NPHS2 mutations in steroid-resistant nephrotic syndrome: a mutation update and the associated phenotypic spectrum.

Mutations in the NPHS2 gene encoding podocin are implicated in an autosomal-recessive form of nonsyndromic steroid-resistant nephrotic syndrome in both pediatric and adult patients. Patients with homozygous or compound heterozygous mutations commonly present with steroid-resistant nephrotic syndrome before the age of 6 years and rapidly progress to end-stage kidney disease with a very low prevalence of recurrence after renal transplantation. Here, we reviewed all the NPHS2 mutations published between October 1999 and September 2013, and also all novel mutations identified in our personal cohort and in international genetic laboratories. We identified 25 novel pathogenic mutations in addition to the 101 already described. The mutations are distributed along the entire coding region and lead to all kinds of alterations including 53 missense, 17 nonsense, 11 small insertions, 26 small deletions, 16 splicing, two indel mutations, and one mutation in the stop codon. In addition, 43 variants were classified as variants of unknown significance, as these missense changes were exclusively described in the heterozygous state and/or considered benign by prediction software. Genotype-phenotype analyses established correlations between specific variants and age at onset, ethnicity, or clinical evolution. We created a Web database using the Leiden Open Variation Database (www.lovd.nl/NPHS2) software that will allow the inclusion of future reports.

Malignancy incidence after renal transplantation in children: a 20-year single-centre experience.

BACKGROUND: Cancer is a well-recognized complication of organ transplantation. The pattern of malignancies that occur in the paediatric graft population is different from that in the general paediatric population and in the population of adult organ transplant recipients. METHODS: We reviewed medical records from 240 consecutive paediatric renal transplantations performed in 219 children, aged less than 19 years, in our centre between April 1987 and March 2007. Data from patients who had been transferred into adult units were extracted from the French registries of dialysis and transplantation. RESULTS: Among the 219 children who underwent renal transplantation during the study period, 16 (7.3%) developed malignancy. The cumulative incidence of cancer was 1.9, 4.0, 6.9 and 10.2% at 1, 5, 10 and 15 years post-transplantation, respectively. The 10-year incidence of post-transplantation lymphoproliferative disorder (PTLD) was 4.5%. Other identified cancers were Hodgkin lymphoma, Burkitt lymphomas, renal papillary carcinoma, thyroid papillary carcinoma, recurrent ovarian seminoma and skin cancer. The mortality rate was 25% (4/16). CONCLUSION: Early detection of cancer in transplant recipients is of great importance. Regular screening for persistent Epstein-Barr virus (EBV) DNA viral load in patients at risk for developing PTLD is recommended. The occurrence of skin cancer in transplanted children is extremely rare during childhood, but cases can develop in early adulthood.

Clinical features and management of arterial hypertension in children with Williams-Beuren syndrome.

BACKGROUND: Hypertension is a common finding in children with Williams-Beuren syndrome (WBS). METHODS: The aim of this retrospective study was to review the clinical presentation of systemic hypertension in WBS children, its origin and management. We included 41 children with confirmed WBS who were referred to the paediatric nephrology or cardiology unit for hypertension. RESULTS: The mean age at diagnosis of hypertension was 4.7 years. Out of 41, 24 patients had systolic blood pressure (BP) between +10 and +30 mmHg above the 95th percentile (1.645 SD), and 20/41 patients had diastolic BP between the 95th percentile (1.645 SD) and >10 mmHg. Thirty-nine patients were asymptomatic. Arteriography, performed in 17/41 patients, revealed a renal artery stenosis (RAS) in 10 patients (58%). Echocardiography was performed in all patients and showed isthmic coarctation in four patients (9%). Calcium channel blockers were used in half of the patients (22/41) and seemed to control hypertension in most cases. Interventional treatment of RAS was performed in five patients (three angioplasty and two surgical bypass). It controlled hypertension in one patient but remained ineffective in the four others. CONCLUSIONS: Medical treatment essentially calcium blockers improved hypertension in most cases. Interventional treatment of RAS has not been encouraging.

Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome.

We sought to ascertain the long-term outcome and genotype-phenotype correlations available for primary hyperoxaluria type 1 in a large retrospective cohort study. We examined the clinical history of 155 patients (129 families primarily from Western Europe, North Africa, or the Middle East) as well as the enzymatic or genetic diagnosis. The median age at first symptom was 4 years, and at diagnosis 7.7 years, at which time 43% had reached end-stage renal disease. Presentations included: (1) early nephrocalcinosis and infantile renal failure, (2) recurrent urolithiasis and progressive renal failure diagnosed during childhood, (3) late onset with occasional stone passage diagnosed in adulthood, (4) diagnosis occurring on post-transplantation recurrence, and (5) family screening. The cumulative patient survival was 95, 86, and 74% at ages 10, 30, and 50 years, respectively, with the cumulative renal survival of 81, 59, 41, and 10% at ages 10, 20, 30, and 50 years, respectively; 72 patients had undergone a total of 97 transplantations. Among the 136 patients with DNA analysis, the most common mutation was p.Gly170Arg (allelic frequency 21.5%), with a median age at end-stage renal disease of 47 years for homozygotes, 35 years for heterozygotes, and 21 years for other mutations. Our results underscore the severe prognosis of primary hyperoxaluria type 1 and the necessity for early diagnosis and treatment, as well as confirm a better prognosis of the p.Gly170Arg mutation.

