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Biomedical subjects

Patrick Niaudet

Publications and source records attributed to Patrick Niaudet.

At least 19 recordsLinked to original sources
PubMed2006

Prognosis of autosomal dominant polycystic kidney disease diagnosed in utero or at birth.

The use of prenatal ultrasonography has resulted in increased numbers of fetuses being diagnosed with autosomal dominant polycystic kidney disease (ADPKD), but the long-term prognosis is still not well-known. Between 1981 and 2006 we followed 26 consecutive children with enlarged hyperechoic kidneys detected between the 12th week of pregnancy and the first day of life (Day 1) as well as one affected parent. Three other fetuses were excluded following the termination of the pregnancy. The mother was the transmitting parent in 16 of the 26 children (ns, p=0.1). Clinical features that presented during follow-up were oligoamnios (5/26), neonatal pneumothorax (3/26), pyelonephritis (5/26), gross hematuria (2/26), hypertension (5/26), proteinuria (2/26) and chronic renal insufficiency (CRI) (2/26). At the last follow-up (mean duration of follow-up: 76 months; range: 0.5-262 months), 19 children (mean age: 5.5 years) were asymptomatic, five (mean age: 8.5 years) had hypertension, two (mean age: 9.7 years) had proteinuria and two (mean age: 19 years) had CRI. Children presenting enlarged kidneys postnatally tended to have more clinical manifestations than their counterparts who did not. Of 25 siblings of the patients, seven had renal cysts; these were detected during childhood in five siblings and in utero in two siblings. In conclusion, prognosis is favourable in most children with prenatal ADPKD, at least during childhood. The sex of the transmitting parent is not a risk factor of prenatal ADPKD. A high proportion of siblings develop early renal cysts. Abnormalities visualized by ultrasonography appear to be associated to more clinical manifestations.

Child↗
PubMed2006

Cyclosporin therapy in patients with Alport syndrome.

Alport syndrome (AS) is a hereditary disorder of type IV collagen characterized by the association of progressive hematuric nephritis and sensorineural hearing loss. An increase in proteinuria is linked with progressive renal failure. Preliminary data have shown that cyclosporin therapy reduces proteinuria, thereby suggesting that it may also slow the progression of AS nephropathy. We treated nine AS patients manifesting proteinuria >1 g/m(2)/day and a glomerular filtration rate (GFR) >50 ml/min/1.73 m(2) with cyclosporin for at least 6 months. At the end of this 6-month period, mean proteinuria had decreased from 2+/-1.06 to 0.65+/-0.73 g/day, and mean albuminemia had increased from 29+/-5.2 to 35+/-6.5 g/l. Mean inulin clearance had decreased from 102+/-29 to 74+/-16.3 ml/min/1.73 m(2). Cyclosporin treatment was stopped in four patients because of inefficacy or adverse effects and continued in the remaining five patients for an additional 14-42 months. At the end of this second treatment period, control renal biopsies revealed significant lesions of cyclosporin nephrotoxicity in three patients. Based on these results we conclude that while cyclosporin therapy can decrease proteinuria in most patients with AS, it may be associated with nephrotoxicity, thereby precluding its long-term use.

Adolescent↗
PubMed2006

WT1 and glomerular diseases.

The WT1 gene encodes a zinc finger transcription factor involved in kidney and gonadal development and, when mutated, in the occurrence of kidney tumor and glomerular diseases. Patients with Denys-Drash syndrome present with early nephrotic syndrome with diffuse mesangial sclerosis progressing rapidly to end-stage renal failure, male pseudohermaphroditism, and Wilms' tumor. Incomplete forms of the syndrome have been described. Germline WT1 missense mutations located in exons 8 or 9 coding for zinc fingers 2 or 3 have been detected in nearly all patients with Denys-Drash syndrome and in some patients with isolated diffuse mesangial sclerosis. Patients with Frasier syndrome present with normal female external genitalia, streak gonads, XY karyotype and progressive nephropathy with proteinuria and nephrotic syndrome with focal and segmental glomerular sclerosis progressing to end-stage renal disease in adolescence or young adulthood. They frequently develop gonadoblastoma. Germline intronic mutations leading to the loss of the +KTS isoforms have been observed in all patients with Frasier syndrome. The same mutations have been observed in genetically female patients with isolated FSGS. Transmission of the mutation is possible. Frasier mutations have also been reported in children with Denys-Drash syndrome.

