMed2004

Skin cancers following pediatric organ transplantation.

BACKGROUND: Organ transplant recipients taking immunosuppressants are at increased risk of skin cancer. Although several studies have been devoted to adult transplant patients, few data are available on the long-term skin malignancies following pediatric organ transplantation. OBJECTIVE: The objective of this study was to present the current state of knowledge on skin malignancies in patients who received their graft during childhood. METHODS: This study reviews data from the literature and includes our personal experience. RESULTS: Skin cancer is the most frequent malignancy following pediatric renal transplantation and the second most common after pediatric nonrenal transplantation. Skin cancers mainly include squamous and basal cell carcinomas. The occurrence of skin cancer in transplanted children is an extremely rare event during childhood. By contrast, skin carcinomas develop in early adulthood at an average age of 27 years. Other reported skin malignancies include anogenital carcinomas and melanoma. Cutaneous forms of Kaposi's sarcoma are exceptional in children. CONCLUSION: The increased risk of skin cancer following pediatric transplantation justifies prevention and adequate education of children and their parents concerning sun avoidance and protection.

Adolescent↗
PubMed2003

A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.

Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)-10 of which are novel-clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion.

Adolescent↗
PubMed2002

A multicenter, open-label, pharmacokinetic/pharmacodynamic safety, and tolerability study of basiliximab (Simulect) in pediatric de novo renal transplant recipients.

BACKGROUND: Basiliximab (Simulect) has been shown to be safe and effective in adult renal transplant recipients, when used in combination with cyclosporine (Neoral) and corticosteroids. We report on the safety and preliminary efficacy of basiliximab in pediatric de novo renal transplant recipients. METHODS: This was an open-label, 12-month study of basiliximab in 41 patients (2 cohorts: <9 and 9 to <16 years). In phase 1, two intravenous (IV) bolus injections of basiliximab (12 mg/m ) were administered (before and 4 days postsurgery). In phase 2, two injections (<40 kg, 10 mg and > or =40 kg, 20 mg) were administered at the same time points. Most patients (26/41 [63%]) received cadaveric kidneys. Almost half of the patients had three human leukocyte antigen mismatches with the organ donors. Concurrent immunosuppression included Neoral and corticosteroids. Azathioprine was allowed after 28 days. RESULTS: All patients completed the 1-year study. The acute tolerability of basiliximab via IV bolus injection was good, without evidence of cytokine-release syndrome or acute local reactions. All patients experienced adverse events, but most (71%) were mild or asymptomatic. No deaths or malignancies occurred. The incidence and types of serious adverse events (59%) and serious infections (44%) were as expected in this patient population, and few were drug-related (7% and 5%, respectively). Thirty-eight patients (93%) had infections, mostly urinary tract infections, as expected for renal transplant patients. Six patients (15%) had drug-related adverse events. Biopsy-confirmed acute rejection episodes occurred in 6/41 (15%) of patients during the first 6 months posttransplantation and in 9/41 (22%) patients during the first 12 months. Five patients (12%) experienced graft loss, none of which were preceded by acute rejection episodes. CONCLUSIONS: Basiliximab is safe and well tolerated when administered by IV bolus injection in de novo pediatric renal transplant recipients. These preliminary data suggest that basiliximab, given in combination with cyclosporine and corticosteroids, is an effective immunosuppressive regimen for the prevention of acute rejection in pediatric renal transplantation.

Adolescent↗
PubMed2002

A rational dosing algorithm for basiliximab (Simulect) in pediatric renal transplantation based on pharmacokinetic-dynamic evaluations.

