RESUMO
BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are prevalent birth defects. Although pathogenic CAKUT genes are known, they are insufficient to reveal the causes for all patients. Our previous studies indicated GEN1 as a pathogenic gene of CAKUT in mice, and this study further investigated the correlation between GEN1 and human CAKUT. METHODS: In this study, DNA from 910 individuals with CAKUT was collected; 26 GEN1 rare variants were identified, and two GEN1 (missense) variants in a non-CAKUT group were found. Mainly due to the stability results of the predicted mutant on the website, in vitro, 10 variants (eight CAKUT, two non-CAKUT) were selected to verify mutant protein stability. In addition, mainly based on the division of the mutation site located in the functional region of the GEN1 protein, 8 variants (six CAKUT, two non-CAKUT) were selected to verify enzymatic hydrolysis, and the splice variant GEN1 (c.1071 + 3(IVS10) A > G) was selected to verify shear ability. Based on the results of in vitro experiments and higher frequency, three sites with the most significant functional change were selected to build mouse models. RESULTS: Protein stability changed in six variants in the CAKUT group. Based on electrophoretic mobility shift assay of eight variants (six CAKUT, two non-CAKUT), the enzymatic hydrolysis and DNA-binding abilities of mutant proteins were impaired in the CAKUT group. The most serious functional damage was observed in the Gen1 variant that produced a truncated protein. A mini-gene splicing assay showed that the variant GEN1 (c.1071 + 3(IVS10) A > G) in the CAKUT group significantly affected splicing function. An abnormal exon10 was detected in the mini-gene splicing assay. Point-mutant mouse strains were constructed (Gen1: c.1068 + 3 A > G, p.R400X, and p.T105R) based on the variant frequency in the CAKUT group and functional impairment in vitro study and CAKUT phenotypes were replicated in each. CONCLUSION: Overall, our findings indicated GEN1 as a risk factor for human CAKUT.
Assuntos
Anormalidades Urogenitais , Refluxo Vesicoureteral , Animais , Feminino , Humanos , Masculino , Camundongos , Predisposição Genética para Doença , Rim/anormalidades , Rim/patologia , Rim/metabolismo , Mutação/genética , Estabilidade Proteica , Fatores de Risco , Sistema Urinário/anormalidades , Sistema Urinário/patologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/patologia , Refluxo Vesicoureteral/genética , Refluxo Vesicoureteral/patologiaRESUMO
Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most common birth defects worldwide and a major cause of kidney failure in children. Extra-renal manifestations are also common. This study reviewed diseases associated with the Genomics England CAKUT-associated gene panel for ocular anomalies. In addition, each gene was examined for expression in the human retina and an ocular phenotype in mouse models using the Human Protein Atlas and Mouse Genome Informatics databases, respectively. Thirty-four (54%) of the 63 CAKUT-associated genes (55 'green' and 8 'amber') had a reported ocular phenotype. Five of the 6 most common CAKUT-associated genes (PAX2, EYA1, SALL1, GATA3, PBX1) that represent 30% of all diagnoses had ocular features. The ocular abnormalities found with most CAKUT-associated genes and with five of the six commonest were coloboma, microphthalmia, optic disc anomalies, refraction errors (astigmatism, myopia, and hypermetropia), and cataract. Seven of the CAKUT-associated genes studied (11%) had no reported ocular features but were expressed in the human retina or had an ocular phenotype in a mouse model, which suggested further possibly-unrecognised abnormalities. About one third of CAKUT-associated genes (18, 29%) had no ocular associations and were not expressed in the retina, and the corresponding mouse models had no ocular phenotype. Ocular abnormalities in individuals with CAKUT suggest a genetic basis for the disease and sometimes indicate the affected gene. Individuals with CAKUT often have ocular abnormalities and may require an ophthalmic review, monitoring, and treatment to preserve vision.
