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SIGNIFICANCE STATEMENT: Pathogenic structural genetic variants, also known as genomic disorders, have been associated with pediatric CKD. This study extends those results across the lifespan, with genomic disorders enriched in both pediatric and adult patients compared with controls. In the Chronic Renal Insufficiency Cohort study, genomic disorders were also associated with lower serum Mg, lower educational performance, and a higher risk of death. A phenome-wide association study confirmed the link between kidney disease and genomic disorders in an unbiased way. Systematic detection of genomic disorders can provide a molecular diagnosis and refine prediction of risk and prognosis. BACKGROUND: Genomic disorders (GDs) are associated with many comorbid outcomes, including CKD. Identification of GDs has diagnostic utility. METHODS: We examined the prevalence of GDs among participants in the Chronic Kidney Disease in Children (CKiD) cohort II ( n =248), Chronic Renal Insufficiency Cohort (CRIC) study ( n =3375), Columbia University CKD Biobank (CU-CKD; n =1986), and the Family Investigation of Nephropathy and Diabetes (FIND; n =1318) compared with 30,746 controls. We also performed a phenome-wide association analysis (PheWAS) of GDs in the electronic MEdical Records and GEnomics (eMERGE; n =11,146) cohort. RESULTS: We found nine out of 248 (3.6%) CKiD II participants carried a GD, replicating prior findings in pediatric CKD. We also identified GDs in 72 out of 6679 (1.1%) adult patients with CKD in the CRIC, CU-CKD, and FIND cohorts, compared with 199 out of 30,746 (0.65%) GDs in controls (OR, 1.7; 95% CI, 1.3 to 2.2). Among adults with CKD, we found recurrent GDs at the 1q21.1, 16p11.2, 17q12, and 22q11.2 loci. The 17q12 GD (diagnostic of renal cyst and diabetes syndrome) was most frequent, present in 1:252 patients with CKD and diabetes. In the PheWAS, dialysis and neuropsychiatric phenotypes were the top associations with GDs. In CRIC participants, GDs were associated with lower serum magnesium, lower educational achievement, and higher mortality risk. CONCLUSION: Undiagnosed GDs are detected both in children and adults with CKD. Identification of GDs in these patients can enable a precise genetic diagnosis, inform prognosis, and help stratify risk in clinical studies. GDs could also provide a molecular explanation for nephropathy and comorbidities, such as poorer neurocognition for a subset of patients.
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Longevidad , Insuficiencia Renal Crónica , Humanos , Estudios de Cohortes , Estudios Prospectivos , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/complicaciones , Genómica , Progresión de la Enfermedad , Factores de RiesgoRESUMEN
BACKGROUND: Preparing children with chronic kidney disease (CKD) for renal replacement therapy (RRT) begins with a discussion about transplant and dialysis, but its typical timing in the course of CKD management is unclear. We aimed to describe participant-reported RRT planning discussions by CKD stage, clinical and sociodemographic characteristics, in the Chronic Kidney Disease in Children (CKiD) cohort. METHODS: Participants responded to the question "In the past year, have you discussed renal replacement therapy with your doctor or healthcare provider?" at annual study visits. Responses were linked to the previous year CKD risk stage based on GFR and proteinuria. Repeated measure logistic models estimated the proportion discussing RRT by stage, with modification by sex, age, race, socioeconomic status, and CKD diagnosis (glomerular vs. non-glomerular). RESULTS: A total of 721 CKiD participants (median age = 12, 62% boys) contributed 2856 person-visits. Proportions of person-visits reporting RRT discussions increased as CKD severity increased (10% at the lowest disease stage and 87% at the highest disease stage). After controlling for CKD risk stage, rates of RRT discussions did not differ by sex, age, race, and socioeconomic status. CONCLUSIONS: Despite participant-reported RRT discussions being strongly associated with CKD severity, a substantial proportion with advanced CKD reported no discussion. While recall bias may lead to underreporting, it is still meaningful that some participants with severe CKD did not report or remember discussing RRT. Initiating RRT discussions early in the CKD course should be encouraged to foster comprehensive preparation and to align RRT selection for optimal health and patient preferences.
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Comunicación , Toma de Decisiones Conjunta , Prioridad del Paciente/estadística & datos numéricos , Insuficiencia Renal Crónica/terapia , Terapia de Reemplazo Renal/psicología , Adolescente , Niño , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Estudios Longitudinales , Masculino , Nefrólogos/estadística & datos numéricos , Relaciones Médico-Paciente , Estudios Prospectivos , Calidad de Vida , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/psicología , Terapia de Reemplazo Renal/efectos adversos , Terapia de Reemplazo Renal/estadística & datos numéricos , Autoinforme/estadística & datos numéricos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Adulto JovenRESUMEN
DNA is now commonly collected in clinical research either for immediate genomic analyses or stored for future studies. Many genomic studies were previously designed without awareness of the ethical issues that might arise regarding the disclosure of genomic test results. At the start of the Chronic Kidney Disease in Children (CKiD) Cohort Study in 2004, we did not foresee the advent of genomic technology or the associated ethical issues pertaining to genetic research in children. Recent genomic studies and ancillary proposals using genomic technology stimulated the CKiD investigators to reassess the current ethical and policy environment pertaining to genomic testing and results disclosure. We consider the issues pertaining to next generation sequencing and individual results disclosure that may guide current and future research practices.
