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1.
Am J Hum Genet ; 91(6): 987-97, 2012 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-23159250

RESUMO

We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.


Assuntos
Variações do Número de Cópias de DNA , Nefropatias/congênito , Nefropatias/genética , Estudos de Casos e Controles , Aberrações Cromossômicas , Estudos de Associação Genética , Genótipo , Humanos , Anotação de Sequência Molecular
2.
G Ital Nefrol ; 29 Suppl 54: S73-7, 2012.
Artigo em Italiano | MEDLINE | ID: mdl-22388835

RESUMO

ANCA-associated vasculitides are a group of inflammatory diseases affecting medium and small vessels with a redundant and hence complex pathogenetic mechanism. Since their first identification, their dismal prognosis has forced researchers to find effective therapies. The prognosis has changed since the advent of immunomodulatory drugs like steroids, cyclophosphamide, azathioprine, mycophenolate mofetil and, more recently, biological drugs. Plasmapheresis in association with immune suppressant drugs has shown beneficial effects in some clinical trials, mostly in dialysis-dependent patients. Apheresis should remove, in a nonselective manner, pathogenetic antibodies like ANCA but also immune complexes, cytokines and inflammatory mediators. A recent meta-analysis took into account 28 randomized clinical trials studying therapeutic interventions in adult vasculitis with renal involvement, six of them scheduling plasmapheresis as adjunctive therapy to immune suppressant drugs. This association significantly reduced the need for dialysis at three (1 trial: RR 0.45, 95% CI 0.24-0.84) and twelve (5 trials: RR 0.47, 95% CI 0.3-0.75) months but not the mortality at one year. We can conclude that plasmapheresis is an effective treatment option for vasculitides with severe renal failure. It can also be considered in case of ineffectiveness of or contraindications to standard treatment.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Remoção de Componentes Sanguíneos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Ensaios Clínicos como Assunto , Humanos , Imunossupressores/uso terapêutico , Metanálise como Assunto , Plasmaferese , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
3.
G Ital Nefrol ; 29(1): 58-69, 2012.
Artigo em Italiano | MEDLINE | ID: mdl-22388907

RESUMO

Kidney damage caused by immunoglobulin free light chains in the setting of plasma cell dyscrasias is common and may involve all renal compartments, from the glomerulus to the tubulointerstitium, in a wide variety of histomorphological and clinical patterns. The knowledge of how free light chains can promote kidney injury is growing: they can cause functional changes, be processed and deposited, mediate inflammation, apoptosis and fibrosis, and obstruct nephrons. Each clone of the free light chain is unique and its primary structure and post-translation modification can determine the type of renal disease. Measurement of serum free light chain concentrations and calculation of the serum kappa/lambda ratio, together with renal biopsy, represent essential diagnostic tools. An early and correct diagnosis of renal lesions due to plasma cell dyscrasias will allow early initiation of disease-specific treatment strategies. The treatment of free light chain nephropathies is evolving and knowledge of the pathways that promote renal damage should lead to further therapeutic developments.


Assuntos
Nefropatias/etiologia , Paraproteinemias/complicações , Humanos , Nefropatias/terapia , Glomérulos Renais , Túbulos Renais
4.
Kidney Int ; 76(5): 528-33, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19536081

RESUMO

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are a major cause of morbidity in children. We measured the risk of progression to end-stage renal disease in 312 patients with CAKUT preselected for the presence of anomalies in kidney number or size. A model of dialysis-free survival from birth was established as a function of the renal CAKUT categories of solitary kidney; unilateral and bilateral hypodysplasia; renal hypodysplasia associated with posterior urethral valves; and multicystic and horseshoe kidney. Cox regression analysis took into account the concomitant presence of vesicoureteral reflux, year of diagnosis, and time-varying values of serum creatinine, proteinuria, and hypertension. By 30 years of age, 58 patients had started dialysis, giving a yearly incidence of 0.023 over a combined 2474 patient risk years. The risk for dialysis was significantly higher for patients with a solitary kidney or with renal hypodysplasia associated with posterior urethral valves (hazard ratios of 2.43 and 5.1, respectively) compared to patients with unilateral or bilateral renal hypodysplasia, or multicystic or horseshoe kidney, and was independent of other prognostic factors. Our study shows that sub-clinical defects of the solitary kidney may be responsible for a poorer prognosis compared to more benign forms of CAKUT. Prospective studies are needed to validate these results.


Assuntos
Rim/anormalidades , Sistema Urinário/anormalidades , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Rim/patologia , Nefropatias/mortalidade , Masculino , Prognóstico , Diálise Renal
5.
Am J Hum Genet ; 80(3): 539-49, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17273976

RESUMO

Nonsyndromic defects in the urinary tract are the most common cause of end-stage renal failure in children and account for a significant proportion of adult nephropathy. The genetic basis of these disorders is not fully understood. We studied seven multiplex kindreds ascertained via an index case with a nonsyndromic solitary kidney or renal hypodysplasia. Systematic ultrasonographic screening revealed that many family members harbor malformations, such as solitary kidneys, hypodysplasia, or ureteric abnormalities (in a total of 29 affected individuals). A genomewide scan identified significant linkage to a 6.9-Mb segment on chromosome 1p32-33 under an autosomal dominant model with reduced penetrance (peak LOD score 3.5 at D1S2652 in the largest kindred). Altogether, three of the seven families showed positive LOD scores at this interval, demonstrating heterogeneity of the trait (peak HLOD 3.9, with 45% of families linked). The chromosome 1p32-33 interval contains 52 transcription units, and at least 23 of these are expressed at stage E12.5 in the murine ureteric bud and/or metanephric mesenchyme. These data show that autosomal dominant nonsyndromic renal hypodysplasia and associated urinary tract malformations are genetically heterogeneous and identify a locus for this common cause of human kidney failure.


Assuntos
Cromossomos Humanos Par 1/genética , Genes Dominantes/fisiologia , Predisposição Genética para Doença , Rim/anormalidades , Doenças Ureterais/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Mapeamento Cromossômico , Feminino , Ligação Genética , Marcadores Genéticos , Genótipo , Humanos , Lactente , Rim/patologia , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , Penetrância
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