RESUMEN
RATIONALE & OBJECTIVE: The relation of vascular stiffness, endothelial function, and kidney function is incompletely elucidated in African Americans. Our hypothesis was that increased vascular stiffness and endothelial dysfunction are associated with low estimated glomerular filtration rate (eGFR) and albuminuria in African Americans. STUDY DESIGN: Cross-sectional cohort analysis of data from the Jackson Heart Study. SETTINGS & PATIENTS: 2,244 Jackson Heart Study participants (2012-2017 after Exam 3) who had undergone noninvasive hemodynamic assessment using arterial tonometry. PREDICTORS: Baseline carotid-femoral pulse wave velocity, pulsatile hemodynamics forward wave amplitude, and hyperemic brachial artery flow were measured. Reduced eGFR was defined as eGFR between 15 and 60 mL/min/1.73 m2. OUTCOMES: Prevalent albuminuria, urinary albumin-creatinine ratio. ANALYTICAL APPROACH: 2-sample t test for continuous variables and χ2 test for categorical variables in addition to logistic and linear regression models to assess the risk for chronic kidney disease with each proposed hemodynamic variable. RESULTS: Among 2,244 participants, mean age was 66 ± 11 years and 64% were women. Reduced eGFR was present in 233 (10.4%), and elevated urinary albumin-creatinine ratio, in 232 (10.4%). In multivariable-adjusted analyses, higher carotid-femoral pulse wave velocity was associated with the presence of reduced eGFR (OR, 1.37 [95% CI, 1.08-1.75] per SD; P = 0.01) and with prevalent albuminuria (OR, 1.66 [95% CI, 1.32-2.11]; P < 0.001). Higher forward wave amplitude was significantly associated with prevalent albuminuria (OR, 1.37 [95% CI, 1.14-1.65]; P = 0.001). LIMITATIONS: Cross-sectional analyses cannot inform causality. CONCLUSIONS: Higher arterial stiffness and pulsatility are associated with higher odds of reduced eGFR in African Americans. Future studies should focus on whether improving arterial stiffness contributes to kidney protection in African Americans.
RESUMEN
Baclofen is a centrally-acting γ-amino butyric acid agonist used mainly in the symptomatic management of spasticity originating from the spinal cord. It is absorbed completely from the gastrointestinal tract, metabolized by the liver to a minor degree, and excreted unchanged by the kidneys. Baclofen is moderately lipophilic and can cross the blood-brain barrier easily. At the usual dosage, it acts mainly at the spinal level without central nervous system (CNS) side effects. During renal failure, however, the elimination of the drug will decrease with a prolonged half-life, resulting in a larger area-under-the-curve exposure and disproportionate CNS toxicity. Clinically, these patients with renal failure may present with a variety of toxic symptoms manifesting at therapeutic/sub-therapeutic doses of baclofen. In cases of unexplained mental status changes in a patient receiving baclofen therapy, a careful assessment of renal function and a high suspicion of baclofen-induced encephalopathy will be key to the diagnosis.â©.
Asunto(s)
Baclofeno/efectos adversos , Enfermedades del Sistema Nervioso Central/inducido químicamente , Relajantes Musculares Centrales/efectos adversos , Insuficiencia Renal/complicaciones , Baclofeno/administración & dosificación , Humanos , Relajantes Musculares Centrales/administración & dosificaciónRESUMEN
[This corrects the article DOI: 10.1371/journal.pgen.1006728.].
RESUMEN
Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
Asunto(s)
Presión Sanguínea/genética , Sitios Genéticos , Hipertensión/genética , Herencia Multifactorial , Negro o Afroamericano/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Cadherinas/genética , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Hipertensión/etnología , Masculino , Proteínas de la Membrana/genética , Ratones , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Controversy exists regarding the association of cigarette smoking and renal dysfunction, particularly among African Americans, who are disproportionately affected by chronic kidney disease; therefore, we evaluated the relationship between cigarette smoking and rapid renal function (RRF) decline in the Jackson Heart Study. METHODS AND RESULTS: Rates of RRF decline were determined among 3648 African American participants enrolled at baseline in the Jackson Heart Study. RRF decline was defined as an absolute decline of estimated glomerular filtration rate of 30% from visit 1 to visit 3. There were 422 current, 659 past, and 2567 never smokers identified at visit 1. After adjustment for age, sex, body mass index, diabetes, hypertension, cholesterol, physical activity, education, alcohol consumption, and prevalent cardiovascular disease, current smokers demonstrated a significantly higher incidence of RRF decline compared with never smokers (incidence rate ratio 1.83, 95% CI 1.31-2.56). Current smokers using 1 to 19 and ≥20 cigarettes daily had an increased incidence of RRF decline (incidence rate ratios of 1.75 [95% CI 1.18-2.59] and 1.97 [95% CI 1.17-3.31], respectively). There was a significant, progressive reduction in estimated glomerular filtration rate from visit 1 to visit 3 in current and past smokers compared with never smokers. Finally, current smokers had a 1.38-fold increase in C-reactive protein compared with never smokers, after controlling for covariates. CONCLUSIONS: In a large African American cohort, current cigarette smoking was independently associated with RRF decline in a dose-dependent manner. There was also evidence of increased inflammation (C-reactive protein) in current smokers, suggesting a potential mechanism for these relationships.