Nephrolithiasis related to inborn metabolic diseases.

Nephrolithiasis associated with inborn metabolic diseases is a very rare condition with some common characteristics: early onset of symptoms, family history, associated tubular impairment, bilateral, multiple and recurrent stones, and association with nephrocalcinosis. The prognosis of such diseases may lead to life threatening conditions, not only because of unabated kidney damage but also because of progressive extra-renal involvement, either in a systemic form (e.g. primary hyperoxaluria type 1, requiring combined liver and kidney transplantation), or in a neurological form (Lesch-Nyhan syndrome leading to auto-mutilation and disability, phosphoribosyl pyrophosphate synthetase superactivity, which is associated with mental retardation). Patients with other inborn metabolic diseases present only with recurrent stone formation, such as cystinuria, adenine phosphoribosyl-transferase deficiency, xanthine deficiency. Finally, nephrolithiasis may be secondarily part of some other metabolic diseases, such as glycogen storage disease type 1 or inborn errors of metabolism leading to Fanconi syndrome (nephropathic cystinosis, tyrosinaemia type 1, fructose intolerance, Wilson disease, respiratory chain disorders, etc.). The diagnosis is based on highly specific investigations, including crystal identification, biochemical analyses and DNA study. The treatment of nephrolithiasis requires hydration as well as specific measures. Compliance is a major issue regarding the progression of renal damage, but the overall outcome mainly depends on extra-renal involvement in relation to the metabolic defect.

HHV-6 infection in a pediatric kidney transplant patient.

Human herpesvirus 6 (HHV-6) infection can induce unusual complications in transplant patients, such as interstitial pneumonitis, encephalitis and marrow aplasia. We describe the clinical course of HHV-6 infection in a girl with renal transplantation. She presented with diarrhea and poor feeding on day 36 post-transplantation (Tx), after a 5-day steroid pulse for clinical signs of acute rejection. A week later she developed fever and had elevated plasma creatinine and lactic dehydrogenase levels, but a physical examination did not reveal any anomalies with respect to suggest rash, pneumonitis, encephalitis or lymphadenopathy. Two weeks later, the patient developed anemia and leucopenia. HHV-6 was the only pathogen detected by the PCR assay of the serum and marrow aspiration. The patient had a successful recovery without specific treatment. This case report highlights the wide spectrum of complications resulting from HHV-6 infection in immunosuppressed patients.

Both extrauterine and intrauterine growth restriction impair renal function in children born very preterm.

A single-center prospective cohort study was designed to identify alterations of renal function during childhood in children born prematurely. A cohort of 143 such babies born over a 4-year period (birth weight less than 1000 g and/or less than 30 weeks of gestation) was prospectively included at birth. A mailing was sent to all parents to propose renal evaluation. Among the 50 included children, 23 had intra-uterine and 16 had extrauterine growth retardation. When comparing both of these groups to 11 children with appropriate pre- and postnatal growth at a mean follow-up of 7.6 years, both groups of growth-restricted children had slightly but significantly lower glomerular filtration rates, measured by inulin clearance, although both groups were still within the normal range for their ages. There were no differences for other renal parameters, neonatal therapies or complications, except for postnatal corticosteroid exposure. Children with extrauterine growth restriction were found to have significantly lower protein-energy intake during their first week of life than the intrauterine growth-restricted or the normotrophic children. Our study found that children with either intra- or extrauterine growth retardation are at risk of decreased glomerular filtration rates during childhood. Extrauterine growth restriction represents a new risk factor for long-term renal impairment in premature children.

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: a multicenter study.

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome was retrospectively studied in 78 children in eight centers for the past 20 years. Median age at onset was 4.4 years (1.1-15.0 years) and the gender ratio was 1.4. Median follow-up period was 7.7 years (1.0-19.7 years). The disease in 45 patients (58%) was initially not steroid-responsive and in 33 (42%) it was later non-responsive. The main therapeutic strategies included administration of ciclosporine (CsA) alone (n = 29; 37%) and CsA + mycophenolate mofetil (n = 18; 23%). Actuarial patient survival rate after 15 years was 97%. Renal survival rate after 5 years, 10 years and 15 years was 75%, 58% and 53%, respectively. An age at onset of nephrotic syndrome (NS) > 10 years was the only independent predictor of end-stage renal disease (ESRD) in a multivariate analysis using a Cox regression model (P < 0.001). Twenty patients (26%) received transplants; ten showed recurrence of the NS: seven within 2 days, one within 2 weeks, and two within 3-5 months. Seven patients lost their grafts, four from recurrence. Owing to better management, kidney survival in idiopathic steroid-resistant nephrotic syndrome (SRNS) has improved during the past 20 years. Further prospective controlled trials will delineate the potential benefit of new immunosuppressive treatment.