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Pruebas Genéticas/ética , Secuenciación de Nucleótidos de Alto Rendimiento/ética , Investigación Cualitativa , Insuficiencia Renal Crónica/genética , Adolescente , Niño , Preescolar , Femenino , Predicción , Pruebas Genéticas/tendencias , Genómica/ética , Política de Salud , Secuenciación de Nucleótidos de Alto Rendimiento/tendencias , Humanos , Consentimiento Informado , Masculino , Pediatría/métodos , Formulación de Políticas , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiología , Proyectos de Investigación , Revelación de la Verdad , Estados UnidosRESUMEN
BACKGROUND: Genome-wide association studies (GWAS) in healthy populations have identified variants associated with erythrocyte traits, but genetic causes of hemoglobin variation in children with CKD are incompletely understood. METHODS: The Pediatric Investigation of Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE), and Cardiovascular Comorbidity in Children with CKD (4C). We performed cross-sectional and longitudinal association studies of single-nucleotide polymorphisms (SNPs) in 1125 patients. RESULTS: Children of European (n = 725) or Turkish (n = 400) ancestry (EA or TA) were included. In cross-sectional analysis, two SNPs (rs10758658 and rs12718597) previously associated with RBC traits were significantly associated with hemoglobin levels in children of EA and TA. In longitudinal analysis, SNP rs2540917 was nominally associated with hemoglobin in EA and TA children. CONCLUSIONS: SNPs associated with erythrocyte traits in healthy populations were marginally significant for an association with hemoglobin. Further analyses/replication studies are needed in larger CKD cohorts to investigate SNPs of unknown significance associated with hemoglobin. Functional studies will be required to confirm that the observed associations between SNPs and clinical phenotype are causal.
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Hemoglobinas/genética , Fallo Renal Crónico/sangre , Fallo Renal Crónico/genética , Polimorfismo de Nucleótido Simple , Adolescente , Presión Sanguínea , Niño , Estudios Transversales , Eritrocitos/metabolismo , Europa (Continente) , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Tasa de Filtración Glomerular , Haplotipos , Humanos , Fallo Renal Crónico/etnología , Estudios Longitudinales , Masculino , Fenotipo , TurquíaRESUMEN
RATIONALE & OBJECTIVE: The KDIGO (Kidney Disease: Improving Global Outcomes) guideline for chronic kidney disease (CKD) presented an international classification system that ranks patients' risk for CKD progression. Few data for children informed guideline development. STUDY DESIGN: Observational cohort study. SETTINGS & PARTICIPANTS: Children aged 1 to 18 years enrolled in the North American Chronic Kidney Disease in Children (CKiD) cohort study and the European Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) trial. PREDICTOR: Level of estimated glomerular filtration rate (eGFR) and proteinuria (urine protein-creatinine ratio [UPCR]) at study entry. OUTCOME: A composite event of renal replacement therapy, 50% reduction in eGFR, or eGFR<15mL/min/1.73m2. eGFR was estimated using the CKiD-derived "bedside" equation. ANALYTICAL APPROACH: Accelerated failure time models of the composite outcome using a conventional generalized gamma distribution. Likelihood ratio statistics of nested models were used to amalgamate levels of similar risk. RESULTS: Among 1,232 children, median age was 12 (IQR, 8-15) years, median eGFR was 47 (IQR, 33-62) mL/min/1.73m2, 60% were males, and 13% had UPCRs>2.0mg/mg at study entry. 6 ordered stages with varying combinations of eGFR categories (60-89, 45-59, 30-44, and 15-29mL/min/1.73m2) and UPCR categories (<0.5, 0.5-2.0, and >2.0mg/mg) described the risk continuum. Median times to event ranged from longer than 10 years for eGFRs of 45 to 90mL/min/1.73m2 and UPCRs<0.5mg/mg to 0.8 years for eGFRs of 15 to 30mL/min/1.73m2 and UPCRs>2mg/mg. Children with glomerular disease were estimated to have a 43% shorter time to event than children with nonglomerular disease. Cross-validation demonstrated risk patterns that were consistent across the 10 subsample validation models. LIMITATIONS: Observational study, used cross-validation rather than external validation. CONCLUSIONS: CKD staged by level of eGFR and proteinuria characterizes the timeline of progression and can guide management strategies in children.