Assuntos
Sistema Urinário , Anormalidades Urogenitais , Refluxo Vesicoureteral , Criança , Camundongos , Animais , Humanos , Rim/metabolismo , Sistema Urinário/anormalidades , Refluxo Vesicoureteral/genética , Refluxo Vesicoureteral/diagnóstico , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/diagnósticoRESUMO
BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent 20-30% of all birth defects and are often associated with extra-renal malformations. We investigated the frequency of brain/spine malformations and neurological features in children with CAKUT. METHODS: We reviewed the clinico-radiological and genetic data of 199 out of 1,165 children with CAKUT evaluated from 2006 to 2023 (99 males, mean age at MRI 6.4 years) who underwent brain and/or spine MRI. Patients were grouped according to the type of CAKUT (CAKUT-K involving the kidney and CAKUT-H involving the inferior urinary tract). Group comparisons were performed using χ2 and Fisher exact tests. RESULTS: Brain/spine malformations were observed in 101/199 subjects (50.7%), 8.6% (101/1165) of our CAKUT population, including midbrain-hindbrain anomalies (40/158, 25.3%), commissural malformations (36/158, 22.7%), malformation of cortical development (23/158, 14.5%), Chiari I anomaly (12/199, 6%), cranio-cervical junction malformations (12/199, 6%), vertebral defects (46/94, 48.9%), caudal regression syndrome (29/94, 30.8%), and other spinal dysraphisms (13/94, 13.8%). Brain/spine malformations were more frequent in the CAKUT-K group (62.4%, p < 0.001). Sixty-two subjects (62/199, 31.2%) had developmental delay/intellectual disability. Neurological examination was abnormal in 40/199 (20.1%). Seizures and/or electroencephalographic anomalies were reported in 28/199 (14%) and behavior problems in 19/199 subjects (9%). Developmental delay/intellectual disability was more frequent in kidney dysplasia (65.2%) and agenesis (40.7%) (p = 0.001). CONCLUSIONS: We report a relative high frequency of brain/spine malformations and neurodevelopmental disorders in children with CAKUT who underwent MRI examinations in a tertiary referral center, widening the spectrum of anomalies associated with this condition.
Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Transtornos do Neurodesenvolvimento , Coluna Vertebral , Anormalidades Urogenitais , Humanos , Masculino , Feminino , Criança , Pré-Escolar , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/diagnóstico , Coluna Vertebral/anormalidades , Coluna Vertebral/diagnóstico por imagem , Anormalidades Urogenitais/epidemiologia , Anormalidades Urogenitais/complicações , Anormalidades Urogenitais/diagnóstico , Encéfalo/diagnóstico por imagem , Encéfalo/anormalidades , Encéfalo/patologia , Estudos Retrospectivos , Lactente , Adolescente , Refluxo VesicoureteralRESUMO
BACKGROUND: The leading cause of advanced chronic kidney disease (CKD) in children is congenital anomalies of the kidney and urinary tract (CAKUT). However, the most appropriate parameters of biochemical urine analysis for detecting CAKUT with kidney dysfunction are not known. METHODS: The present observational study analyzed data on children with CAKUT (stage 2-4 CKD) and the general pediatric population obtained from school urine screenings. The sensitivity and specificity of urine alpha 1-microglobulin-, beta 2-microglobulin-, protein-, and the albumin-to-creatinine ratios (AMCR, BMCR, PCR, ACR, respectively) in detecting CAKUT with kidney dysfunction were compared with those of the conventional urine dipstick, and the most appropriate of these four parameters were evaluated. RESULTS: In total, 77 children with CAKUT and 1712 subjects in the general pediatric population fulfilled the eligibility criteria. Conventional dipstick urinalysis was insufficient due to its low sensitivity; even when the threshold of proteinuria was +/-, its sensitivity was only 29.7% for stage 2 and 44.1% for stage 3 CKD. Among the four parameters assessed, the AMCR and BMCR were adequate for detecting CAKUT in children with stage 3-4 CKD (the respective sensitivity and specificity of the AMCR for detecting CAKUT in stage 3 CKD was 79.4% and 97.5% while that of BMCR was 82.4% and 97.5%). These data were validated using national cohort data. CONCLUSION: AMCR and BMCR are superior to dipstick urinalysis, PCR, and ACR in detecting CAKUT with kidney dysfunction, particularly stage 3 CKD. However, for AMCR, external validation is required. A higher resolution version of the Graphical abstract is available as Supplementary information.