Renal function in pediatric liver transplantation: a long-term follow-up study.

BACKGROUND: Renal impairment is a frequent complication after orthotopic liver transplantation (OLT). However, most studies in children use inaccurate renal assessment based on serum creatinine, and long-term follow-up data are lacking. The purpose of this study was to determine incidence, determinants, and progression of long-term chronic renal insufficiency (CRI) in a single-center series of pediatric liver transplant recipients. METHODS: The true glomerular filtration rate was measured by inulin clearance before and serially after OLT in 69 consecutive patients followed more than 2 years after transplantation. Cumulative incidence of CRI (glomerular filtration rate<60 mL/min/1.73 m2) was determined using a Kaplan-Meier method. A Cox proportional hazard model was performed to identify predictors of CRI. RESULTS: The median age at OLT was 3.2 years. The median follow-up time after OLT was 9.3 years (interquartile range 6.3-11.9). At 10 years post-OLT, the cumulative incidence of CRI was 25%. In a multivariate Cox regression model, arterial hypertension during follow-up as time dependant variable (P=0.03), cyclosporine as primary immunosuppression (P=0.048), and liver diseases with potential renal involvement including inborn errors of metabolism, Alagille syndrome, and hepatic fibrosis (P=0.003) were associated with CRI. CONCLUSIONS: Renal function is a major concern long after OLT in children. Renal dysfunction post-OLT may be reduced by optimal control of arterial hypertension, immunosuppression protocols adapted to primary liver disease, and calcineurin inhibitor sparing regimen.

Pseudohypoaldosteronisms, report on a 10-patient series.

BACKGROUND: Type 1 pseudohypoaldosteronism (PHA1) is a salt-wasting syndrome caused by mineralocorticoid resistance. Autosomal recessive and dominant hereditary forms are caused by Epithelial Na Channel and Mineralocorticoid Receptor mutation respectively, while secondary PHA1 is usually associated with urological problems. METHODS: Ten patients were studied in four French pediatric units in order to characterize PHA1 spectrum in infants. Patients were selected by chart review. Genetic, clinical and biochemistry data were collected and analyzed. RESULTS: Autosomal recessive PHA1 (n = 3) was diagnosed at 6 and 7 days of life in three patients presenting with severe hyperkalaemia and weight loss. After 8 months, 3 and 5 years on follow-up, neurological development and longitudinal growth was normal with high sodium supplementation. Autosomal dominant PHA1 (n = 4) was revealed at 15, 19, 22 and 30 days of life because of failure to thrive. At 8 months, 3 and 21 years of age, longitudinal growth was normal in three patients who were given salt supplementation; no significant catch-up growth was obtained in the last patient at 20 months of age. Secondary PHA1 (n = 3) was diagnosed at 11, 26 days and 5 months of life concomitantly with acute pyelonephritis in three children with either renal hypoplasia, urinary duplication or bilateral megaureter. The outcome was favourable and salt supplementation was discontinued after 3, 11 and 13 months. CONCLUSIONS: PHA1 should be suspected in case of severe hyperkalemia and weight loss in infants and need careful management. Pathogenesis of secondary PHA1 is still challenging and further studies are mandatory to highlight the link between infection, developing urinary tract and pseudohypoaldosteronism.

Report of a family with two different hereditary diseases leading to early nephrocalcinosis.

The etiologies of early onset nephrocalcinosis in consanguineous families include five major inherited recessive disorders: primary hyperoxaluria (PH), familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), distal renal tubular acidosis (dRTA), hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and antenatal Bartter syndrome. In this paper, we describe two girls from consanguineous parents with early onset nephrocalcinosis. Based on both clinical and biochemical assessment in combination with molecular genetics, we have shown that the etiology of nephrocalcinosis is different in each girl: one had FHHNC and her sister had dRTA.

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.

[Current management of Fabry disease]. / Actualités dans le traitement de la maladie de Fabry.

Fabry disease is a rare X-linked lysosomal storage disease leading to systemic involvement, mainly through GL-3 endothelial deposition. Initial symptoms may occur during childhood (acroparesthesia, angiokeratoma), prior to adulthood complications, i.e. renal, ocular, cerebral, neurological and cardiovascular involvement. An early diagnosis of the disease may be challenging because of a frequent atypical clinical presentation. Indeed, independent of conservative treatment (pain, proteinuria, chronic renal failure, arterial hypertension, heart failure, etc), enzyme therapy using recombinant alpha-galactosidase (agalsidase) has provided a safe pathophysiological approach, leading to significant organ functional improvement (mainly kidney and heart) and improved quality of life, which parallels tissue GL-3 clearance. Such a treatment is safe and efficient but its biweekly intravenous administration is still uncomfortable, so that further alternative therapeutic approaches may be encouraged.