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Progresión de la Enfermedad , Fallo Renal Crónico/etiología , Proteinuria/diagnóstico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/diagnóstico , Adolescente , Factores de Edad , Niño , Preescolar , Estudios de Cohortes , Bases de Datos Factuales , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Lactante , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/terapia , Pruebas de Función Renal , América del Norte , Proteinuria/epidemiología , Diálisis Renal/métodos , Insuficiencia Renal Crónica/terapia , Medición de Riesgo , Factores Sexuales , Factores de Tiempo , Resultado del TratamientoRESUMEN
Children with CKD are at increased risk for neurocognitive impairment, but whether neurocognitive dysfunction is solely attributable to impaired renal function is unclear. Data from the CKD in Children Study Chronic Kidney Disease in Children (CKiD) Study indicate that a subset of children with CKD have unsuspected genomic disorders that predispose them to organ malformations and neurocognitive impairment. We therefore tested whether the CKiD Study participants with genomic disorders had impaired neurocognitive performance at enrollment. Compared with noncarriers (n=389), children with genomic disorders (n=31) scored significantly poorer on all measures of intelligence, anxiety/depressive symptoms, and executive function (differences of 0.6-0.7 SD; P=1.2×10-3-2.4×10-4). These differences persisted after controlling for known modifiers, including low birth weight, maternal education, seizure disorder, kidney disease duration, and genetically defined ancestry. The deleterious effect of genomic disorders on neurocognitive function was significantly attenuated in offspring of mothers with higher education, indicating the potential for modification by genetic and/or environmental factors. These data indicate that impaired neurocognitive function in some children with CKD may be attributable to genetic lesions that affect both kidney and neurocognitive development. Early identification of genomic disorders may provide opportunity for early diagnosis and personalized interventions to mitigate the effect on neurocognitive function.
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Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/genética , Enfermedades Genéticas Congénitas/complicaciones , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades del Sistema Nervioso/genética , Insuficiencia Renal Crónica/complicaciones , Niño , Femenino , Genómica , Humanos , MasculinoRESUMEN
BACKGROUND: Chronic kidney disease (CKD) in children is characterized by rapid progression and a high incidence of end-stage renal disease and therefore constitutes an important health problem. While unbiased genetic screens have identified common risk variants influencing renal function and CKD in adults, the presence and identity of such variants in pediatric CKD are unknown. METHODS: The international Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) and Cardiovascular Comorbidity in Children with CKD (4C). Clean genotype data from > 10 million genotyped or imputed single-nucleotide polymorphisms (SNPs) were available for 1136 patients with measurements of serum creatinine at study enrollment. Genome-wide association studies were conducted to relate the SNPs to creatinine-based estimated glomerular filtration rate (eGFR crea) and proteinuria (urinary albumin- or protein-to-creatinine ratio ≥ 300 and ≥ 500 mg/g, respectively). In addition, European-ancestry PediGFR patients (cases) were compared with 1347 European-ancestry children without kidney disease (controls) to identify genetic variants associated with the presence of CKD. RESULTS: SNPs with suggestive association P-values < 1 × 10(-5) were identified in 10 regions for eGFR crea, four regions for proteinuria and six regions for CKD including some plausible biological candidates. No SNP was associated at genome-wide significance (P < 5 × 10(-8)). Investigation of the candidate genes for proteinuria in adults from the general population provided support for a region on chromosome 15 near RSL24D1/UNC13C/RAB27A. Conversely, targeted investigation of genes harboring GFR-associated variants in adults from the general population did not reveal significantly associated SNPs in children with CKD. CONCLUSIONS: Our findings suggest that larger collaborative efforts will be needed to draw reliable conclusions about the presence and identity of common variants associated with eGFR, proteinuria and CKD in pediatric populations.