Assuntos
Insuficiência Renal Crônica , Insuficiência Renal , Criança , Humanos , Creatinina/urina , Microglobulina beta-2 , Taxa de Filtração Glomerular , Rim , Insuficiência Renal Crônica/epidemiologiaRESUMO
RATIONALE & OBJECTIVE: Several maternal chronic diseases have been reported as risk factors for congenital anomalies of the kidney and urinary tract (CAKUT) in offspring. However, these investigations used case-control designs, and cases with isolated genitourinary CAKUT were not distinguished from cases in which CAKUT were present with extrarenal congenital anomalies (complicated CAKUT). We examined the association of maternal diseases with isolated and complicated CAKUT in offspring using data from a prospective cohort study. STUDY DESIGN: A nationwide prospective birth cohort study. SETTING & PARTICIPANTS: 100,239 children enrolled in the Japan Environment and Children's Study between January 2011 and March 2014 at 15 research centers. Physicians' diagnoses in mothers and children were collected from medical record transcripts and questionnaires. EXPOSURES: Medical histories of maternal noncommunicable diseases, including obesity, hypertension, diabetes mellitus, kidney disease, hyperthyroidism, hypothyroidism, psychiatric disease, epilepsy, cancer, and autoimmune disease. OUTCOMES: CAKUT diagnosed during the first 3 years of life, classified as isolated or complicated. ANALYTICAL APPROACH: Multivariable Poisson regression with generalized estimating equations accounting for clustering by clinical center. RESULTS: Among the 100,239 children, 560 (0.6%) had CAKUT, comprising 454 (81%) isolated and 106 (19%) complicated forms. The risk of isolated CAKUT was increased in children of mothers who experienced kidney disease (adjusted risk ratio [RR], 1.80 [95% CI, 1.12-2.91]) or cancer (RR, 2.11 [95% CI, 1.15-3.86]). Furthermore, the risk of complicated CAKUT was increased in children of mothers with diabetes mellitus (RR, 3.04 [95% CI, 1.64-5.61]). LIMITATIONS: Lack of standardization or prespecification of clinical definitions, diagnostic criteria, measurements, and testing. Genetic testing was not performed. CONCLUSIONS: Isolated CAKUTs and complicated CAKUTs were associated with different maternal diseases. The results may inform clinical management of pregnancy and highlight potential differences in the genesis of isolated and complicated forms of CAKUT.
Assuntos
Sistema Urinário , Anormalidades Urogenitais , Criança , Gravidez , Feminino , Humanos , Japão/epidemiologia , Estudos Prospectivos , Estudos de Coortes , Sistema Urinário/anormalidades , Rim/anormalidades , Anormalidades Urogenitais/epidemiologia , Doença CrônicaRESUMO
Adult nephrologists often look after patients who have been diagnosed with kidney disease in childhood. This does present unique challenges to the adult nephrologist, who may be unfamiliar with the underlying cause of kidney disease as well as the complications of chronic kidney disease (CKD) that may have accumulated during childhood. This review discusses common causes of childhood CKD, in particular congenital anomalies of the kidney and urinary tract (CAKUT), autosomal dominant tubulointerstitial kidney disease (ADTKD), polycystic kidney disease, hereditary stone disease, nephrotic syndrome and atypical haemolytic uraemic syndrome. The long-term consequences of childhood CKD, such as the cardiovascular consequences, cognition and education as well as bone health, nutrition and growth are also discussed.