Child↗
PubMed2006

[Nephronophtisis].

Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure. It is an heterogeneous entity at the clinical as well as at the genetic level. There are three main clinical forms of nephronophtisis which have been associated with five gene defects. Juvenile nephronophtisis, the most frequent, progress to end stage renal failure before age 15. It is an autosomal recessive disease which is responsible for a urine concentration defect starting after age 2, failure to thrive and a progressive deterioration of renal function without signs of glomerular disease. Kidney size is normal. Histologic lesions concern tubular basement membranes which are thickened and multilayered or thinned. There is an associated interstitial fibrosis. Some children present with extrarenal symptoms: tapetoretinal degeneration (Senior-Loken syndrome), mental retardation, cerebellar ataxia, bone anomalies or liver involvement. Infantile nephronophtisis is a recessive autosomic tubulo-interstitial nephritis with cortical microcysts which progress to end stage renal failure before age 5. Adolescent nephronophtisis is a less frequent form of nephronophtisis. Medullary cystic disease is transmitted as an autosomic dominant trait. Clinical and histological signs are similar to nephronophthisis, but the disease progress later to terminal renal failure and is not accompanied by extra-renal symptoms. Several genes which are involved in nephronophtisis, encode proteins that localize in different cell compartments, in particular to the primary apical cilia, as it is the case for many other cystic kidney diseases.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Congenital disorders of glycosylation type I: a rare but new cause of hyperechoic kidneys in infants and children due to early microcystic changes.

BACKGROUND: There are numerous causes of bilateral hyperechoic kidneys. Congenital disorders of glycosylation (CDGs) are a rapidly growing family of inherited disorders due to defects in the synthesis of the glycans of glycoproteins or other glycoconjugates. OBJECTIVE: To describe renal sonographic abnormalities in CDG type I in infants and children. MATERIAL AND METHODS: A retrospective study of renal US in 12 infants and children: 8 CDG-Ia (6 multivisceral forms, 2 neurological forms), 2 CDG-Ib, and 2 CDG-Ix, with detailed functional renal tests in 6. Histology of the kidneys of one 35-week fetus with CDG-Ia was available. RESULTS: Renal US was normal in the two children with the neurological form of CDG-Ia. All patients with the multivisceral form of CDG-Ia or with CDG-Ib showed increased cortical echogenicity, and/or abnormal pyramids (small +/- hyperechoic). The two patients with CDG-Ix showed predominant involvement of the medulla, with inverted corticomedullary differentiation in one. Kidney size was normal in all but two patients. The fetal kidneys exhibited diffuse microcysts arising from the distal tubules. CONCLUSIONS: Hyperechoic kidneys are common in CDG-I patients, contrasting with grossly preserved renal function. The US pattern seems to differ slightly according to the type of CDG-I, and is consistent with microcystic changes of the renal parenchyma, which occur prenatally, and may be due to ciliary dysfunction secondary to altered glycosylation of tubular glycoproteins. CDG-I, which remains largely underdiagnosed at present, should be added to the causes of hyperechoic kidneys in children, especially in cases of multivisceral involvement, after ruling out other more frequent causes.

Carbohydrate Metabolism, Inborn Errors↗
PubMed2005

Improvement of renal function in pediatric heart transplant recipients treated with low-dose calcineurin inhibitor and mycophenolate mofetil.

