RESUMO
The transfer of renal transplant patients from pediatric to adult care is a crucial step with a high risk of subsequent graft loss. Therefore, the transition should be a thoroughly planned, well-designed and multidisciplinary process focused on the individual patient. Our pediatric nephrology department introduced a structured step-by-step transition program supported by a multidisciplinary team of health professionals. The purpose of our study was to determine the effects of the transition program on eGFR and number of ARs in comparison to a group without a transition program at one and three yr after transfer. We conducted a single-center retrospective cohort study of renal transplant patients prior to and after the introduction of the transition program. Multiple regression analysis revealed a significantly lower decline of eGFR in the group with transition program (-11.3 ± 44 mL/min/1.73 m(2) ) compared to the group without transition program (-28.4 ± 33 mL/min/1.73 m(2) ) at three yr after transfer. The number of AR episodes significantly decreased from 34.6% in the group without transition program to 9.1% in the group with transition program. The standardized multilevel transition program seems to have significant positive effects on eGFR and number of AR episodes in renal transplant patients.
Assuntos
Taxa de Filtração Glomerular , Rejeição de Enxerto/prevenção & controle , Transplante de Rim , Cuidados Pós-Operatórios/métodos , Transição para Assistência do Adulto/organização & administração , Adolescente , Adulto , Feminino , Humanos , Masculino , Avaliação de Processos e Resultados em Cuidados de Saúde , Análise de Regressão , Estudos Retrospectivos , Adulto JovemRESUMO
Inherited and acquired dysregulation of the complement alternative pathway plays an important role in multiple renal diseases. In recent years, the identification of disease-causing mutations and genetic variants in complement regulatory proteins has contributed significantly to our knowledge of the pathogenesis of complement associated glomerulopathies. In these diseases defective complement control leading to the deposition of activated complement products plays a key role. Consequently, complement-related glomerulopathies characterized by glomerular complement component 3 (C3) deposition in the absence of local immunoglobulin deposits are now collectively described by the term "C3 glomerulopathies." Therapeutic strategies for reestablishing complement regulation by either complement blockade with the anti-C5 monoclonal antibody eculizumab or plasma substitution have been successful in several cases of C3 glomerulopathies. However, further elucidation of the underlying defects in the alternative complement pathway is awaited to develop pathogenesis-specific therapies.
Assuntos
Proteínas do Sistema Complemento/imunologia , Nefropatias/imunologia , Ativação do Complemento/imunologia , Humanos , Nefropatias/genética , Nefropatias/metabolismoRESUMO
Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of end-stage renal failure. Identification of single-gene causes of SRNS has generated some insights into its pathogenesis; however, additional genes and disease mechanisms remain obscure, and SRNS continues to be treatment refractory. Here we have identified 6 different mutations in coenzyme Q10 biosynthesis monooxygenase 6 (COQ6) in 13 individuals from 7 families by homozygosity mapping. Each mutation was linked to early-onset SRNS with sensorineural deafness. The deleterious effects of these human COQ6 mutations were validated by their lack of complementation in coq6-deficient yeast. Furthermore, knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused apoptosis that was partially reversed by coenzyme Q10 treatment. In rats, COQ6 was located within cell processes and the Golgi apparatus of renal glomerular podocytes and in stria vascularis cells of the inner ear, consistent with an oto-renal disease phenotype. These data suggest that coenzyme Q10-related forms of SRNS and hearing loss can be molecularly identified and potentially treated.