Assuntos
Nefrologia , Doenças Renais Policísticas , Insuficiência Renal Crônica , Sistema Urinário , Adulto , Criança , Humanos , Rim/anormalidades , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/terapia , Sistema Urinário/anormalidadesRESUMO
BACKGROUND: Urinary screening for 3-year-olds cannot adequately detect congenital anomalies of the kidney and urinary tract (CAKUT). METHODS: Urinary screening for 3-year-olds was investigated over 30 years. Dipsticks for proteinuria, hematuria, glycosuria, leukocyturia, and nitrite at first screening, and dipsticks, urinary sediments, and renal ultrasonography at second screening were performed. Screening results were evaluated. RESULTS: The positive rates of proteinuria, hematuria, leukocyturia, and nitrite relative to 218,831 children at the first screening were 1.0%, 4.6%, 2.3%, and 0.88%, respectively. Thirty-seven glomerular disease, 122 CAKUT, and 5 urological disease cases were found. We detected 6 stage 3-4 chronic kidney disease (CKD) and 3 end-stage kidney disease cases, including 3 CAKUT, comprising 2 bilateral renal hypoplasia and 1 vesicoureteral reflux (VUR), and 6 glomerular diseases, comprising 4 focal segmental glomerulosclerosis and 2 Alport syndrome. The positive rates relative to 218,831 children and CKD detection rates for each tentative diagnosis of mild hematuria, severe hematuria, proteinuria and hematuria, proteinuria, and suspected urinary tract infection were 1.4% and 0.67%, 0.11% and 3.7%, 0.01% and 28.6%, 0.02% and 45.0%, and 0.08% and 9.7%, respectively. Among 14 VUR cases with significant bacteriuria, 13 were found by leukocyturia, 12 had grade ≥ IV VUR, and 10 had severe renal scars. CONCLUSIONS: Nine stage 3-5 CKD cases comprising 3 CAKUT and 6 glomerular disease were found by urinary screening of 3-year-olds among 218,831 children. The combination of urine dipsticks including leukocyturia at the first screening and ultrasonography at the second screening appeared useful.
Assuntos
Falência Renal Crônica , Insuficiência Renal Crônica , Refluxo Vesicoureteral , Criança , Humanos , Pré-Escolar , Hematúria/diagnóstico por imagem , Hematúria/etiologia , Nitritos , Rim/diagnóstico por imagem , Rim/anormalidades , Refluxo Vesicoureteral/diagnóstico , Ultrassonografia , Insuficiência Renal Crônica/diagnóstico por imagem , Insuficiência Renal Crônica/epidemiologia , Proteinúria/diagnóstico por imagemRESUMO
BACKGROUND: Non-syndromic congenital anomalies of kidney and urinary tract (CAKUT) are usually sporadic in nature but familial clustering of cases have been observed suggesting a genetic predisposition to this condition. We aimed to determine the frequency and pattern of renal anomalies in first-degree relatives of children with non-syndromic CAKUT. METHODS: We screened all the first-degree relatives of children with CAKUT. A total of 149 first-degree relatives, belonging to 62 families were screened with ultrasonography. RESULTS: A renal anomaly was detected in 9 out of the 62 families. Two of these nine families had identical anomalies (child and a parent) indicating single-gene disorders with possible autosomal dominant inheritance, while the rest of families had a non-identical anomaly. The anomalies detected in the first-degree relatives were renal hypodysplasia (n = 2), multicystic dysplastic kidney (n = 3), pelviureteric junction obstruction (n = 2) and mild hydronephrosis (n = 2). The incidence of a sonographically detected anatomic renal anomaly in first-degree relatives of children with CAKUT was found to be 6.0%. Familial cystic kidney disease was found in two out of the 4 families with cystic kidney disease. CONCLUSION: Significant renal anomalies were identified in first-degree relatives of children with non-syndromic CAKUT and hence, attempts must be made to screen the family members of children with non-syndromic CAKUT.
Assuntos
Rim/anormalidades , Sistema Urinário/anormalidades , Criança , Pré-Escolar , Estudos Transversais , Família , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
RATIONALE & OBJECTIVE: Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders. STUDY DESIGN: Cross-sectional cohort study. SETTING & PARTICIPANTS: 174 unrelated patients were recruited for exome sequencing and categorized into 7 disease groups according to their clinical presentation. They included autosomal dominant tubulointerstitial kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, ciliopathy, focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome, VACTERL association, and "other." RESULTS: A genetic diagnosis (either likely pathogenic or pathogenic variant according to the guidelines of the American College of Medical Genetics) was established using exome sequencing in 52 of 174 (30%) cases. A phenocopy was identified for 10 of the 52 exome sequencing-solved cases (19%), representing 6% of the total cohort. The most frequent phenocopies (n=5) were associated with genetic Alport syndrome presenting clinically as focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. Strictly targeted gene panels (<25 kilobases) did not identify any of the phenocopy cases. LIMITATIONS: The spectrum of described phenocopies is small. Selection bias may have altered the diagnostic yield within disease groups in our study population. The study cohort was predominantly of non-Finnish European descent, limiting generalizability. Certain hereditary kidney diseases cannot be diagnosed by using exome sequencing (eg, MUC1-autosomal dominant tubulointerstitial kidney disease). CONCLUSIONS: Phenocopies led to the recategorization of disease and altered clinical management. This study highlights that exome sequencing can detect otherwise occult genetic heterogeneity of kidney diseases.