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Estudio de Asociación del Genoma Completo/métodos , Tasa de Filtración Glomerular/fisiología , Polimorfismo de Nucleótido Simple , Insuficiencia Renal Crónica/genética , Adolescente , Niño , Preescolar , Progresión de la Enfermedad , Europa (Continente)/epidemiología , Femenino , Sitios Genéticos , Genotipo , Humanos , Lactante , Masculino , Morbilidad/tendencias , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/fisiopatología , Factores de RiesgoRESUMEN
The genome-wide association study (GWAS) has become an established scientific method that provides an unbiased screen for genetic loci potentially associated with phenotypes of clinical interest, such as chronic kidney disease (CKD). Thus, GWAS provides opportunities to gain new perspectives regarding the genetic architecture of CKD progression by identifying new candidate genes and targets for intervention. As such, it has become an important arm of translational science providing a complementary line of investigation to identify novel therapeutics to treat CKD. In this review, we describe the method and the challenges of performing GWAS in the pediatric CKD population. We also provide an overview of successful GWAS for kidney disease, and we discuss the established pediatric CKD cohorts in North America and Europe that are poised to identify genetic risk variants associated with CKD progression.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Insuficiencia Renal Crónica/genética , Niño , HumanosRESUMEN
OBJECTIVE: Reliable identification of individuals at risk for developing diabetes is critical to instituting preventative strategies. Studies suggest that the accuracy of using hemoglobin A1c as a sole diagnostic criterion for diabetes may be variable across different ethnic groups. We postulate that there will be lack of concordance between A1c and the oral glucose tolerance test (OGTT) for diagnosing prediabetes across Hispanic and non-Hispanic white (NHW) populations. METHODS: A total of 218 asymptomatic adults at risk for type 2 diabetes (T2D) were assessed with A1c and OGTT for the diagnosis of prediabetes. Glucose homeostasis status was assigned as no diabetes (A1c <5.7% [39 mmol/mol]), prediabetes (A1c 5.7 to 6.4% [46 mmol/mol]), and T2D (A1c >6.4% [46 mmol/mol]). Inclusion criteria were age >18 years and at least one of the following: a family history of diabetes, a history of gestational diabetes, Hispanic ethnicity, non-Caucasian race, or obesity. Subjects received a fasting 75-g OGTT and A1c on the same day. Bowker's test of symmetry was employed to determine agreement between the tests. RESULTS: Data from 99 Hispanic patients and 79 NHW patients were analyzed. There was no concordance between A1c and OGTT for Hispanic (P = .002) or NHW individuals (P = .003) with prediabetes. CONCLUSION: A1c is discordant with OGTT among Hispanic and NHW subjects for the diagnosis of prediabetes. Sole use of A1c to designate glycemic status will result in a greater prevalence of prediabetes among Hispanic and NHW New Mexicans. ABBREVIATIONS: A1c = hemoglobin A1c BMI = body mass index CDC = Centers for Disease Control CI = confidence interval FPG = fasting plasma glucose NHW = non-Hispanic white OGTT = oral glucose tolerance test T2D = type 2 diabetes WHO = World Health Organization.
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Diabetes Mellitus Tipo 2/sangre , Prueba de Tolerancia a la Glucosa/métodos , Hemoglobina Glucada/análisis , Hispánicos o Latinos , Estado Prediabético/sangre , Población Blanca/etnología , Adulto , Diabetes Mellitus Tipo 2/etnología , Femenino , Prueba de Tolerancia a la Glucosa/normas , Humanos , Masculino , Persona de Mediana Edad , New Mexico/etnología , Estado Prediabético/etnología , Valor Predictivo de las PruebasRESUMEN
Prior to conducting genome-wide association studies (GWAS) of renal traits and diseases, systematic checks to ensure data integrity and analytical work flow should be conducted. Using positive controls (ie, known associations between a single-nucleotide polymorphism [SNP] and a corresponding trait) allows for identifying errors that are not apparent solely from global evaluation of summary statistics. Strong genetic control associations of chronic kidney disease (CKD), as derived from GWAS, are lacking in the non-African ancestry CKD population; thus, in this perspective, we provide examples of and considerations for using positive controls among patients with CKD. Using data from individuals with CKD who participated in the CRIC (Chronic Renal Insufficiency Cohort) Study or PediGFR (Pediatric Investigation for Genetic Factors Linked to Renal Progression) Consortium, we evaluated 2 kinds of positive control traits: traits unrelated to kidney function (bilirubin level and body height) and those related to kidney function (cystatin C and urate levels). For the former, the proportion of variance in the control trait that is explained by the control SNP is the main determinant of the strength of the observable association, irrespective of adjustment for kidney function. For the latter, adjustment for kidney function can be effective in uncovering known associations among patients with CKD. For instance, in 1,092 participants in the PediGFR Consortium, the P value for the association of cystatin C concentrations and rs911119 in the CST3 gene decreased from 2.7×10(-3) to 2.4×10(-8) upon adjustment for serum creatinine-based estimated glomerular filtration rate. In this perspective, we give recommendations for the appropriate selection of control traits and SNPs that can be used for data checks prior to conducting GWAS among patients with CKD.