Assuntos
Perda Auditiva Neurossensorial/genética , Mutação , Síndrome Nefrótica/genética , Ubiquinona/genética , Animais , Células COS , Criança , Pré-Escolar , Chlorocebus aethiops , Células HeLa , Perda Auditiva Neurossensorial/complicações , Homozigoto , Humanos , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular/genética , Glomérulos Renais/metabolismo , Laminina/genética , Proteínas de Membrana/genética , Síndrome Nefrótica/complicações , Fenótipo , Podócitos/metabolismo , Ratos , Proteínas WT1/genética , Peixe-ZebraRESUMO
BACKGROUND AND OBJECTIVES: The risk of developing Wilms tumor (WT) can be present or absent in patients with nephrotic syndrome (NS) caused by WT1 mutations. Here, the genotype/phenotype correlation regarding the outcome and risk for WT in 52 patients from 51 families with NS due to WT1 mutations is described. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study followed 19 patients with mutations in intron 9 splice donor site (KTS mutations), 27 patients with missense mutations, 4 patients with nonsense mutations, 1 patient with a splice site mutation in intron 8, and 1 patient with a deletion. RESULTS: Twenty-four different WT1 mutations were detected. Sixteen of the 19 patients with KTS mutations were females. These patients had isolated NS if karyotype was 46,XX and Frasier syndrome if karyotype was 46,XY. Patients with KTS mutations presented at a significantly older age and with a slower progression toward chronic kidney disease (CKD) stage 5, compared with missense mutations. Patients with nonsense mutations presented initially with WT. Six patients with missense mutations developed WT after the diagnosis of NS (interval-range from NS onset to WT of 0.1 to 1.4 years). CONCLUSIONS: (1) KTS mutations cause isolated NS with absence of WT in 46,XX females. (2) KTS mutations cause Frasier syndrome with gonadoblastoma risk in 46,XY phenotypic females. (3) KTS mutations cause NS with a slower progression when compared with missense mutations. (4) Missense mutations can occur with and without WT. (5) WT1 analysis is important in young patients with NS for early detection and tumor prophylaxis.
Assuntos
Síndrome de Frasier/genética , Genes do Tumor de Wilms , Gonadoblastoma/genética , Falência Renal Crônica/genética , Neoplasias Renais/genética , Mutação , Síndrome Nefrótica/genética , Tumor de Wilms/genética , Idade de Início , Criança , Pré-Escolar , Códon sem Sentido , Análise Mutacional de DNA , Progressão da Doença , Feminino , Síndrome de Frasier/etnologia , Síndrome de Frasier/mortalidade , Estudos de Associação Genética , Predisposição Genética para Doença , Gonadoblastoma/etnologia , Gonadoblastoma/mortalidade , Humanos , Lactente , Íntrons , Israel , Estimativa de Kaplan-Meier , Cariotipagem , Falência Renal Crônica/etnologia , Falência Renal Crônica/mortalidade , Neoplasias Renais/etnologia , Neoplasias Renais/mortalidade , Masculino , Mutação de Sentido Incorreto , Síndrome Nefrótica/etnologia , Síndrome Nefrótica/mortalidade , Linhagem , Fenótipo , Medição de Risco , Fatores de Risco , Deleção de Sequência , Fatores de Tempo , Turquia , Estados Unidos , Tumor de Wilms/etnologia , Tumor de Wilms/mortalidadeRESUMO
The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1-NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are "ciliopathies". Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.
Assuntos
Aminopeptidases/metabolismo , Doenças Genéticas Inatas/enzimologia , Rim/enzimologia , Mitocôndrias/enzimologia , Proteínas Mitocondriais/metabolismo , Insuficiência Renal/enzimologia , Aminopeptidases/genética , Animais , Centrossomo/enzimologia , Centrossomo/patologia , Mapeamento Cromossômico/métodos , Cílios/enzimologia , Cílios/genética , Cílios/patologia , Família , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Estudo de Associação Genômica Ampla/métodos , Humanos , Rim/patologia , Masculino , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Ratos , Ratos Sprague-Dawley , Insuficiência Renal/genética , Insuficiência Renal/patologia , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismoRESUMO
BACKGROUND: Recessive mutations in the NPHS1 gene encoding nephrin account for approximately 40% of infants with congenital nephrotic syndrome (CNS). CNS is defined as steroid-resistant nephrotic syndrome (SRNS) within the first 90 days of life. Currently, more than 119 different mutations of NPHS1 have been published affecting most exons. METHODS: We here performed mutational analysis of NPHS1 in a worldwide cohort of 67 children from 62 different families with CNS. RESULTS: We found bi-allelic mutations in 36 of the 62 families (58%) confirming in a worldwide cohort that about one-half of CNS is caused by NPHS1 mutations. In 26 families, mutations were homozygous, and in 10, they were compound heterozygous. In an additional nine patients from eight families, only one heterozygous mutation was detected. We detected 37 different mutations. Nineteen of the 37 were novel mutations (approximately 51.4%), including 11 missense mutations, 4 splice-site mutations, 3 nonsense mutations and 1 small deletion. In an additional patient with later manifestation, we discovered two further novel mutations, including the first one affecting a glycosylation site of nephrin. CONCLUSIONS: Our data hereby expand the spectrum of known mutations by 17.6%. Surprisingly, out of the two siblings with the homozygous novel mutation L587R in NPHS1, only one developed nephrotic syndrome before the age of 90 days, while the other one did not manifest until the age of 2 years. Both siblings also unexpectedly experienced an episode of partial remission upon steroid treatment.