Asunto(s)
Fumar Cigarrillos/efectos adversos , Insuficiencia Renal Crónica/etiología , Adulto , Negro o Afroamericano/etnología , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Proteína C-Reactiva/metabolismo , Fumar Cigarrillos/etnología , Fumar Cigarrillos/fisiopatología , Tasa de Filtración Glomerular/fisiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Mississippi/epidemiología , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/fisiopatología , Adulto JovenRESUMEN
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Asunto(s)
Predisposición Genética a la Enfermedad , Insuficiencia Renal Crónica/genética , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , HumanosRESUMEN
BACKGROUND: Rare genetic variants influence blood pressure (BP). METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; ß=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (ß=-4.11; P=2.8×10(-4)), mean arterial pressure (ß=-3.50; P=8.9×10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; ß=-3.30; P=5.0×10(-7)). CONCLUSIONS: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.
Asunto(s)
Alelos , Presión Sanguínea/genética , Canales de Cloruro/genética , Exoma , Frecuencia de los Genes , Hipertensión/genética , Población Negra , Femenino , Humanos , Masculino , Factores de Riesgo , Población BlancaRESUMEN
Previously, genetic analyses identified that variants in Arhgef11 may influence kidney injury in the Dahl salt-sensitive (S) rat, a model of hypertensive chronic kidney disease. To understand the potential mechanism by which altered expression and/or protein differences in Arhgef11 could play a role in kidney injury, stably transduced Arhgef11 knockdown cell lines as well as primary cultures of proximal tubule cells were studied. Genetic knockdown of Arhgef11 in HEK293 and NRK resulted in reduced RhoA activity, decreased activation of Rho-ROCK pathway, and less stress fiber formation versus control, similar to what was observed by pharmacological inhibition (fasudil). Primary proximal tubule cells (PTC) cultured from the S exhibited increased expression of Arhgef11, increased RhoA activity, and up regulation of Rho-ROCK signaling compared to control (small congenic). The cells were also more prone (versus control) to TGFß-1 induced epithelial-mesenchymal transition (EMT), a hallmark feature of the development of renal interstitial fibrosis, and characterized by development of spindle shape morphology, gene expression changes in EMT markers (Col1a3, Mmp9, Bmp7, and Ocln) and increased expression of N-Cadherin and Vimentin. S derived PTC demonstrated a decreased ability to uptake FITC-albumin compared to the small congenic in vitro, which was confirmed by assessment of albumin re-uptake in vivo by infusion of FITC-albumin and immunofluorescence imaging. In summary, these studies suggest that genetic variants in the S form of Arhgef11 via increased expression and/or protein activity play a role in promoting kidney injury in the S rat through changes in cell morphology (Rho-Rock and/or EMT) that impact the function of tubule cells.