BACKGROUND: The pharmacokinetics and immunodynamics of basiliximab were assessed in 39 pediatric de novo kidney allograft recipients to rationally chose a dose regimen for this age group. METHODS: In study part 1, patients were given 12 mg/m(2) of basiliximab by bolus intravenous injection before surgery and on day 4. An interim pharmacokinetic evaluation supported a fixed-dose approach for study part 2 in which infants and children received two 10-mg doses and adolescents received two 20-mg doses. Blood samples were collected over a 12-week period for analysis of basiliximab and soluble interleukin-2 receptor concentrations, flow cytometry, and screening for anti-idiotype antibodies. RESULTS: Basiliximab clearance in infants and children (n=25) was reduced by approximately half compared with adults from a previous study and was independent of age (1-11 years), weight (9-37 kg), and body surface area (0.44-1.20 m(2) ). Clearance in adolescents (12-16 years, n=14) approached or reached adult values. CD25-saturating basiliximab concentrations were maintained for 31+/-12 days in study part 1 with mg/m(2) dosing and for 36+/-14 days in study part 2 based on the fixed-dose regimen ( P=0.31). A single patient experienced a rejection episode during CD25 saturation. The duration of CD25 saturation in patients who experienced a rejection episode after desaturation did not differ from those who remained rejection-free for the full 6-month period: 34+/-6 days (n=6) vs. 35+/-14 days (n=33 patients); P=0.74. Anti-idiotype antibodies were detected in two patients; however, this did not influence the clearance of basiliximab or the duration of CD25 saturation. CONCLUSIONS: To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients <35 kg should receive two 10-mg doses and those > or =35 kg should receive two 20-mg doses of basiliximab by intravenous infusion or bolus injection. The first dose is given before surgery and the second on day 4 after transplantation.

Algorithms↗
PubMed2002

Identification of 14 novel CTNS mutations and characterization of seven splice site mutations associated with cystinosis.

Cystinosis is an autosomal recessive disorder characterized by intra-lysosomal accumulation of cystine. Three disease forms exist, infantile, juvenile, and ocular nonnephropathic cystinosis, delineated on the basis of severity of symptoms and age of onset. Mutations in the causative gene, CTNS, which encodes cystinosin, the seven transmembrane domain lysosomal cystine transporter, have been identified in all forms confirming their allelic status. By screening for mutations in the CTNS exons and promotor region, we report 14 novel mutations associated with cystinosis: 11 underlying infantile cystinosis, two juvenile cystinosis, and one associated with an atypical form of the disease. These mutations, all situated in the exons or immediately flanking intronic sequences, comprise in-frame insertions and deletions, as well as missense, nonsense, and putative splice-site mutations. Furthermore, we confirmed the putative splice-site mutations we have reported to date (five novel and two previously reported) by isolation of RNA from the affected carriers and characterization of the resultant transcripts using RT-PCR. Since the cloning of CTNS, we have screened for mutations in 108 affected individuals, which has resulted in a high mutation detection rate of 95.8%. Interestingly, the few undetectable mono- or bi-allelic mutations segregated mostly in the noninfantile forms, suggesting that these individuals carry mutations either in the introns or in unidentified regulatory sequences.

Adolescent↗
PubMed2002

Toxicity of chloroacetaldehyde is similar in adult and pediatric kidney tubules.

The nephrotoxicity of chloroacetaldehyde (CAA), one of the main products of hepatic ifosfamide metabolism, was compared in isolated human pediatric and adult renal tubules. Tubules metabolizing lactate were incubated in the presence of various concentrations of CAA (0.1-0.5 mM). Both at low, clinically relevant (0.2 mM), and at higher concentrations (0.3, 0.4 and 0.5 mM), CAA induced a cellular depletion of thiol compounds, i.e. glutathione, coenzyme A and acetyl-coenzyme A that are involved in CAA detoxication and cellular energy metabolism, respectively. The toxicity to renal cells was clearly observed in the presence of 0.4 and 0.5 mM CAA, which led to a fall of the cellular ATP level, to the accumulation of pyruvate and the inhibition of glucose synthesis from lactate. Inhibition of lactate uptake and an increase in the release of lactate dehydrogenase were observed only in the presence of 0.5 mM CAA. The sensitivity of pediatric tubules to the toxic effects of CAA and the rate of their CAA uptake were not statistically different from those found in adult tubules. It is concluded that an increased susceptibility of pediatric tubules to CAA toxicity cannot be put forward to explain the increased risk for ifosfamide-induced nephrotoxicity in children relative to adults.

Acetaldehyde↗
PubMed2002

Transient hyperphosphatasemia after organ transplantation in children.

Transient, isolated hyperphosphatasemia is a rare, benign condition of childhood. Few cases have been described in transplant patients. We report six cases: three after liver transplantation and three after kidney transplantation. Such a phenomenon was found to be as benign after organ transplantation as it is in healthy children. Hence, an isolated increase in the serum alkaline phosphatase level following transplantation should not be of concern in this population of patients.

Alkaline Phosphatase↗
PubMed2002

Better long-term functional adaptation to the child's size with pediatric compared to adult kidney donors.