Assuntos
Proteínas de Membrana/genética , Mutação/genética , Síndrome Nefrótica/congênito , Síndrome Nefrótica/genética , Estudos de Coortes , Éxons/genética , Família , Feminino , Genótipo , Saúde Global , Heterozigoto , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Síndrome Nefrótica/patologia , Fenótipo , PrognósticoRESUMO
Previous studies in children with focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS) in the USA have revealed inter-ethnic differences in their clinical presentation and outcome. However, ethnicity was based on self-identification rather than on molecular genetic data. Here, we show that genetic heterogeneity exists in self-identified Hispanic (Spanish-American) patients with steroid-resistant nephrotic syndrome (SRNS), as patients may be either of Caucasian or Mesoamerican (Native-American) genetic background. Twenty-one self-identified Hispanic patients with SRNS from 18 families were initially evaluated for mutations in the NPHS2 and WT1 genes. All patients resided and were cared for in the USA. We performed a total genome search for linkage in all Hispanic patients using 250K single nucleotide polymorphism microarrays, comparing Caucasian with Mesoamerican allele frequencies to determine regions of homozygosity by descent and to establish the correct allele frequency for each family. We found that only ten families (56%) of the 18 self-identified Hispanic families are genetically of Mesoamerican descent, whereas the other eight families (44%) are of Caucasian descent. Due to the small number of families examined, we were unable to draw any conclusion on the prevalence of NPHS2 and WT1 in this ethnic group, but the data do suggest that self-identification of ethnicity in Hispanic-American patients is not an adequate basis for genetic studies, as this cohort may represent not only patients of Mesoamerican origin but also patients of Caucasian origin. Thus, one needs to critically review previous studies of FSGS/SRNS patients that involved Hispanic patients as a group. Future larger studies may employ a total genome search for linkage to test self-identified Hispanic ethnicity for true Mesoamerican versus Caucasian ethnicity in order to generate valid genetic data.
Assuntos
Glomerulosclerose Segmentar e Focal/genética , Hispânico ou Latino/genética , Síndrome Nefrótica/etnologia , Síndrome Nefrótica/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Bases de Dados Genéticas , Resistência a Medicamentos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genômica , Glomerulosclerose Segmentar e Focal/etnologia , Glomerulosclerose Segmentar e Focal/patologia , Hispânico ou Latino/etnologia , Humanos , Indígenas Sul-Americanos/etnologia , Indígenas Sul-Americanos/genética , Lactente , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana , Síndrome Nefrótica/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Esteroides/uso terapêutico , Proteínas WT1/genética , População Branca/etnologia , População Branca/genéticaRESUMO
BACKGROUND: TRPC6, encoding a member of the transient receptor potential (TRP) superfamily of ion channels, is a calcium-permeable cation channel, which mediates capacitive calcium entry into the cell. Until today, seven different mutations in TRPC6 have been identified as a cause of autosomal-dominant focal segmental glomerulosclerosis (FSGS) in adults. METHODOLOGY/PRINCIPAL FINDINGS: Here we report a novel TRPC6 mutation that leads to early onset FSGS. We identified one family in whom disease segregated with a novel TRPC6 mutation (M132T), that also affected pediatric individuals as early as nine years of age. Twenty-one pedigrees compatible with an autosomal-dominant mode of inheritance and biopsy-proven FSGS were selected from a worldwide cohort of 550 families with steroid resistant nephrotic syndrome (SRNS). Whole cell current recordings of the mutant TRPC6 channel, compared to the wild-type channel, showed a 3 to 5-fold increase in the average out- and inward TRPC6 current amplitude. The mean inward calcium current of M132T was 10-fold larger than that of wild-type TRPC6. Interestingly, M132T mutants also lacked time-dependent inactivation. Generation of a novel double mutant M132T/N143S did not further augment TRPC6 channel activity. CONCLUSIONS: In summary, our data shows that TRPC6 mediated FSGS can also be found in children. The large increase in channel currents and impaired channel inactivation caused by the M132T mutant leads to an aggressive phenotype that underlines the importance of calcium dose channeled through TRPC6.