Asunto(s)
Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Insuficiencia Renal Crónica/genética , Alelos , Animales , Animales Congénicos , Línea Celular , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/fisiología , Técnicas de Silenciamiento del Gen , Variación Genética , Factores de Intercambio de Guanina Nucleótido/antagonistas & inhibidores , Células HEK293 , Humanos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Masculino , Plaquinas/metabolismo , Ratas , Ratas Endogámicas Dahl , Ratas Endogámicas SHR , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Factores de Intercambio de Guanina Nucleótido Rho/antagonistas & inhibidores , Factores de Intercambio de Guanina Nucleótido Rho/genética , Factores de Intercambio de Guanina Nucleótido Rho/metabolismo , Transducción de Señal , Proteínas de Unión al GTP rho/metabolismo , Quinasas Asociadas a rho/metabolismoRESUMEN
BACKGROUND: Studies suggest 24-h blood pressure (BP) variability has prognostic value for cardiovascular disease. Several factors associated with high 24-h BP variability are also common among individuals with chronic kidney disease (CKD). We hypothesized 24-h BP variability would be higher for individuals with versus without CKD. METHODS: We analyzed 1,022 Jackson Heart Study participants who underwent ambulatory blood pressure monitoring (ABPM). Twenty-four hour BP variability was defined by two metrics: day-night standard deviation (SDdn) and average real variability (ARV). CKD was defined as ACR ≥ 30 mg/g or eGFR <60 mL/min/1.73 m(2). RESULTS: The mean SDdn of systolic BP (SBP) was 10.2 ± 0.2 and 9.1 ± 0.1 mmHg and the mean ARV of SBP was 9.2 ± 0.2 and 8.6 ± 0.1 mmHg for those with and without CKD, respectively (each p ≤ 0.001). After adjustment for age and sex, SDdn and ARV were 0.98 mmHg (95 % CI 0.59, 1.38) and 0.52 mmHg (95 % CI 0.18, 0.86), respectively, higher among participants with versus without CKD. These differences were not statistically significant after further multivariable adjustment including 24-h mean SBP. Older age, and higher total cholesterol and 24-h mean SBP were associated with higher SDdn and ARV of SBP among participants with CKD. Mean SDdn and ARV of diastolic BP (DBP) were higher for participants with versus without CKD but these associations were not present after multivariable adjustment. CONCLUSION: Data from the current study suggest that CKD is associated with higher 24-h BP variability, but the association is primarily explained by higher mean BP among those with CKD.
Asunto(s)
Negro o Afroamericano , Presión Sanguínea/fisiología , Insuficiencia Renal Crónica/fisiopatología , Factores de Edad , Monitoreo Ambulatorio de la Presión Arterial , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/fisiopatología , Estudios de Casos y Controles , Colesterol/sangre , HDL-Colesterol/sangre , Estudios Transversales , Diástole , Femenino , Humanos , Hipercolesterolemia/epidemiología , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/epidemiología , Factores de Riesgo , SístoleRESUMEN
OBJECTIVES: The safety and efficacy of percutaneous renal biopsy (PKB) are relatively little studied in a training setting. We sought to review our recent experience with bedside PKB in our training program. METHODS: We performed a retrospective cohort review of our consecutive 2.5-year renal biopsy experience (May 2007-November 2009) at the University of Mississippi Nephrology Fellowship. All of the biopsies were performed exclusively by renal fellows using real-time ultrasound (US) visualization within the framework of a structured US-PKB training course. RESULTS: A total of 64 patients underwent PKB during the index period; 50 (78.1%) of these procedures were performed on native kidneys. Participant age was 39.8 ± 13.7 years, blood pressures measured 140.1/85.3 ± 21.5/14.9 mm Hg, serum creatinine was 3.05 ± 3.15 mg/dL, and median random urine protein:creatinine ratio was 2.38 (25%-75% interquartile range 0.49-7.32). The biopsied kidneys measured 11.8 (±1.6) cm. We recovered 18.8 ± 11.5 glomeruli per procedure; two biopsies were unsuccessful. Focal glomerular sclerosis and lupus nephritis (22% and 25%, respectively) predominated among the specimens. Only three specimens returned with no diagnostic changes. There was a close correlation between preceding history and recovered diagnoses of diabetic changes and lupus nephritis (r 0.605 and 0.842; P < 0.0001 for both). Initial hemoglobin of 10.8 ± 1.8 g/dL dropped to 10.2 (1.9) g/dL after the procedure (P < 0.0001). Five (7.8%) patients needed transfusion; one patient experienced persistent urine leakage; however, none of the patients needed surgical or radiological intervention or died. CONCLUSIONS: In the setting of a well-structured training environment, US-guided PKB is a reasonably safe and valuable component of renal fellowship training.