Assuntos
Sequenciamento do Exoma , Nefropatias/genética , Fenótipo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole-exome sequencing (WES) and trio-WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio-WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.
Assuntos
Exoma/genética , Predisposição Genética para Doença , Doenças Renais Císticas/genética , Insuficiência Renal Crônica/genética , Criança , Pré-Escolar , China/epidemiologia , Estudos de Coortes , Feminino , Testes Genéticos , Humanos , Rim/metabolismo , Rim/patologia , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/patologia , Masculino , Fenótipo , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/patologia , Sistema Urinário/metabolismo , Sistema Urinário/patologia , Sequenciamento do ExomaRESUMO
BACKGROUND: The purpose of this study was to resolve the clinical question as to whether all patients with unilateral multicystic dysplastic kidney (MCDK) should receive voiding cystourethrography (VCUG). METHODS: This is a retrospective study using cross-sectional analysis. Seventy-five children with unilateral MCDK were enrolled, excluding patients with other genetic or chromosome abnormalities, spinal cord diseases, or anal atresia. We reviewed their records from medical charts and calculated risk factors for abnormal VCUG using multivariate logistic regression analysis. RESULTS: Abnormal VCUG findings were present in 24 of 75 patients (32.0%), specifically, vesicoureteral reflux (VUR) in 8 (10.6%), including high-grade VUR in 2 (2.7%), and only lower urinary tract or bladder disease in 16 (21.3%). In multivariate analysis, only abnormal findings by ultrasonography was an independent risk factor for abnormal VCUG findings with statistical significance in multivariate analysis (OR 6.57; 95% CI 1.99-26.26; P = 0.002). When we excluded five patients who showed similar findings by ultrasonography and VCUG, abnormal findings by ultrasonography were again calculated as an independent risk factor (OR 4.44; 95% CI 1.26-28.42; P = 0.02). Sensitivity, specificity, positive predictive value, and negative predictive value of abnormal findings by ultrasonography to predict urologic anomalies by VCUG in these children were 83%, 59%, 49%, and 88%, respectively. Two children required a third ultrasonography to detect abnormal findings. CONCLUSIONS: We can select, using only abnormal findings by ultrasonography, children with unilateral MCDK who should undergo VCUG. We would also like to emphasize that ultrasonography should be performed repeatedly to detect congenital anomalies of the urinary tract.
Assuntos
Cistografia , Rim Displásico Multicístico/complicações , Uretra/diagnóstico por imagem , Bexiga Urinária/diagnóstico por imagem , Refluxo Vesicoureteral/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Imageamento por Ressonância Magnética , Masculino , Análise Multivariada , Seleção de Pacientes , Estudos Retrospectivos , Fatores de Risco , Ultrassonografia , Uretra/fisiopatologia , Bexiga Urinária/fisiopatologia , Micção/fisiologia , Refluxo Vesicoureteral/etiologia , Refluxo Vesicoureteral/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT. METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT. RESULTS: In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%). CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.
Assuntos
Sequenciamento do Exoma/métodos , Predisposição Genética para Doença/epidemiologia , Linhagem , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Animais , Humanos , Incidência , Rim/anormalidades , Camundongos , Fenótipo , Prognóstico , Medição de Risco , Sensibilidade e Especificidade , Distribuição por Sexo , Sistema Urinário/anormalidades , Anormalidades Urogenitais/epidemiologia , Refluxo Vesicoureteral/epidemiologiaRESUMO
Chronic kidney disease (CKD) is becoming a global burden, despite recent advances in management. CKD can begin in early life by so-called "developmental programming" or "developmental origins of health and disease" (DOHaD). Early-life insults cause structural and functional changes in the developing kidney, which is called renal programming. Epidemiological and experimental evidence supports the proposition that early-life adverse events lead to renal programming and make subjects vulnerable to developing CKD and its comorbidities in later life. In addition to low nephron endowment, several mechanisms have been proposed for renal programming. The DOHaD concept opens a new window to offset the programming process in early life to prevent the development of adult kidney disease, namely reprogramming. Here, we review the key themes on the developmental origins of CKD. We have particularly focused on the following areas: evidence from human studies support fetal programming of kidney disease; insight from animal models of renal programming; hypothetical mechanisms of renal programming; alterations of renal transcriptome in response to early-life insults; and the application of reprogramming interventions to prevent the programming of kidney disease.