Assuntos
Regulação da Expressão Gênica , Glomerulosclerose Segmentar e Focal/genética , Mutação , Canais de Cátion TRPC/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Saúde da Família , Feminino , Genes Dominantes , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Canal de Cátion TRPC6RESUMO
In steroid-resistant nephrotic syndrome (SRNS) Machuca et al. report that mutations of the recessive podocin gene cause adult-onset SRNS if the R229Q genetic variant occurs in a compound heterozygous state with another podocin mutation. Learning to tell apart the specific allele combinations of podocin mutations will be important for prognosis, genetic counseling in living related kidney donation, accurate etiologic classification within treatment studies, and the understanding of podocin function.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Mutação/fisiologia , Síndrome Nefrótica/epidemiologia , Síndrome Nefrótica/genética , Adulto , Idade de Início , Resistência a Medicamentos , Humanos , Síndrome Nefrótica/diagnóstico , PrognósticoRESUMO
Wilms' tumour suppressor gene 1 (WT1) encodes a transcription factor required for normal development of the genitourinary system. In the kidney, mutations in WT1 can cause diffuse mesangial sclerosis or focal segmental glomerulosclerosis. Here, we report on a girl with a mutation in WT1, who developed membranoproliferative glomerulonephritis (MPGN) 3 years after completion of treatment for Wilms' tumour. This finding extends the spectrum of glomerular disease seen with WT1 mutations and could have implications for the screening of children with MPGN.
Assuntos
Genes do Tumor de Wilms , Glomerulonefrite Membranoproliferativa/genética , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Feminino , Glomerulonefrite Membranoproliferativa/complicações , Glomerulonefrite Membranoproliferativa/fisiopatologia , Humanos , Imunossupressores/uso terapêutico , Lactente , Transplante de Rim , Mutação , Nefrectomia , Vincristina/uso terapêutico , Tumor de Wilms/complicações , Tumor de Wilms/genética , Tumor de Wilms/cirurgiaRESUMO
The identification of recessive disease-causing genes by homozygosity mapping is often restricted by lack of suitable consanguineous families. To overcome these limitations, we apply homozygosity mapping to single affected individuals from outbred populations. In 72 individuals of 54 kindred ascertained worldwide with known homozygous mutations in 13 different recessive disease genes, we performed total genome homozygosity mapping using 250,000 SNP arrays. Likelihood ratio Z-scores (ZLR) were plotted across the genome to detect ZLR peaks that reflect segments of homozygosity by descent, which may harbor the mutated gene. In 93% of cases, the causative gene was positioned within a consistent ZLR peak of homozygosity. The number of peaks reflected the degree of inbreeding. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations within a single ZLR peak of homozygosity as short as 2 Mb, containing an average of only 16 candidate genes. As many specialty clinics have access to cohorts of individuals from outbred populations, and as our approach will result in smaller genetic candidate regions, the new strategy of homozygosity mapping in single outbred individuals will strongly accelerate the discovery of novel recessive disease genes.