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Bases de Datos Genéticas , Estudio de Asociación del Genoma Completo/métodos , Nefrología/métodos , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/genética , Bases de Datos Genéticas/normas , Estudio de Asociación del Genoma Completo/normas , Humanos , Nefrología/normas , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: Few studies have prospectively evaluated the progression of chronic kidney disease (CKD) in children and adolescents, as well as factors associated with progression. STUDY DESIGN: Prospective multicenter observational cohort study. SETTING & PARTICIPANTS: 496 children and adolescents with CKD enrolled in the Chronic Kidney Disease in Children (CKiD) Study. PREDICTORS: Proteinuria, hypoalbuminemia, blood pressure, dyslipidemia, and anemia. OUTCOMES: Parametric failure-time models were used to characterize adjusted associations between baseline levels and changes in predictors and time to a composite event of renal replacement therapy or 50% decline in glomerular filtration rate (GFR). RESULTS: 398 patients had nonglomerular disease and 98 had glomerular disease; of these, 29% and 41%, respectively, progressed to the composite event after median follow-ups of 5.2 and 3.7 years, respectively. Demographic and clinical characteristics and outcomes differed substantially according to the underlying diagnosis; hence, risk factors for progression were assessed in stratified analyses, and formal interactions by diagnosis were performed. Among patients with nonglomerular disease and after adjusting for baseline GFR, times to the composite event were significantly shorter with urinary protein-creatinine ratio > 2mg/mg, hypoalbuminemia, elevated blood pressure, dyslipidemia, male sex, and anemia, by 79%, 69%, 38%, 40%, 38%, and 45%, respectively. Among patients with glomerular disease, urinary protein-creatinine ratio >2mg/mg, hypoalbuminemia, and elevated blood pressure were associated with significantly reduced times to the composite event by 94%, 71%, and 67%, respectively. Variables expressing change in patient clinical status over the initial year of the study contributed significantly to the model, which was cross-validated internally. LIMITATIONS: Small number of events in glomerular patients and use of internal cross-validation. CONCLUSIONS: Characterization and modeling of risk factors for CKD progression can be used to predict the extent to which these factors, either alone or in combination, would shorten the time to renal replacement therapy or 50% decline in GFR in children with CKD.
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Anemia/epidemiología , Dislipidemias/epidemiología , Glomerulonefritis/epidemiología , Hipertensión/epidemiología , Hipoalbuminemia/epidemiología , Fallo Renal Crónico/epidemiología , Proteinuria/epidemiología , Insuficiencia Renal Crónica/epidemiología , Adolescente , Niño , Preescolar , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Fallo Renal Crónico/terapia , Masculino , Estudios Prospectivos , Insuficiencia Renal Crónica/fisiopatología , Terapia de Reemplazo Renal , Factores de Riesgo , Factores Sexuales , Factores de TiempoRESUMEN
BACKGROUND/AIMS: Urea clearance during continuous renal replacement therapy (CRRT) is not representative of middle molecular weight solute clearances. We aimed to characterize iohexol, molecular weight 821 Da, clearance during continuous hemofiltration (CH) and continuous hemodialysis (CHD). METHODS: Using an in vitro model, iohexol sieving coefficients (SC) and saturation coefficients (SA) were determined with the M100 membrane at ultrafiltration/dialysate rates of 1, 2, 3, 4, and 6 l/h. Iohexol transmembrane clearance was calculated using the measured SC and SA. RESULTS: During CH, the value of iohexol SC remained approximately 1 at all ultrafiltration rates studied. In contrast, during CHD iohexol the mean SA was 1.02 ± 0.05 at a dialysate rate 1 l/h and decreased significantly with higher dialysate rates to a mean SA of 0.57 ± 0.12 at a dialysate rate of 6 l/h. CONCLUSIONS: At higher effluent flow rates, CH was more effective in removing iohexol than CHD. CH transmembrane clearance of iohexol appears to approximate the ultrafiltration rate.
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Medios de Contraste/metabolismo , Hemofiltración/métodos , Yohexol/metabolismo , Modelos Biológicos , Diálisis Renal/métodos , Animales , Bovinos , Soluciones para Diálisis/química , Hemorreología , Humanos , Cinética , Membranas Artificiales , Ultrafiltración , Urea/sangreRESUMEN
BACKGROUND/AIMS: There is limited data regarding trimethoprim (TMP)/sulfamethoxazole (SMX) continuous renal replacement therapy (CRRT) dosing. We aimed to estimate TMP/SMX transmembrane clearance (CLtm) during continuous hemofiltration (CH) and continuous hemodialysis (CD) to guide dosing. METHODS: Using an in vitro model, TMP/SMX sieving coefficients (SC) and saturation coefficients (SA) were determined with high-flux polyarylethersulfone and polyacrylonitrile-sodium methallyl sulfonate copolymer hemodiafilters at ultrafiltration/dialysate rates of 1, 2, 3, and 6 l/h. TMP/SMX CLtm was calculated using measured SC and SA. TMP/SMX CRRT doses were modeled using CLtm and published TMP/SMX pharmacokinetic parameters. RESULTS: TMP SC/SA during CH/CD were significantly higher than SMX SC/SA. During modeling, TMP 10 mg/kg/day and its corresponding SMX dose, 50 mg/kg/day, resulted in steady state TMP/SMX peak concentrations associated with efficacy against Pneumocystis jirovecii. CONCLUSIONS: CRRT resulted in greater TMP CLtm than SMX. TMP 10 mg/kg/day divided q12h may be an appropriate initial dose to consider in patients undergoing CRRT.