Assuntos
Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Epigênese Genética , Regulação da Expressão Gênica , Glucocorticoides/metabolismo , Humanos , Estresse Oxidativo , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/prevenção & controle , Sistema Renina-Angiotensina , Fatores Sexuais , Canais de Sódio/metabolismo , Sistema Nervoso Simpático , TranscriptomaRESUMO
World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. Chronic kidney disease (CKD) in childhood differs from that in adults, as the largest diagnostic group among children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease in the setting of diabetes being relatively uncommon. In addition, many children with acute kidney injury will ultimately develop sequelae that may lead to hypertension and CKD in later childhood or in adult life. Children born early, or who are small-for-date newborns, have a relatively increased risk for the development of CKD later in life. Persons with a high-risk birth and early childhood history should be watched closely in order to help detect early signs of kidney disease in time to provide effective prevention or treatment. Successful therapy is feasible for advanced CKD in childhood; there is evidence that children fare better than adults if they receive kidney replacement therapy including dialysis and transplantation, while only a minority of children may require this ultimate intervention. Because there are disparities in access to care, effort is needed so that those children with kidney disease, wherever they live, may be treated effectively, irrespective of their geographic or economic circumstances. Our hope is that World Kidney Day will inform the general public, policy-makers, and caregivers about the needs and possibilities surrounding kidney disease in childhood.
Assuntos
Saúde Global , Promoção da Saúde , Insuficiência Renal Crônica/terapia , Idade de Início , Progressão da Doença , Acessibilidade aos Serviços de Saúde , Disparidades em Assistência à Saúde , Humanos , Prognóstico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/genética , Fatores de Risco , Transição para Assistência do AdultoRESUMO
UNLABELLED: Congenital anomalies of the kidney and urinary tract are common findings on fetal ultrasound. The aim of this prospective observational study was to describe outcome and risk factors in 115 patients born 1995-2001. All prenatally diagnosed children were stratified into low- and high-risk group and followed postnatally clinically and by imaging at defined endpoints. Risk factors were evaluated using odds ratios. Neonatal diagnosis included pelvi-ureteric junction obstruction (n = 33), vesicoureteral reflux (n = 27), solitary mild pelvic dilatation (postnatal anteroposterior diameter 5-10 mm; n = 25), and further diagnosis as primary obstructive megaureter, unilateral multicystic dysplastic kidney, renal dysplasia and posterior urethral valves. In 38 children with prenatal isolated hydronephrosis, ultrasound normalized at median age of 1.2 years (range 0.1-9). Surgery was performed in 34 children at median age of 0.4 years (0.1-10.8). Persistent renal anomalies without surgery were present in 43 children and followed in 36 for median time of 16 years (12.2-18). Oligohydramnios and postnatal bilateral anomalies were significantly associated with surgery and impaired renal function. CONCLUSION: The majority of children had a favourable postnatal outcome, in particular children with prenatally low risk, i.e. isolated uni- or bilateral hydronephrosis. Oligohydramnios and postnatal bilateral anomalies were risk factors for non-favourable outcome. WHAT IS KNOWN: ⢠In congenital anomalies of the kidney and urinary tract significantly poorer outcome is known in patients with bilateral renal hypoplasia or solitary kidney associated with posterior urethral valves. ⢠Other factors as proteinuria and vesicoureteral reflux were associated with a higher risk of progression to chronic renal failure in these patients. What is New: ⢠Unlike other studies giving us above-mentioned information, we included all patients with any kind of prenatally diagnosed congenital anomalies of the kidney and urinary tract. Our study shows long-term follow up (median 16 years, range 12.2-18 years), especially in patients not needing surgery, but with persistent anomalies. ⢠During postnatal long-term follow up (median 2.2 years, range 0.1-18 years) one third each showed normalization, need of surgery or persistence of anomalies without need of surgery. Our study revealed a good prognosis in the majority of these children, in particular with prenatally low risk, i.e. isolated uni- or bilateral hydronephrosis, and revealed oligohydramnios and postnatal bilateral anomalies as risk factors for a non-favourable outcome, defined as need of surgery, persistent anomalies with impaired renal function, end stage renal failure or death.