Assuntos
Genes Recessivos , Análise Mutacional de DNA , Reações Falso-Positivas , Saúde da Família , Feminino , Marcadores Genéticos , Genética Populacional , Homozigoto , Humanos , Doenças Renais Císticas/genética , Masculino , Modelos Genéticos , Síndrome Nefrótica/genética , Linhagem , Esteroides/farmacologiaRESUMO
Nephrotic syndrome presenting in the first year of life is often challenging, with substantial risk of progression to end-stage renal disease (ESRD). Focal segmental glomerulosclerosis (FSGS) comprises up to 20% of biopsy-proven glomerular disease in children and adults. We report on a 9-month-old infant who presented with nephrotic syndrome, hypertension and progressive deterioration of renal function due to FSGS. As immunosuppressive agents are often unsuccessful in treating this condition, we adopted renoprotection as the mainstay treatment for this patient, through rigorous control of blood pressure and proteinuria with a multi-drug regimen including renin-angiotensin axis blockade. Initially, there was partial improvement, with a gradual decline in proteinuria and a concomitant rise in the glomerular filtration rate, before the disease eventually passed into complete clinical and laboratory remission. We speculate that infants with steroid-resistant nephrotic syndrome due to FSGS may benefit from tight control of hypertension, mainly though early blockade of the renin-angiotensin axis. We believe that its renoprotecive mechanism counteracts the deleterious effects of both hypertension and proteinuria, thereby not only preventing progressive renal disease, but even paving the way for a remission, as in our patient. To the best of our knowledge, this is the first report of an infant with nephrotic syndrome (NS) due to FSGS that passed into complete remission while the patient was on renoprotective measures including the use of angiotensin-converting enzyme inhibitors (ACEis).
Assuntos
Angiotensinas/antagonistas & inibidores , Anti-Hipertensivos/uso terapêutico , Captopril/uso terapêutico , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Síndrome Nefrótica/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Albuminas/uso terapêutico , Anlodipino/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Quimioterapia Combinada , Furosemida/uso terapêutico , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Lactente , Labetalol/uso terapêutico , Masculino , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/patologia , Prednisolona/farmacologia , Indução de Remissão , Sistema Renina-Angiotensina/fisiologiaRESUMO
In African American (AA) children, focal segmental glomerulosclerosis (FSGS) is the leading cause of nephrotic syndrome (NS). It has been shown that AA children suffer from FSGS and steroid-resistant nephrotic syndrome (SRNS) at a higher frequency and with a more severe renal outcome in comparison with Caucasian children. Previous mutation analysis of large cohorts revealed that a high percentage of childhood SRNS is monogenic and that mutations in podocin (NPHS2) and Wilms' tumor gene 1 (WT1) account for approximately 30% of SRNS in children. To test whether AA children with SRNS have a similar or a higher mutation rate, we performed mutation analysis of NPHS2 and WT1 in a cohort of AA children with SRNS. Direct sequencing was carried out for all exons of NPHS2 and for exons 8 and 9 of WT1. We ascertained 18 children of AA descent in whom renal biopsy findings showed FSGS in 13 patients (72%) and minimal-change disease in five patients (28%). In both NPHS2 and WT1, no disease-causing mutations were detected. Our data strongly suggest that in AA children with SRNS, the frequency of NPHS2 mutations is much lower than in large cohorts of pediatric SRNS patients in the general population. Knowledge of mutation rate of NPHS2 in different populations of SRNS patients facilitates the physician in planning a suitable genetic screening strategy for patients.