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Antibacterianos/farmacocinética , Diálisis Renal/métodos , Combinación Trimetoprim y Sulfametoxazol/farmacocinética , Proteínas Sanguíneas/análisis , Cromatografía Líquida de Alta Presión , Soluciones para Diálisis/química , Hemodiafiltración/instrumentación , Hemofiltración/instrumentación , Hemofiltración/métodos , Hemoglobinas/análisis , Humanos , Técnicas In Vitro , Membranas Artificiales , Tasa de Depuración Metabólica , Modelos Químicos , Concentración Osmolar , Permeabilidad , Diálisis Renal/instrumentación , Albúmina Sérica/análisis , Combinación Trimetoprim y Sulfametoxazol/sangre , Urea/sangreRESUMEN
BACKGROUND: Escherichia coli O157:H7 is the leading cause of hemolytic uremic syndrome (HUS). Risk factors for development of this complication warrant identification. METHODS: We enrolled children infected with E. coli O157:H7 within 1 week of the onset of diarrhea in this prospective cohort study. The study was conducted in 5 states over 9.5 years . The primary and secondary outcomes were HUS (hematocrit <30% with smear evidence of hemolysis, platelet count <150 × 10(3)/µL, and serum creatinine concentration > upper limit of normal for age) and oligoanuric HUS. Univariate and multivariable and ordinal multinomial regression analyses were used to test associations between factors apparent during the first week of illness and outcomes. RESULTS: Of the 259 children analyzed, 36 (14%) developed HUS. Univariate analysis demonstrated that children who received antibiotics during the diarrhea phase more frequently developed HUS than those who did not (36% vs 12%; P = .001). The higher rate of HUS was observed across all antibiotic classes used. In multivariable analysis, a higher leukocyte count (adjusted odds ratios [aOR] 1.10; 95% CI, 1.03-1.19), vomiting (aOR 3.05; 95% CI, 1.23-7.56), and exposure to antibiotics (aOR 3.62; 95% CI, 1.23-10.6) during the first week of onset of illness were each independently associated with development of HUS. Multinomial ordinal logistic regression confirmed that initial leukocyte count and antibiotic use were independently associated with HUS and, additionally, these variables were each associated with the development of oligoanuric HUS. CONCLUSIONS: Antibiotic use during E. coli O157:H7 infections is associated with a higher rate of subsequent HUS and should be avoided.
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Infecciones por Escherichia coli/complicaciones , Escherichia coli O157/aislamiento & purificación , Síndrome Hemolítico-Urémico/microbiología , Antibacterianos/uso terapéutico , Niño , Preescolar , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/epidemiología , Femenino , Síndrome Hemolítico-Urémico/epidemiología , Humanos , Lactante , Recién Nacido , Recuento de Leucocitos , Modelos Logísticos , Masculino , Análisis Multivariante , Oliguria/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Vómitos/microbiologíaRESUMEN
Background: Single-center studies suggest that neonatal acute kidney injury (AKI) is associated with poor outcomes. However, inferences regarding the association between AKI, mortality, and hospital length of stay are limited due to the small sample size of those studies. In order to determine whether neonatal AKI is independently associated with increased mortality and longer hospital stay, we analyzed the Assessment of Worldwide Acute Kidney Epidemiology in Neonates (AWAKEN) database. Methods: All neonates admitted to 24 participating neonatal intensive care units from four countries (Australia, Canada, India, United States) between January 1 and March 31, 2014, were screened. Of 4273 neonates screened, 2022 (47·3%) met study criteria. Exclusion criteria included: no intravenous fluids ≥48 hours, admission ≥14 days of life, congenital heart disease requiring surgical repair at <7 days of life, lethal chromosomal anomaly, death within 48 hours, inability to determine AKI status or severe congenital kidney abnormalities. AKI was defined using a standardized definition -i.e., serum creatinine rise of ≥0.3 mg/dL (26.5 mcmol/L) or ≥50% from previous lowest value, and/or if urine output was <1 mL/kg/h on postnatal days 2 to 7. Findings: Incidence of AKI was 605/2022 (29·9%). Rates varied by gestational age groups (i.e., ≥22 to <29 weeks =47·9%; ≥29 to <36 weeks =18·3%; and ≥36 weeks =36·7%). Even after adjusting for multiple potential confounding factors, infants with AKI had higher mortality compared to those without AKI [(59/605 (9·7%) vs. 20/1417 (1·4%); p< 0.001; adjusted OR=4·6 (95% CI=2·5-8·3); p=<0·0001], and longer hospital stay [adjusted parameter estimate 8·8 days (95% CI=6·1-11·5); p<0·0001]. Interpretation: Neonatal AKI is a common and independent risk factor for mortality and longer hospital stay. These data suggest that neonates may be impacted by AKI in a manner similar to pediatric and adult patients. Funding: US National Institutes of Health, University of Alabama at Birmingham, Cincinnati Children's, University of New Mexico.