BACKGROUND: Pros and cons for pediatric kidney donors have been debated, especially with respect to survival rates. However, the effect of donor age on kidney function remains conflicting. The aim of this study was to compare short and long-term renal function according to the age of the donor, in grafts from adult living related (LRD), adult cadaveric and pediatric cadaveric donors (PedCD) following pediatric transplantation (Tx). METHODS: One hundred and thirty-four children were repeatedly followed for four years, and 44 were followed for eight years. Absolute and relative glomerular filtration rate (GFR; inulin clearance, mL/min and mL/min/1.73 m(2), respectively) were determined within 6 months, and yearly thereafter. RESULTS: Absolute GFR increased along with body growth in the PedCD group (P < 0.001) during the 4 years following Tx, leading to stable relative GFR, whereas absolute GFR of the LRD group did not change, with a progressive decrease of relative GFR (P < 0.001). Relative GFR did not differ between PedCD and LRD recipients by the sixth month but became higher in PedCD 4 years post-Tx (70 +/- 25 vs 52 +/- 19 mL/min/1.73 m(2), P < 0.001). Among those followed for 8 years, relative GFR showed a slow decrease in both recipient groups from 6 years post-Tx. At 8 years post-Tx, relative GFR was still significantly higher in PedCD than in LRD (57 +/- 19 vs. 45 +/- 19; P < 0.05). CONCLUSIONS: Adult-sized grafts may adapt to pediatric recipients during the first months post-Tx, but graft function cannot improve thereafter along with the increase in body size of the recipient. Interestingly, the absolute GFR of children receiving pediatric grafts increased along with body growth, leading to a stable relative GFR up to 6 years post-Tx.

Adaptation, Physiological↗
PubMed2001

Characterization of a putative founder mutation that accounts for the high incidence of cystinosis in Brittany.

Cystinosis is an autosomal recessive disorder, characterized by an accumulation of intralysosomal cystine, with an incidence of 1 in 100,000 to 200,000 live births. A higher incidence of cystinosis, 1 in 26,000 live births, has been reported in the western French province of Brittany. PCR amplification and sequencing has identified a 27-bp deletion starting 3 bp before the end of exon 8 and continuing into intron 8, 898-900+24del27, which has only been detected in families from this region. Reverse transcription-PCR amplification of RNA from an affected individual has shown that this mutation is indeed a splice-site mutation and results in the production of aberrant transcripts. These transcripts are predicted to either severely truncate cystinosin or alter its topology, thus accounting for the severe phenotype of these individuals. The mutation 898-900+24del27 has been identified in 7 of 18 alleles studied. This mutation is likely to be a founder mutation and would account for the higher incidence of cystinosis in Brittany.(1)

Adolescent↗
PubMed2001

Human kidney tubules detoxify chloroacetaldehyde, a presumed nephrotoxic metabolite of ifosfamide.

The nephrotoxic effects of the antineoplastic drug ifosfamide have been attributed to its hepatic metabolite chloroacetaldehyde. The effects of chloroacetaldehyde on isolated human kidney cortex tubules metabolizing lactate (a physiologic substrate in human kidneys) were investigated. At concentrations of > or =0.5 mM, chloroacetaldehyde was toxic to the human kidney tubules, as demonstrated by a dramatic decrease in cellular ATP levels and a large increase in lactate dehydrogenase release; chloroacetaldehyde also stimulated pyruvate accumulation and inhibited lactate removal and glucose synthesis. These effects, which were associated with incomplete disappearance of chloroacetaldehyde and extensive depletion of the cellular CoA, acetyl-CoA, and glutathione contents, were prevented by the addition of thiol-protecting drugs (mesna and amifostine). Human kidney tubules were demonstrated to metabolize chloroacetaldehyde at high rates, presumably via aldehyde dehydrogenase, which is very active in human kidneys. Carbon-13 nuclear magnetic resonance spectroscopy measurements indicated that human kidney tubules converted [2-(13)C]chloroacetaldehyde to [2-(13)C]chloroacetate, the further metabolism of which was very limited. At equimolar concentrations, chloroacetate was much less toxic than chloroacetaldehyde, indicating that chloroacetate synthesis from chloroacetaldehyde by human kidney tubules represents a detoxification mechanism that could play a role in vivo in preventing or limiting the nephrotoxic effects observed during ifosfamide therapy.

Acetaldehyde↗