Assuntos
Nefropatias/diagnóstico , Rim/anormalidades , Diagnóstico Pré-Natal/métodos , Sistema Urinário/anormalidades , Doenças Urológicas/diagnóstico , Adulto , Causas de Morte/tendências , Feminino , Seguimentos , Humanos , Incidência , Recém-Nascido , Rim/diagnóstico por imagem , Nefropatias/congênito , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/etiologia , Masculino , Gravidez , Estudos Prospectivos , Fatores de Risco , Suíça/epidemiologia , Ultrassonografia Pré-Natal/métodos , Sistema Urinário/diagnóstico por imagem , Urografia/métodos , Doenças Urológicas/complicações , Doenças Urológicas/congênitoRESUMO
BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the primary cause of chronic kidney disease in children. The relevance of timing of diabetes mellitus (DM) exposure on risk of CAKUT in exposed children is unknown. STUDY DESIGN: Population-based nested case-control study. SETTING & PARTICIPANTS: Infants born between fiscal years 1996/1997 and 2009/2010 in Manitoba, Canada, identified using administrative data housed at the Manitoba Centre for Health Policy. PREDICTORS: Pregestational (including first 20 weeks' gestation) and gestational (>20 weeks) DM and relevant confounders (maternal age; renin-angiotensin-aldosterone system inhibitor use; low socioeconomic status; alcohol, illicit drug, and smoking use during pregnancy; region of residence; and size for gestational age [surrogate of glycemic control]). OUTCOME: CAKUT identified by International Classification of Diseases codes. RESULTS: 945 case patients with CAKUT and 4,725 controls (matched for gestational age, sex, and birth year) were identified. Maternal pregestational DM occurred in 39 (4.1%) of the CAKUT group and 111 (2.3%) controls (P = 0.002), whereas gestational DM occurred in 40 (4.2%) of the CAKUT group and 157 (3.3%) controls (P = 0.2). In the conditional multivariable logistic regression model, pregestational DM was associated with CAKUT (OR, 1.67; 95% CI, 1.14-2.46), whereas gestational DM was not (OR, 1.29; 95% CI, 0.90-1.85). Both large (LGA) and small for gestational age (SGA) also were associated significantly with CAKUT (LGA: OR, 1.34 [95% CI, 1.11-1.63]; SGA: OR, 1.59 [95% CI, 1.26-2.01]). LIMITATIONS: Lack of data for maternal glycemic control and body mass index. CONCLUSIONS: This study suggests that DM in the first 20 weeks of pregnancy is associated with CAKUT in exposed infants. The association between CAKUT and LGA suggests that poor glycemic control increases risk. Screening and intervention studies in women of childbearing age with DM are warranted to determine whether the risk of chronic kidney disease in children can be modified.
Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Gestacional/epidemiologia , Gravidez em Diabéticas/epidemiologia , Refluxo Vesicoureteral/epidemiologia , Adulto , Criança , Comorbidade , Feminino , Humanos , Modelos Logísticos , Masculino , Gravidez , Anormalidades UrogenitaisRESUMO
Abnormalities in renal fusion represent a subset of congenital anomalies of the kidneys and urinary tract (CAKUT). Horseshoe kidneys (HSKs) are the fusion of kidneys at their lower poles. It is the most common form of CAKUT. Symptoms are usually subtle. The diagnosis is usually made incidentally during childhood. Rarely does an HSK become symptomatic later in life. We present the case of an 88-year-old female with a history of HSK who presented to the emergency department (ED) with a three-week history of left-sided flank pain, intermittent nausea, and reduced urine output. Her inpatient workup included imaging that revealed an HSK and bilateral hydronephrosis, which was more prominent on the left. The onset of symptoms for an HSK late in life is extremely rare.