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BACKGROUND AND OBJECTIVES: African-American (AA) children with focal segmental glomerulosclerosis (FSGS) have later onset disease that progresses more rapidly than in non-AA children. It is unclear how APOL1 genotypes contribute to kidney disease risk, progression, and cardiovascular morbidity in children. DESIGN SETTING PARTICIPANTS AND MEASUREMENTS: We examined the prevalence of APOL1 genotypes and associated cardiovascular phenotypes among children with FSGS in the Chronic Kidney Disease in Children (CKiD) study; an ongoing multicenter prospective cohort study of children aged 1-16 years with mild to moderate kidney disease. RESULTS: A total of 140 AA children in the CKiD study were genotyped. High risk (HR) APOL1 genotypes were present in 24% of AA children (33/140) and were associated with FSGS, p < 0.001. FSGS was the most common cause of glomerular disease in children with HR APOL1 (89%; 25/28). Of 32 AA children with FSGS, 25 (78%) had HR APOL1. Compared to children with low risk APOL1 and FSGS (comprising 36 non-AA and 7 AA), children with HR APOL1 developed FSGS at a later age, 12.0 (IQR: 9.5, 12.5) vs. 5.5 (2.5, 11.5) years, p = 0.004, had a higher prevalence of uncontrolled hypertension (52 vs. 33%, p = 0.13), left ventricular hypertrophy (LVH) (53 vs. 12%, p < 0.01), C-reactive protein > 3 mg/l (33 vs. 15%, p = 0.12), and obesity (48 vs. 19%, p = 0.01). There were no differences in glomerular filtration rate, hemoglobin, iPTH, or calcium-phosphate product. CONCLUSION: AA children with HR APOL1 genotype and FSGS have increase prevalence of obesity and LVH despite a later age of FSGS onset, while adjusting for socioeconomic status. Treatment of obesity may be an important component of chronic kidney disease and LVH management in this population.
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BACKGROUND AND OBJECTIVES: Congenital anomalies of the kidney and urinary tract and genetic disorders cause most cases of CKD in children. This study evaluated the relationships between baseline proteinuria and BP and longitudinal changes in GFR in children with these nonglomerular causes of CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Urine protein-to-creatinine ratio, casual systolic and diastolic BP (normalized for age, sex, and height), and GFR decline were assessed in the prospective CKD in Children cohort study. RESULTS: A total of 522 children, median age 10 years (interquartile range, 7, 14 years) with nonglomerular CKD were followed for a median of 4.4 years. The mean baseline GFR in the cohort was 52 ml/min per 1.73 m(2) (95% confidence interval [95% CI], 50 to 54) and declined 1.3 ml/min per 1.73 m(2) per year on average (95%CI, 1.6 to 1.1). A 2-fold higher baseline urine protein-to-creatinine ratio was associated with an accelerated GFR decline of 0.3 ml/min per 1.73 m(2) per year (95% CI, 0.4 to 0.1). A 1-unit higher baseline systolic BP z-score was associated with an additional GFR decline of 0.4 ml/min per 1.73 m(2) per year (95% CI, 0.7 to 0.1). Among normotensive children, larger GFR declines were associated with larger baseline urine protein-to-creatinine ratios; eGFR declines of 0.8 and 1.8 ml/min per 1.73 m(2) per year were associated with urine protein-to-creatinine ratio <0.5 and ≥0.5 mg/mg, respectively. Among children with elevated BP, average GFR declines were evident but were not larger in children with higher levels of proteinuria. CONCLUSIONS: Baseline proteinuria and systolic BP levels are independently associated with CKD progression in children with nonglomerular CKD.
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Presión Sanguínea , Riñón/fisiopatología , Proteinuria/etiología , Insuficiencia Renal Crónica/etiología , Adolescente , Factores de Edad , Biomarcadores/orina , Niño , Creatinina/orina , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Estudios Longitudinales , Masculino , América del Norte , Estudios Prospectivos , Proteinuria/diagnóstico , Proteinuria/fisiopatología , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/fisiopatología , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: There is frequent uncertainty in the identification of specific etiologies of chronic kidney disease (CKD) in children. Recent studies indicate that chromosomal microarrays can identify rare genomic imbalances that can clarify the etiology of neurodevelopmental and cardiac disorders in children; however, the contribution of unsuspected genomic imbalance to the incidence of pediatric CKD is unknown. METHODS: We performed chromosomal microarrays to detect genomic imbalances in children enrolled in the Chronic Kidney Disease in Children (CKiD) prospective cohort study, a longitudinal prospective multiethnic observational study of North American children with mild to moderate CKD. Patients with clinically detectable syndromic disease were excluded from evaluation. We compared 419 unrelated children enrolled in CKiD to multiethnic cohorts of 21,575 children and adults that had undergone microarray genotyping for studies unrelated to CKD. RESULTS: We identified diagnostic copy number disorders in 31 children with CKD (7.4% of the cohort). We detected 10 known pathogenic genomic disorders, including the 17q12 deletion HNF1 homeobox B (HNF1B) and triple X syndromes in 19 of 419 unrelated CKiD cases as compared with 98 of 21,575 control individuals (OR 10.8, P = 6.1 × 10⻲°). In an additional 12 CKiD cases, we identified 12 likely pathogenic genomic imbalances that would be considered reportable in a clinical setting. These genomic imbalances were evenly distributed among patients diagnosed with congenital and noncongenital forms of CKD. In the vast majority of these cases, the genomic lesion was unsuspected based on the clinical assessment and either reclassified the disease or provided information that might have triggered additional clinical care, such as evaluation for metabolic or neuropsychiatric disease. CONCLUSION: A substantial proportion of children with CKD have an unsuspected genomic imbalance, suggesting genomic disorders as a risk factor for common forms of pediatric nephropathy. Detection of pathogenic imbalances has practical implications for personalized diagnosis and health monitoring in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00327860. FUNDING: This work was supported by the NIH, the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute.