Assuntos
Negro ou Afro-Americano/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Mutação , Síndrome Nefrótica/genética , Adolescente , Corticosteroides/uso terapêutico , Criança , Pré-Escolar , Resistência a Medicamentos , Feminino , Genes do Tumor de Wilms , Humanos , Lactente , Recém-Nascido , Rim/patologia , Masculino , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/patologiaRESUMO
BACKGROUND: Congenital nephrotic syndrome (CNS) is de- fined as nephrotic syndrome that manifests at birth or within the first 3 months of life. Most patients develop end-stage renal disease (ESRD) within 2 to 3 years of life. CNS of the Finnish-type (CNF) features a rather specific renal histology and is caused by recessive mutations in the NPHS1 gene encoding nephrin, a major structural protein of the glomerular slit-diaphragm. So far, more than 80 different mutations of NPHS1 causing CNF have been published. METHODS: Here, we performed mutation analysis of NPHS1 by exon sequencing in a worldwide cohort of 32 children with CNS from 29 different families. RESULTS: Sixteen of the 29 families (55%) were found to have two disease-causing alleles in NPHS1. Two additional patients had a single heterozygous mutation in NPHS1. Thirteen of a total of 20 different mutations detected were novel (65%). These were five missense mutations, one nonsense mutation, three deletions, one insertion and three splice-site mutations. CONCLUSION: Our data expand the spectrum of known NPHS1 mutations by >15% in a worldwide cohort. Surprisingly, two patients with disease-causing mutations showed a relatively mild phenotype, as one patient had a partial remission with steroid treatment and one patient had normal renal function 1 year after the onset of disease. The increased number of known mutations will facilitate future studies into genotype/phenotype correlations.
Assuntos
Proteínas de Membrana/genética , Mutação/genética , Síndrome Nefrótica/congênito , Síndrome Nefrótica/genética , Códon sem Sentido/genética , Estudos de Coortes , Feminino , Deleção de Genes , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Mutagênese Insercional/genética , Mutação de Sentido Incorreto/genética , FenótipoRESUMO
Mutations in the gene encoding podocin (NPHS2) cause autosomal recessive steroid-resistant nephrotic syndrome (SRNS). For addressing the possibility of a genotype-phenotype correlation between podocin mutations and age of onset, a worldwide cohort of 430 patients from 404 different families with SRNS were screened by direct sequencing. Recessive podocin mutations were present in 18.1% (73 of 404) of families with SRNS, and 69.9% of these mutations were nonsense, frameshift, or homozygous R138Q. Patients with these mutations manifested symptoms at a significantly earlier age (mean onset <1.75 years) than any other patient group, with or without podocin mutations, in this study (mean onset >4.17 yr). All but one patient affected by truncating or homozygous R138Q mutations developed SRNS before 6 yr of age. Patient groups with other recessive podocin mutations, with single heterozygous podocin mutations, with sequence variants, and with no podocin changes could not be distinguished from each other on the basis of age of onset. In conclusion, nephrotic syndrome in children with truncating or homozygous R138Q mutations manifests predominantly before 6 yr of life, and the onset of disease is significantly earlier than for any other podocin mutations. Because the age of onset can vary by several years among those with identical mutations, additional factors may modify the phenotype.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Síndrome Nefrótica/genética , Síndrome Nefrótica/fisiopatologia , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Códon sem Sentido , Resistência a Medicamentos , Mutação da Fase de Leitura , Genótipo , Homozigoto , Humanos , Lactente , Recém-Nascido , Síndrome Nefrótica/tratamento farmacológico , Fenótipo , Esteroides/uso terapêuticoRESUMO
Distinct eye abnormalities have been described in children with nephrotic syndrome, particularly in diffuse mesangial sclerosis (i.e. Pierson syndrome). The aim of the study was to investigate whether there were any associated ocular anomalies in children with steroid-resistant nephrotic syndrome (SRNS), all of whom had revealed primary focal segmental glomerulosclerosis in biopsy. Thirty-three SRNS patients (16 male, 17 female) with a median age of 10.5 years (range 3-25 years) were enrolled in the study. Twenty steroid-sensitive nephrotic syndrome (SSNS) patients (ten male, ten female) with a median age of 8 years (range 3-15 years) served as controls. All SRNS patients were examined by mutational analysis for mutations in the NPHS2, WT1, and LAMB2 genes. Nine out of 33 SRNS patients (27.2%) showed various eye abnormalities. However, no abnormal ocular findings were detected in any of the SSNS patients. Abnormal eye findings detected in SRNS patients were anisometropic amblyopia (n = 4), Mittendorf's dots (n = 4), myopic astigmatism (n = 3) and exotropia (n = 1). Macular pigment changes (n = 1), posterior subcapsular opacities (n = 1) and cataract (n = 1) were considered as steroid-induced side effects. In four patients, more than one eye abnormality was found. Mutational analysis for the NPHS2, WT1 and LAMB2 genes revealed disease-causing mutations in 24.2% of patients. Homozygous NPHS2 mutations were detected in five patients (15.1%), all of whom had parental consanguinity. In three patients (9%) from non-consanguineous parents, heterozygous de novo WT1 mutations were detected as disease-causing mutations. No LAMB2 mutation was detected in any patient. While four out of five (80%) patients with homozygous NPHS2 mutations showed at least one abnormal ocular finding (i.e. Mittendorf's dot or anisometric amblyopia), none of the patients with a WT1 mutation had ocular involvement. In conclusion, ocular involvement may accompany SRNS caused by primary focal segmental glomerulosclerosis (FSGS). Ophthalmologic evaluation at the time of diagnosis might be beneficial to characterize further the spectrum of this possible association.