RESUMO
BACKGROUND: Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of prenatally diagnosed developmental malformation. This study aimed to assess the relationship between maternal diseases and CAKUT in offspring. METHODS: This retrospective study enrolled all pregnant women registered from January 2020 to December 2022 at one medical center. Medical information on maternal noncommunicable diseases, including obesity, hypertension, diabetes mellitus, kidney disease, hyperthyroidism, hypothyroidism, psychiatric disease, epilepsy, cancer, and autoimmune disease was collected. Based on the records of ultrasound scanning during the third trimester, the diagnosis was classified as isolated urinary tract dilation (UTD) or kidney anomalies. Multivariate logistic regression was performed to establish models to predict antenatal CAKUT. RESULTS: Among the 19,656 pregnant women, perinatal ultrasound detected suspicious CAKUT in 114 (5.8/1000) fetuses, comprising 89 cases with isolated UTD and 25 cases with kidney anomalies. The risk of antenatal CAKUT was increased in the fetuses of mothers who experienced gestational diabetes, thyroid dysfunction, neuropsychiatric disease, anemia, ovarian and uterine disorders. A prediction model for isolated UTD was developed utilizing four confounding factors, namely gestational diabetes, gestational hypertension, maternal thyroid dysfunction, and hepatic disease. Similarly, a separate prediction model for kidney anomalies was established based on four distinct confounding factors, namely maternal thyroid dysfunction, gestational diabetes, disorders of ovarian/uterine, and kidney disease. CONCLUSIONS: Isolated UTD and kidney anomalies were associated with different maternal diseases. The results may inform the clinical management of pregnancy and highlight potential differences in the genesis of various subtypes of CAKUT.
RESUMO
PURPOSE: To evaluate the impact of surgical intervention on long-term renal outcomes for adult patients with congenital ureteropelvic junction obstruction (UPJO). METHODS: We queried service members diagnosed with UPJO from the United States Military Health System electronic health records from 2005 to 2020. We assessed demographic, laboratory, radiology, surgical intervention, and outcome data. We evaluated the impact of surgical intervention on renal function based on the estimated glomerular filtration rate (eGFR), hypertension (HTN, defined as any prescription for blood pressure [BP] medication and/or average of two BP readings ≥ 130/80 mmHg more than 2 weeks apart), and changes in renal excretory function on radionuclide scans. RESULTS: We identified 108 individuals diagnosed with congenital UPJO; mean follow-up of 7 years. Mean age at diagnosis was 25 years; 95% male; 69% White, 15% Black. At diagnosis, median BP was 130/78 mmHg and mean eGFR 93 ml/min/1.73m2. Subsequently, 85% had pyeloplasty and 23% had stent placement. There were no significant differences in mean eGFR pre- and post-intervention (94 vs. 93 ml/min/1.73m2, respectively; p = 0.15) and prevalence of defined HTN (59% vs. 61%, respectively; p = 0.20). Surgical intervention for right-sided UPJO significantly reduced the proportion of patients with delayed cortical excretion (54% pre vs. 35% post, p = 0.01) and T½ emptying time (35 min vs. 19 min, p = 0.009). Similar trends occurred with left-sided UPJO but were not significant. CONCLUSION: Surgical intervention was not associated with significant differences in the long-term outcomes of kidney function and HTN prevalence in our young adult cohort. However, renal excretory function improved on radionuclide scans.
RESUMO
The global prevalence of chronic kidney disease (CKD) is increasing rapidly, due to increasing environmental stressors through the life cycle. Congenital anomalies of kidney and urinary tract (CAKUT) account for most CKD in children, with a spectrum that can lead to kidney failure from early postnatal to late adult life. A stressed fetal environment can impair nephrogenesis, now recognized as a significant risk factor for the development of adult CKD. Congenital urinary tract obstruction is the leading cause of CKD due to CAKUT and can itself impair nephrogenesis as well as contribute to progressive nephron injury. Early diagnosis by ultrasonography in fetal life by an obstetrician/perinatologist can provide important information for guiding prognosis and future management. This review focuses on the critical role played by the pediatrician in providing timely evaluation and management of the patient from the moment of birth to the transfer to adult care. In addition to genetic factors, vulnerability of the kidney to CKD is a consequence of evolved modulation of nephron number in response to maternal signaling as well as to susceptibility of the nephron to hypoxic and oxidative injury. Future advances in the management of CAKUT will depend on improved biomarkers and imaging techniques.