Worldwide view of nephropathic cystinosis: results from a survey from 30 countries.

BACKGROUND: Nephropathic cystinosis is a rare inherited metabolic disorder leading to progressive renal failure and extra-renal comorbidity. The prognosis relies on early adherence to cysteamine treatment and symptomatic therapies. Developing nations [DiN] experience many challenges for management of cystinosis. The aim of this study was to assess the management characteristics in DiN compared with developed nations [DeN]. METHODS: A questionnaire was sent between April 2010 and May 2011 to 87 members of the International Pediatric Nephrology Association, in 50 countries. RESULTS: A total of 213 patients were included from 41 centres in 30 nations (109 from 17 DiN and 104 from 13 DeN). 7% of DiN patients died at a median age of 5 years whereas no death was observed in DeN. DiN patients were older at the time of diagnosis. In DiN, leukocyte cystine measurement was only available in selected cases for diagnosis but never for continuous monitoring. More patients had reached end-stage renal disease in DiN (53.2 vs. 37.9%, p = 0.03), within a shorter time of evolution (8 vs. 10 yrs., p = 0.0008). The earlier the cysteamine treatment, the better the renal outcome, since the median renal survival increased up to 16.1 [12.5-/] yrs. in patients from DeN treated before the age of 2.5 years of age (p = 0.0001). However, the renal survival was not statistically different between DeN and DiN when patients initiated cysteamine after 2.5 years of age. The number of transplantations and the time from onset of ESRD to transplantation were not different in DeN and DiN. More patients were kept under maintenance dialysis in DiN (26% vs.19%, p = 0.02); 79% of patients from DiN vs. 45% in DeN underwent peritoneal dialysis. CONCLUSIONS: Major discrepancies between DiN and DeN in the management of nephropathic cystinosis remain a current concern for many patients living in countries with limited financial resources.

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.

Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome.

BACKGROUND: Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCepsilon1) have been recently described in patients with early onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported. METHOD: In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, mutational analysis was performed in a worldwide cohort of 139 patients (95 familial cases belonging to 68 families and 44 sporadic cases) with steroid resistant NS presenting at a median age of 23.0 months (range 0-373). RESULTS: Homozygous or compound heterozygous mutations were identified in 33% (8/24) of DMS cases. PLCE1 mutations were found in 8% (6/78) of FSGS cases without NPHS2 mutations. Nine were novel mutations. No clear genotype-phenotype correlation was observed, with either truncating or missense mutations detected in both DMS and FSGS, and leading to a similar renal evolution. Surprisingly, three unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families. CONCLUSION: PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although additional variants in 19 candidate genes (16 other PLC genes, BRAF,IQGAP1 and NPHS1) were not identified, it is speculated that other modifier genes or environmental factors may play a role in the renal phenotype variability observed in individuals bearing PLCE1 mutations. This observation needs to be considered in the genetic counselling offered to patients.

AGXT Gene Mutations and Prevalence of Primary Hyperoxaluria Type 1 in Moroccan Population.

INTRODUCTION: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by deficiency of alanine glyoxylate aminotransferase, due to a defect in the AGXT gene. Several mutations in this gene have been reported and some of them have been observed in multiple populations. The aim of our study was to analyze the mutations causing PH1 in the Moroccan population and to estimate its prevalence in Morocco. METHODS: Molecular studies of 29 unrelated Moroccan patients with PH were performed by direct sequencing of all exons of the AGXT gene. In addition, to estimate the prevalence of PH1, we screened for the recurrent p.Ile244Thr mutation in 250 unrelated Moroccan newborns using real-time polymerase chain reaction. RESULTS: Four pathogenic mutations were detected in 25 unrelated patients. The c.731T>C (p.Ile244Thr) was the most frequent mutation with a frequency of 84%. The other three mutations were c.33delC, c.976delG, and c.331C>T. The prevalence of the PH1 mutation among Moroccans was then estimated to range from 1/7267 to 1/6264. CONCLUSION: PH1 is one of the most prevalent genetic diseases in the Moroccan population and is probably underdiagnosed. Front line genetic testing for PH1 in Morocco should be initiated using an assay for the recurrent p.Ile244Thr mutation. This strategy would provide a useful tool for precocious diagnosis of presymptomatic individuals and to prevent their rapid progression to renal failure.

Intraperitoneal pressure in children: fill-volume related and impacted by body mass index.

OBJECTIVE: Prescription of intraperitoneal volume (IPV) in children on peritoneal dialysis (PD) should be individualized in order to optimize both efficiency and tolerance. Intraperitoneal pressure (IPP) can be used as an objective assessment of IPV. Despite IPP being correlated with IPV, there is an important interindividual variability presumed to be secondary to other implicated factors. DESIGN: Over the past 2 years, we conducted a prospective study in our patients on PD (N = 17). For each child, we recorded, at every third month of follow-up, IPV (in milliliters per square meter body surface area), age, gender, body mass index (BMI), and IPP (measured as centimeters of water), collecting a total of 53 data points. RESULTS: There was a positive correlation between IPV and IPP (r = 0.36), but this correlation was weak in contrast to the strong correlation noted between BMI and IPP (r = 0.82). Age had a different influence on IPP: in the younger-aged group (< 2 years), IPP decreased with age; in the older-aged group (> 2 years), IPP increased with age. In some infants, we noted a paradoxical result: a low IPV with a high IPP. CONCLUSIONS: The strong correlation noted between IPP and BMI gives a better understanding of the interindividual variability of the previously described unique relationship between IPP and IPV. The more obese the child (i.e., the higher the BMI), the higher is his IPP for a fixed IPV.

[Acute postinfectious glomerulonephritis]. / Glomérulonéphrites aiguës postinfectieuses.

Acute postinfectious glomerulonephritis are defined by an acute nonsuppurative inflammatory insult predominantly glomerular. Its current incidence is uncertain because of the frequency of subclinical forms. The most common infectious agent involved is beta hemolytic streptococcus group A. Acute postinfectious glomerulonephritis is uncommon in adults, and its incidence is progressively declining in developed countries. Humoral immunity plays a key role in the pathogenesis of kidney damage. Complement activation by the alternative pathway is the dominant mechanism, but a third way (lectin pathway) has been recently identified. The classic clinical presentation is sudden onset of acute nephritic syndrome after a free interval from a streptococcal infection. Treatment is essentially symptomatic and prevention is possible through improved hygiene and early treatment of infections.