Assuntos
Oftalmopatias/etiologia , Glomerulosclerose Segmentar e Focal/complicações , Síndrome Nefrótica/complicações , Adolescente , Adulto , Criança , Pré-Escolar , Resistência a Medicamentos , Oftalmopatias/genética , Feminino , Genes do Tumor de Wilms , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lamina Tipo B/genética , Masculino , Proteínas de Membrana/genética , Síndrome Nefrótica/tratamento farmacológico , Esteroides/uso terapêuticoRESUMO
BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Mesângio Glomerular/patologia , Mutação , Nefroesclerose/genética , Fosfoinositídeo Fosfolipase C/genética , Biópsia , Pré-Escolar , DNA , Análise Mutacional de DNA , Éxons , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Laminina/genética , Laminina/metabolismo , Masculino , Nefroesclerose/metabolismo , Nefroesclerose/patologia , Fosfoinositídeo Fosfolipase C/metabolismo , Reação em Cadeia da Polimerase , Prognóstico , Índice de Gravidade de Doença , Proteínas WT1/genética , Proteínas WT1/metabolismoRESUMO
BACKGROUND: The course of idiopathic membranous nephropathy (iMN) is variable in untreated patients. Accurate prediction of renal outcome would allow optimal treatment decisions. We demonstrated that urinary beta2-microglobulin (beta2M) predicted prognosis in iMN with high sensitivity and specificity. It has been suggested that focal segmental glomerulosclerosis (FSGS) is a discriminative parameter with independent prognostic value. METHODS: We selected patients with iMN biopsied between 1988 and 2002. Biopsies were analysed for the presence of FSGS, interstitial fibrosis and vascular lesions. Serum creatinine, creatinine clearance, proteinuria and blood pressure were recorded at baseline. Outcome variables included remission of proteinuria, renal death (RD) defined as serum creatinine >135 micromol/l or increase of serum creatinine of >50%, or end-stage renal disease (ESRD). In a subgroup of patients, urinary beta2-microglobulin (beta2M) was measured. RESULTS: We included 53 patients (33M, 20F). Mean age was 51 years, serum creatinine 99 micromol/l, and proteinuria 7.0 g/10 mmol creatinine. FSGS was present in 22 patients. These patients were characterized by a higher serum creatinine at time of biopsy (P = 0.035), more severe interstitial fibrosis (P = 0.001) and higher stage of membranous nephropathy (P = 0.001). During follow-up 24 patients developed RD, almost equally distributed between patients with and without FSGS. Renal survival was numerically, but not significantly, lower in patients with FSGS. In Cox proportional hazard analysis, only serum creatinine at the time of biopsy was an independent predictor of RD or ESRD (P < 0.001). In patients with known urinary beta2M, there was no significant correlation with FSGS score (P = 0.174). CONCLUSION: FSGS is not an accurate prognostic marker in iMN. Histological scoring of FSGS is inferior to measurement of urinary proteins in predicting renal outcome in iMN.