Asunto(s)
Biopsia/métodos , Riñón/citología , Adulto , Estudios de Cohortes , Humanos , Riñón/patología , Glomérulos Renales/citología , Glomérulos Renales/patología , Nefritis Lúpica/patología , Nefrología/educación , Estudios Retrospectivos , SeguridadRESUMEN
Previous studies have indicated that cytochrome P450 (CYP) metabolites of arachidonic acid (AA), i.e., 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs), play an important role in the regulation of renal tubular and vascular function. The present study for the first time profiled HETEs and epoxygenase derived dihydroxyeicosatetraenoic acid diHETEs levels in spot urines and plasma in 262 African American patients from the University of Mississippi Chronic Kidney Disease Clinic and 31 African American controls. Significant correlations in eGFR and urinary 20-HETE/creatinine and 19-HETE/creatinine levels were observed. The eGFR increased by 17.47 [p=0.001] and 60.68 [(p=0.005]ml/min/for each ng/mg increase in 20-HETE and 19-HETE levels, respectively. Similar significant positive associations were found between the other urinary eicosanoids and eGFR and also with 19-HETE/urine creatinine concentration and proteinuria. We found that approximately 80% of plasma HETEs and 30% diHETEs were glucuronidated and the fractional excretion of 20-HETE was less than 1%. These results suggest that there is a significant hepatic source of urinary 20-HETE glucuronide and EETs with extensive renal biotransformation to metabolites which may play a role in the pathogenesis of CKD.
Asunto(s)
Negro o Afroamericano , Sistema Enzimático del Citocromo P-450/orina , Eicosanoides/orina , Tasa de Filtración Glomerular/fisiología , Insuficiencia Renal Crónica/etnología , Insuficiencia Renal Crónica/orina , Adulto , Creatinina/sangre , Creatinina/orina , Eicosanoides/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteinuria/orina , Análisis de Regresión , Insuficiencia Renal Crónica/fisiopatología , Estados UnidosRESUMEN
High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.
Asunto(s)
Población Negra/genética , Presión Sanguínea/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Carácter Cuantitativo Heredable , África , Estudios de Cohortes , Bases de Datos Genéticas , Sitios Genéticos/genética , Humanos , Polimorfismo de Nucleótido Simple/genética , Reproducibilidad de los ResultadosRESUMEN
The relative effectiveness of anticoagulation strategies during continuous renal replacement therapy (CRRT) may vary according to the clinical circumstances. In this study, the case of a 46-year-old man who developed fungal mediastinitis with the pathogen Scedosporium prolificans after coronary bypass surgery is reported. Numerous debridements and multiple antifungal agents were not effective in this patient. Miltefosine, a non-Food and Drug Administration-approved agent, was started after institutional review board request and approval. CRRT was initiated with regional citrate anticoagulation (RCA) for clinical sepsis with acute kidney injury. Subsequently, crescendo clotting of the extracorporeal circuit (ECC) occurred. Multiple interventions, including escalating RCA, adding increasing heparin to RCA and exchanging the dialysis catheter, were not effective. Argatroban anticoagulation was started without further ECC clotting, and the patient recovered from both acute kidney injury and septic shock, despite continued miltefosine administration. Sepsis may contribute to recurrent ECC clotting. Argatroban, a direct thrombin inhibitor, had a disproportionate effectiveness to maintain ECC patency in this patient.
Asunto(s)
Antitrombinas/administración & dosificación , Coagulación Sanguínea/efectos de los fármacos , Puente de Arteria Coronaria/efectos adversos , Mediastinitis , Micosis , Ácidos Pipecólicos/administración & dosificación , Complicaciones Posoperatorias , Terapia de Reemplazo Renal , Scedosporium , Sepsis , Antifúngicos/administración & dosificación , Arginina/análogos & derivados , Humanos , Masculino , Mediastinitis/etiología , Mediastinitis/microbiología , Mediastinitis/terapia , Persona de Mediana Edad , Micosis/etiología , Micosis/microbiología , Micosis/terapia , Fosforilcolina/administración & dosificación , Fosforilcolina/análogos & derivados , Sepsis/etiología , Sepsis/microbiología , Sepsis/terapia , SulfonamidasRESUMEN
A previous genetic analysis comparing the Dahl salt-sensitive (S) rat with the spontaneously hypertensive rat identified a major locus on chromosome 2 that influences proteinuria in the S rat. In the present study, blood pressure, proteinuria, and renal hemodynamics were evaluated in congenic strains with small segments of the protective spontaneously hypertensive rat genome on the S background. Proteinuria and renal function were significantly improved in the congenic strains compared with the S. The causative locus interval was narrowed to <375 kb on the basis of congenic strains, haplotype data, comparative mapping, and concordance with human genetic studies. Sequencing of the coding region of genes in this region identified 36 single nucleotide polymorphisms (13 nonsynonymous and 23 synonymous). Gene expression profiling indicated that only a few genes exhibited differential expression. Arhgef11, Pear1, and Sh2d2 were identified as important candidate genes that may be linked to kidney injury in the S rat. In particular, Arhgef11 plays an important role in the activation of the Rho-ROCK signaling pathway. Inhibition of this pathway using fasudil resulted in a significant reduction of proteinuria in treated S rats (compared with untreated S). However, no difference was observed between treated or untreated spontaneously hypertensive rat or congenic strains. The homologous region in humans was found to be associated with estimated glomerular filtration rate in the Candidate Gene Association Resource population. In summary, these findings demonstrate that allelic variants in Arhgef11, acting through the Rho-ROCK pathway, could influence kidney injury in the S as well as provide insight into human kidney disease.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Factores de Intercambio de Guanina Nucleótido/genética , Enfermedades Renales/genética , Polimorfismo de Nucleótido Simple , Ratas Endogámicas Dahl/genética , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Animales , Animales Congénicos , Presión Sanguínea/genética , Western Blotting , Mapeo Cromosómico , Perfilación de la Expresión Génica , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Riñón/irrigación sanguínea , Riñón/metabolismo , Riñón/fisiopatología , Enfermedades Renales/metabolismo , Enfermedades Renales/fisiopatología , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Proteinuria/genética , Proteinuria/metabolismo , Sitios de Carácter Cuantitativo/genética , Ratas , Ratas Endogámicas Dahl/metabolismo , Ratas Endogámicas SHR , Circulación Renal , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-valueâ=â5.3×10(-7)) and FNDC1 (p-valueâ=â3.0×10(-7)) for UACR, and KCNQ1 with eGFR (pâ=â3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
Asunto(s)
Población Negra/genética , Sitios Genéticos , Tasa de Filtración Glomerular/genética , Canal de Potasio KCNQ1/genética , Fallo Renal Crónico/genética , Riñón/fisiología , Proteínas Adaptadoras Transductoras de Señales , Proteínas Adaptadoras del Transporte Vesicular/genética , Adulto , Anciano , Animales , Femenino , Técnicas de Silenciamiento del Gen , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Pez Cebra/genética , Pez Cebra/crecimiento & desarrolloRESUMEN
The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
Asunto(s)
Negro o Afroamericano/genética , Estudio de Asociación del Genoma Completo , Hipertensión/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Presión Sanguínea , Estudios de Cohortes , Diástole , Femenino , Sitios Genéticos , Genotipo , Humanos , Hipertensión/epidemiología , Masculino , Persona de Mediana Edad , Fenotipo , Sístole , Población Blanca/genéticaRESUMEN
Slow extended daily dialysis (SLEDD) is the newest form of dialysis that is being used increasingly to replace continuous venovenous hemodialysis (CVVHD) for critically ill patients; it is less expensive to administer and has similar safety for patients who are prone to hemodynamic instability. Unfortunately, there are limited data regarding the appropriate dosing of antimicrobial agents for patients undergoing SLEDD. Furthermore, many nonnephrologists are not familiar with the differences between SLEDD, other continuous renal replacement therapies--for example, CVVHD--and routine hemodialysis. Thus, there is potential for inaccurate and, at worst, inadequate dosing of critical antimicrobial agents for this patient population. We review the available pharmacokinetic data on SLEDD and give preliminary recommendations for how to approach dosing in this situation.
Asunto(s)
Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Infecciones Bacterianas/tratamiento farmacológico , Diálisis/métodos , Insuficiencia Renal/terapia , Antibacterianos/uso terapéutico , Enfermedad Crítica , HumanosRESUMEN
BACKGROUND: Chronic renal failure (CRF) has been shown to significantly reduce the nonrenal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine. OBJECTIVES: The purpose of this article is to review all significant animal and clinical studies dealing with the effect of CRF on drug metabolism and transport. METHODS: A search of the National Library of Medicine PubMed was done with terms such as chronic renal failure, cytochrome P450 [CYP], liver metabolism, efflux drug transport and uptake transport, including relevant articles back to 1969. RESULTS: Animal studies in CRF have shown a significant downregulation (40-85%) of hepatic and intestinal CYP metabolism. High levels of parathyroid hormone, cytokines and uremic toxins have been shown to reduce CYP activity. Phase II reactions and drug transporters such as P-glycoprotein and organic anion transporting polypeptide are also affected. CONCLUSION: CRF alters intestinal, renal and hepatic drug metabolism and transport producing a clinically significant impact on drug disposition and increasing the risk for adverse drug reactions.