BACKGROUND: Renal dysfunction is a major complication in heart transplant recipients treated with calcineurin inhibitors. The goal of the study was to investigate the effect of a reduction of calcineurin inhibitor dosage with the concomitant introduction of mycophenolate mofetil on both renal function and cardiac allograft function. METHODS: Fourteen of 52 consecutive pediatric cardiac allograft recipients experienced a progressive decrease of renal function. A renal biopsy was performed before the dose of calcineurin inhibitors was reduced by 50% and azathioprine was replaced by mycophenolate mofetil. Renal function was evaluated by inulin clearance and maximal urinary osmolality before and yearly after the therapeutic changes. Acute rejection was monitored clinically, by echocardiography and endomyocardial biopsies. RESULTS: Inulin clearance in the fourteen children decreased from 84.2 mL/min/1.73 m at one year posttransplantation to 46.5+/-9.6 mL/min/1.73 m at the time of the change in immunosuppressive therapy. Significant renal lesions were observed in the renal biopsies performed before the change. At 1 year, inulin clearance had increased by 67%. In six patients who had a second determination 2 years after the switch, inulin clearance was not significantly different from the value at 1 year. There were three reversible acute rejection episodes in three patients. The incidence of rejection episodes was not different from a control group of patients whose treatment was not changed. CONCLUSION: The reduction of calcineurin inhibitor dosage and replacement of azathioprine by mycophenolate mofetil is a safe way to improve renal function in children with heart transplants and calcineurin inhibitor induced nephrotoxicity.

Calcineurin Inhibitors↗
PubMed2005

[Congenital and infantile nephrotic syndrome].

Congenital nephrotic syndrome is present at birth or appears during the first three months of life and infantile nephrotic syndrome during the first year. Finnish type congenital nephrotic syndrome is an autosomal recessive disease. Nephrotic syndrome is present at birth, severe and does not respond to therapy. Infectious and nutritional complications are frequent. Renal function deteriorates necessitating a dialysis-transplantation program. Between age five and eight. The disease does not recur after transplantation. Diffuse mesangial sclerosis is the second cause of congenital and infantile nephrotic syndrome. It may be isolated or part of a Denys-Drash syndrome (association of the nephropathy with male pseudohermaphroditism and Wilm's tumor). Nephrotic syndrome is resistant to therapy. Renal failure develops in early childhood. Therapy is aimed to prevent oedema, denutrition, infections and thrombosis. Proteinuria does not recur after renal transplantation. Other causes are less frequent.

Female↗
PubMed2005

Respiratory chain deficiency presenting as congenital nephrotic syndrome.

Nephrotic syndrome (NS) in infancy includes NS of Finnish type (mutation of the nephrin gene), diffuse mesangial sclerosis (idiopathic or linked to WT1 mutation), idiopathic NS, most often steroid resistant, and NS related to infections during pregnancy (virus, syphilis, toxoplasmosis). Later in life, NS has a large variety of etiologies. It has been described in association with neuromuscular symptoms, deafness, and diabetes in a few children and adults with respiratory chain (RC) disorders. To date, however, NS has never been observed in neonates with RC disorders. Here, we report RC deficiency in one infant with certain congenital NS and two siblings with acute neonatal cardiac and renal disease with probable NS. Although clinical and histopathological presentations were initially close to congenital NS of Finnish type, clinical outcome was atypical and nephrin mutation was excluded. Mitochondrial RC complex II+V deficiency was identified in the three patients. Based on these observations, we suggest that RC disorders should be considered in patients with congenital NS.

Biopsy↗
PubMed2004

Glucocorticoid pharmacokinetics and growth retardation in children with renal transplants.

