[Show abstract][Hide abstract] ABSTRACT: Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available.
Journal of the American Society of Nephrology 06/2015; 26(6):1279-89. · 9.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction and Aims: Autosomal recessive polycystic kidney disease (ARPKD) occurs in 1:20,000 live births and is the most common cystic kidney
disease in childhood. Since kidney and liver manifestations progress differently in ARPKD, the decision of the right type
of transplantation may be challenging. Most often kidney-alone transplantation (KT) is performed first, followed by liver
transplantation (LT) or directly combined liver kidney transplantation (CLKT). The choice for CLKT is more and more discussed
because (1) 64-80% of the mortality occurring in ARPKD with KT patients is attributed to cholangitis/sepsis related to liver
disease; (2) liver allograft is immunologically protective of the kidney graft and (3) CLKT from the same donor probably provides
better long-term. However, there is no consensus yet and long-term outcome data are scarce. In the present study, we aimed
to analyse the characteristics and outcomes of children with ARPKD of the ESPN/ERA-EDTA registry and compare the outcome of
the different transplantation strategies.
Methods: 239 incident ARPKD patients were identified from the ESPN/ERA-EDTA registry who started RRT since 1995. Data included date
of birth, gender, age at RRT, treatment modality of RRT, type of transplantation (KT or CLKT), changes in RRT modality during
follow-up, survival and cause of death.
Results: Mean age at start of RRT was 12.8 and 11.4 years in males and females respectively. Five year patient survival on RRT was
88.1%. Patients starting RRT before the age of 1 had a 20% lower 5-year survival (72.9%). Twenty nine patients died and the
causes of death were infection (28%), cardiovascular disease (16%), hemorrhage (6.9%), and unknown (31%). There were 197 transplantations
among 179 incident patients. Median age at time of the first transplantation was 9.3 years (IQR 3.9 to 13.6), which took place
after a median of 0.4 years on dialysis (IQR 0.0-1.3). Twenty three patients (13%) received a CLKT, while 123 (69%) received
a KT and in 33 (18%) the type of transplantation was unknown. There was a significant difference in 5-year patient survival
according to the type of transplantation (78.6% for CLKT vs. 96.2% for KT) (p=0.03). Five year death censored renal graft
survival was 74.3% (71.5% and 77.0% for CLKT and KT respectively p=0.83). There were 18 patients with at least 2 transplantations
(1 patients received 3). Renal graft survival tended to be worse for the second as compared to the first renal allograft (HR
1.56 95%CI 0.71 to 3.43).
Conclusions: The need for RRT in the first year of life for ARPKD adversely impacts survival. CLKT is a significant risk factor for mortality
on short-term, and is not associated with better 5-year graft survival. Long term follow-up data are needed to better delineate
the best transplantation strategy.
[Show abstract][Hide abstract] ABSTRACT: Diffuse mesangial sclerosis (DMS) is a histologically distinct variant of nephrotic syndrome (NS) that is characterized by early onset and by progression to end-stage kidney disease (ESKD). Besides syndromic DMS, isolated (non-syndromic) DMS (IDMS) has been described. The etiology and pathogenesis of DMS is not understood. We recently identified by positional cloning recessive mutations in the gene PLCE1/NPHS3 as a novel cause of IDMS. We demonstrated a role of PLCE1 in glomerulogenesis. Mutations in two other genes WT1 and LAMB2 may also cause IDMS. We therefore determine in this study the relative frequency of mutations in PLCE1, WT1 or LAMB2 as the cause of IDMS in a worldwide cohort.
We identified 40 children from 35 families with IDMS from a worldwide cohort of 1368 children with NS. All the subjects were analyzed for mutations in all exons of PLCE1 by multiplex capillary heteroduplex analysis and direct sequencing, by direct sequencing of exons 8 and 9 of WT1, and all the exons of LAMB2.
The median (range) age at onset of NS was 11 (1-72) months. We detected truncating mutations in PLCE1 in 10/35 (28.6%) families and WT1 mutations in 3/35 (8.5%) families. We found no mutations in LAMB2.
PLCE1 mutation is the most common cause of IDMS in this cohort. We previously reported that one child with truncating mutation in PLCE1 responded to cyclosporine therapy. If this observation is confirmed in a larger study, mutations in PLCE1 may serve as a biomarker for selecting patients with IDMS who may benefit from treatment.
[Show abstract][Hide abstract] ABSTRACT: Hemolytic uremic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The non-Shiga toxin-associated HUS (atypical HUS [aHUS]) has been shown to be a disease of complement dysregulation. Mutations in the plasma complement regulators factor H and factor I and the widely expressed membrane cofactor protein (MCP; CD46) have been described recently. This study looked for MCP mutations in a panel of 120 patients with aHUS. In this cohort, approximately 10% of patients with aHUS (11 patients; nine pedigrees) have mutations in MCP. The onset typically was in early childhood. Unlike patients with factor I or factor H mutations, most of the patients do not develop end-stage renal failure after aHUS. The majority of patients have a mutation that causes reduced MCP surface expression. A small proportion expressed normal levels of a dysfunctional protein. As in other studies, incomplete penetrance is shown, suggesting that MCP is a predisposing factor rather than a direct causal factor. The low level of recurrence of aHUS in transplantation in patients with MCP mutations is confirmed, and the first MCP null individuals are described. This study confirms the association between MCP deficiency and aHUS and further establishes that a deficiency in complement regulation, specifically cofactor activity, predisposes to severe thrombotic microangiopathy in the renal vasculature.
Journal of the American Society of Nephrology 08/2006; 17(7):2017-25. DOI:10.1681/ASN.2005101051 · 9.34 Impact Factor