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Trastornos de los Cromosomas/genética , Cromosomas Humanos/genética , Dosificación de Gen , Insuficiencia Renal Crónica/genética , Adolescente , Causalidad , Niño , Preescolar , Trastornos de los Cromosomas/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Análisis por Micromatrices , Prevalencia , Estudios Prospectivos , Eliminación de Secuencia , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVES: To determine if interventions during the pre-hemolytic uremic syndrome (HUS) diarrhea phase are associated with maintenance of urine output during HUS. DESIGN: Prospective observational cohort study. SETTINGS: Eleven pediatric hospitals in the United States and Scotland. PARTICIPANTS: Children younger than 18 years with diarrhea-associated HUS (hematocrit level <30% with smear evidence of intravascular erythrocyte destruction), thrombocytopenia (platelet count <150 × 10³/mm³), and impaired renal function (serum creatinine concentration > upper limit of reference range for age). INTERVENTIONS: Intravenous fluid was given within the first 4 days of the onset of diarrhea. OUTCOME MEASURE: Presence or absence of oligoanuria (urine output ≤ 0.5 mL/kg/h for >1 day). RESULTS: The overall oligoanuric rate of the 50 participants was 68%, but was 84% among those who received no intravenous fluids in the first 4 days of illness. The relative risk of oligoanuria when fluids were not given in this interval was 1.6 (95% confidence interval, 1.1-2.4; P = .02). Children with oligoanuric HUS were given less total intravenous fluid (r = -0.32; P = .02) and sodium (r = -0.27; P = .05) in the first 4 days of illness than those without oligoanuria. In multivariable analysis, the most significant covariate was volume infused, but volume and sodium strongly covaried. CONCLUSIONS: Intravenous volume expansion is an underused intervention that could decrease the frequency of oligoanuric renal failure in patients at risk of HUS.
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Lesión Renal Aguda/etiología , Diarrea/terapia , Fluidoterapia , Síndrome Hemolítico-Urémico/terapia , Oliguria/etiología , Oliguria/prevención & control , Lesión Renal Aguda/prevención & control , Adolescente , Niño , Preescolar , Diarrea/complicaciones , Diarrea/microbiología , Femenino , Síndrome Hemolítico-Urémico/complicaciones , Síndrome Hemolítico-Urémico/orina , Humanos , Lactante , Modelos Logísticos , Masculino , Análisis Multivariante , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: Children with chronic kidney disease (CKD) have an increased risk of progression to ESRD. There is a need to identify treatments to slow the progression of CKD, yet there are limited data regarding clinical risk factors that may be suitable targets to slow progression. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a retrospective cohort study using the North American Pediatric Renal Trials and Cooperative Studies CKD database. There were 4166 pediatric subjects with CKD stages II to IV. Disease progression was defined as a GFR on follow-up of <15 ml/min per 1.73 m(2) or termination in the registry because of dialysis or transplantation. We used Kaplan-Meier and Cox proportional hazards methods to describe progression rates and determine factors associated with CKD progression. RESULTS: In the univariate analysis, CKD progression was associated with age, gender, race, primary disease, CKD stage, registration year, hematocrit, albumin, corrected calcium, corrected phosphorus, and use of certain medications. Factors that remained significant in the multivariate analysis were age, primary disease, CKD stage, registration year, hypertension, corrected phosphorus, corrected calcium, albumin, hematocrit, and medication proxies for anemia and short stature. CONCLUSIONS: There are multiple risk factors associated with disease progression in the pediatric CKD population. Factors that may be amenable to intervention include anemia, hypoalbuminemia, hyperphosphatemia, hypocalcemia, hypertension, and short stature. Because of the retrospective nature of our study, confirmation of our results from ongoing prospective studies is warranted before recommending prospective interventional trials.