Long-term glucocorticoid treatment contributes to the growth retardation in children after renal transplantation. We investigated whether determination of prednisone (PN) and prednisolone (PL) in plasma and PN, PL, and 6-beta-hydroxyprednisolone (betaOH-PL) in urine could help to predict growth. PN and PL pharmacokinetics were studied in 36 children, from 5 to 15 years of age, receiving daily (D) or alternate-day (AD) oral PN treatment. Statural growth velocity was evaluated over a 1-year period. We compared three groups of children according to the growth kinetics during the study year (catch-up, stable, or decline) for clinical and pharmacokinetic parameters. A multiple linear regression analysis was performed in order to determine pharmacokinetic parameters able to explain height 1 year after inclusion. Height at the beginning of the study, creatinine clearance, and type of D or AD treatment explained 94.2% of height variance 1 year after inclusion. Only PL clearance was associated with growth evolution, but introduction of PL clearance in the multivariate model did not improve the variance of height accounted for by the previous model. We, therefore, do not recommend using glucocorticoid pharmacokinetics to predict growth retardation in children with renal transplantation.

Adolescent↗
PubMed2004

Long-term social outcome of children after kidney transplantation.

BACKGROUND: There are few data concerning the social outcome at adult age of children who received a kidney transplant. The aim of this study was to collect information on this outcome in a cohort of 366 children who underwent transplantation between 1973 and 1985. METHODS: Information was obtained through a simple questionnaire in 244 patients. The mean age of the patients was 31.7 years, and they had undergone grafting at a mean age of 11.9 years. RESULTS: As of December 2000 or at last visit, 77% had a functioning graft. The mean height was 156.6 cm for male patients and 147.4 cm for female patients. The distribution of educational level was lower than national averages: 27.4% were at the lowest level versus 3% of the general population, 41.4% were at the middle level, 31.2% had reached the baccalaureate level, and 11% had followed a university cursus. Activity was similar to the general population: 73% had paid employment versus 72%, 6.5% were unemployed versus 10.5%, and 18.7% received a disablement pension. Among the 149 male patients, 39 (27%) had a marital life and 12 (8.3%) had children, whereas among the 95 female patients, 48 (50%) had a marital life and 26 (27%) had at least one child. Lodging was the parent's home in 46% and independent in 54%. Multivariate analysis showed a significant correlation between educational level, paid activity, marital life, and independent housing with final height. CONCLUSIONS: The long-term social outcome of patients who underwent grafting in childhood more than 15 years previously is encouraging. The importance of reaching a normal height is stressed.

Adolescent↗
PubMed2004

Genetic forms of nephrotic syndrome.

Mutations of NPHS1, NPHS2, or WT1 may be responsible for severe forms of nephrotic syndrome in children, progressing to end-stage renal failure. Recent studies have shown that congenital nephrotic syndrome may be secondary to mutations of one of these three genes and that some patients have a digenic inheritance of NPHS1 and NPHS2 mutations. The clinical spectrum of NPHS2 mutations has broadened, with the demonstration that mutations in the respective gene podocin may be responsible for nephrotic syndrome occurring at birth, in childhood, or in adulthood. It is now well recognized that podocin mutations are found in 10%-30% of sporadic cases of steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis. Data from large cohorts indicate that the risk of recurrence of nephrotic syndrome after renal transplantation in patients with podocin mutations is very low.

Child↗
PubMed2004

Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases.

Factor H (FH) is the major regulatory protein of the complement alternative pathway, with a structure consisting of a tandem array of 20 homologous units, called short consensus repeats (SCR). Reported are 16 FH-deficient patients. Among six patients with homozygous deficiency, four presented with membranoproliferative glomerulonephritis, and two with atypical hemolytic uremic syndrome (HUS). The ten other patients had heterozygous FH deficiency and developed atypical HUS. HUS onset occurred from birth to midadulthood, and disease progression was variable. Four children with homozygous or heterozygous FH deficiency and HUS underwent renal transplantation, which was successful in three but failed as a result of recurrence of HUS in one patient. All but one patient exhibited alternative pathway-mediated complement consumption, with no detectable FH antigenic levels or with 50% immunochemical or functional FH levels in the case of complete or partial deficiency, respectively. The molecular mechanisms of the deficiency were documented in all cases by exon-specific sequencing analysis. These mechanisms included nucleotide substitutions, insertion, or deletion located in SCR 2, 7, 11, 13, 15, and 20, leading to an amino acid substitution or to a stop codon. This report emphasizes the variability in the clinical progression of kidney diseases associated with FH deficiencies. Genetic analysis reveals the molecular abnormalities associated with FH deficiencies to be polymorphous.

Adult↗
PubMed2004

NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.

BACKGROUND: Mutations of NPHS2 are causative in familial autosomal-recessive (AR) and sporadic steroid-resistant nephrotic syndrome (SRNS). This study aimed to determine the spectrum of NPHS2 mutations and to establish genotype-phenotype correlations. METHODS: NPHS2 mutation analysis was performed in 338 patients from 272 families with SRNS: 81 families with AR SRNS, 172 patients with sporadic SRNS, and 19 patients with diffuse mesangial sclerosis (DMS). RESULTS: Twenty-six different pathogenic NPHS2 mutations were detected, including 13 novel mutations. The mutation detection rate was 43% for familial AR and 10.5% for sporadic SRNS, confirming genetic heterogeneity. No pathogenic NPHS2 mutations were found in DMS patients. Age at onset in patients with two pathogenic mutations was earlier, especially in cases with frameshift, truncating, and the R138Q missense mutations. Patients with only one NPHS2 mutation or variant had late-onset NS. Triallelic inheritance was observed in one patient with a homozygous R138Q mutation and a de novo NPHS1 mutation. Among 32 patients with two NPHS2 mutations who underwent kidney transplantation, only one developed late recurrence of focal segmental glomerulosclerosis (FSGS). Among 25 patients with sporadic SRNS and post-transplantation recurrence, we detected a heterozygous NPHS2 mutation in one case, and heterozygous variants/polymorphisms in 3 cases. CONCLUSION: Patients with two pathogenic NPHS2 mutations present with early-onset SRNS and very low incidence of post-transplantation recurrence. Heterozygous NPHS2 variants may play a role in atypical cases with mild, late-onset course, and recurrence after transplantation.

Age of Onset↗
PubMed2003

[Lipoid nephrosis in childhood].

Lipoid nephrosis or idiopathic nephrotic syndrome, the most frequent glomerular disease in childhood, is defined by the association of a nephrotic syndrome and minimal changes on renal biopsy or unspecific lesions such as focal and segmental glomerular sclerosis or diffuse mesangial proliferation. Several complications related to the nephrotic syndrome may occur: infections particularly bacterial infections, thrombo-embolic accidents, hypovolemia with shock. Other complications are secondary to the treatment: steroid therapy, immunosuppressants. The outcome is related to the response to steroid therapy. In case of steroid responsiveness, the risk is the relapse when the steroid dosage is tapered or stopped and the complications related to the treatment which is given to maintain remission. In case of steroid resistance, the risk is that of progression to renal failure which occurs in approximately 50% of patients after 5 years. Moreover, the nephrotic syndrome may recur after renal transplantation.

Adrenal Cortex Hormones↗
PubMed2003

The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children.

We reviewed the literature to analyze the risk of recurrence of hemolytic uremic syndrome (HUS) after renal transplantation in children. Among 118 children transplanted after post-diarrheal (D+) HUS, 1 (0.8%) had recurrence with graft loss. Among 63 children transplanted after HUS not associated with a prodrome of diarrhea (D-) of unknown mechanism, 13 (21%) had recurrence with graft loss. Of 11 patients with HUS associated with factor H deficiency who were transplanted, 5 lost the graft because of recurrence. Of 7 patients with HUS associated with normal factor H concentration but mutations in factor H gene who were transplanted, probably 2 had recurrence. Three patients with HUS associated with low serum C3, but no factor H deficiency or mutation lost their graft because of recurrence. The risk of recurrence in the autosomal recessive forms of HUS of unknown mechanism is not documented in children, but is around 60% in adults. A similar risk has been reported in the autosomal dominant forms. The only transplant patient with a constitutional deficiency of von Willebrand factor-cleaving protease had recurrence. Further efforts to document the post-transplant course of patients with D- HUS and progress in the understanding of the mechanisms and genetics of the disease are needed to allow more accurate prediction of the recurrence risk and to define therapeutic approaches.

ADAM Proteins↗
PubMed2003

Truncation of C-mip (Tc-mip), a new proximal signaling protein, induces c-maf Th2 transcription factor and cytoskeleton reorganization.

Several arguments suggest that minimal change nephrotic syndrome (MCNS) results from yet unknown systemic disorder of T cell function. By screening a cDNA library from T cell relapse, we identified a new pleckstrin homology (PH) domain-containing protein encoded by a gene located on chromosome 16q24. Two alternative transcripts were identified. The first species (c-mip) was expressed in fetal liver, kidney, and peripheral blood mononuclear cells (PBMCs), but weakly detected in PBMCs from MCNS patients. The second form (Tc-mip, standing for truncated c-maf inducing protein), corresponds to subtracted transcript and lacks the NH2-terminal PH domain. The expression of Tc-mip was restricted to fetal liver, thymus, and MCNS PBMCs where it was specifically recruited in CD4+ T cells subset. Overexpression of Tc-mip in T cell Jurkat induced c-maf, transactivated the interleukin 4 gene and down-regulated the interferon gamma expression, characteristic of a Th2 commitment. Moreover, the overexpression of Tc-mip induced Src phosphorylation, T cell clustering, and a cellular redistribution of the cytoskeleton-associated L-plastin, by a PI3 kinase independent pathway. Tc-mip represents therefore the first identified protein, which links proximal signaling to c-maf induction.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Everolimus in pediatric de nova renal transplant patients.

BACKGROUND: The steady-state pharmacokinetics of everolimus were longitudinally assessed in pediatric de novo kidney allograft recipients during a 6-month period. METHODS: Nineteen patients received everolimus 0.8 mg/m2 (maximum 1.5 mg) twice daily as a dispersible tablet in water in addition to cyclosporine and corticosteroids. Everolimus and cyclosporine trough concentrations were obtained on days 3, 5, 6, and 7 and at months 1, 2, 3, and 6; an everolimus pharmacokinetic profile was obtained on day 7 and month 3. RESULTS: There were 9 boys and 10 girls with a median age of 9.9 (range, 1-16) years. Steady-state pharmacokinetic parameters were as follows (median, range): C(min) (trough level), 4.7 (2.3- 9.5) ng/mL; peak concentration, 13.5 (5.9-22.2) ng/mL; area under the concentration-time curve (AUC), 77 (53-147) ng x hr/mL; and apparent oral clearance, 10.2 (5.5-15.6) L/hr/m2. Clearance (unadjusted for demographic factors) was positively correlated with age (r=0.66), body surface area (r=0.68), and weight (r=0.67). There were no trends in C(min) or AUC versus patient age when everolimus was dosed on a mg/m2 basis. Everolimus C(min) were stable over time with median values of 3.9, 3.4, and 3.1 ng/mL at months 1, 3, and 6, respectively. Intra- and interpatient variability in AUC was 29% and 35%, similar to that in adults. During the observation period, eight patients maintained stable AUCs and nine patients had increases or decreases, generally between 30% and 50% compared with the AUC at week 1. The concurrent median cyclosporine C(min) were generally at the lower end of conventional target ranges: 156, 83, and 69 ng/mL at months 1, 3, and 6, respectively. There were no graft losses and only three mild or moderate, reversible rejection episodes occurred. Everolimus was generally safe and well tolerated. CONCLUSIONS: These data support the use of body surface area-adjusted dosing for everolimus in pediatric patients. Although exposure is generally stable over time with moderate variability in AUC, therapeutic monitoring would be a helpful adjunct for individualizing everolimus exposure, assessing regimen adherence, and adjusting doses as the child matures.

Adolescent↗