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Progression of chronic kidney disease: Adrenergic genetic influence on glomerular filtration rate decline in hypertensive nephrosclerosis.

ABSTRACT: African-Americans are likely to develop hypertension and hypertensive nephrosclerosis. This grave prognosis, coupled with familial aggregation of end-stage renal disease (ESRD) in Blacks, prompts a search for genetic risk factors for ESRD. Recent evidence implicates a crucial role for the sympathetic nervous system in progressive renal disease.We used the African-American Study of Kidney Disease to probe whether beta2-adrenergic receptor (ADRB2) predicts glomerular filtration rate (GFR) decline rate. A total of 580 participants were included. Baseline GFR was 51.2 +/- 0.5 ml/min/1.73 m2. Subjects were randomized in a 2 x 3 block design: to intensively lowered (MAP < or = 92 mm Hg) versus 'usual' (MAP = 102-107 mm Hg) blood pressure goal groups, and also divided by three randomized antihypertensive drugs (ramipril, metoprolol, or amlodipine). We scored 4 SNPs at the ADRB2 locus.Haplotypes at ADRB2 predicted chronic GFR decline rate, GFR declined more slowly in individuals with haplotype-1 (-804G-->173T-->16Gly-->27GIn), and faster in those who carried haplotype-3 (-804G-->173T-->16Arg-->27Gln). ADRB2 genotype interacted with antihypertensive drug class to influence GFR slope (p = 0.001-0.037). We extended our findings to an independent case/control sample of Black hypertensive ESRD, in which we found that variant Gly16Arg that tagged the GFR slope-determining ADRB2 haplotype also conferred risk for the ESRD trait in Blacks.The GFR decline/progression rate in hypertensive renal disease is controlled in part by genetic variation within the adrenergic pathway.

SUBMITTER: Chen Y

PROVIDER: S-EPMC2914391 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Progression of chronic kidney disease: Adrenergic genetic influence on glomerular filtration rate decline in hypertensive nephrosclerosis.

Chen Yuqing Y Lipkowitz Michael S MS Salem Rany M RM Fung Maple M MM Bhatnagar Vibha V Mahata Manjula M Nievergelt Caroline M CM Rao Fangwen F Mahata Sushil K SK Schork Nicholas J NJ Hicks Pamela J PJ Bowden Donald W DW Freedman Barry I BI Brophy Victoria H VH O'Connor Daniel T DT

American journal of nephrology 20100519 1

<h4>Background</h4>African-Americans are likely to develop hypertension and hypertensive nephrosclerosis. This grave prognosis, coupled with familial aggregation of end-stage renal disease (ESRD) in Blacks, prompts a search for genetic risk factors for ESRD. Recent evidence implicates a crucial role for the sympathetic nervous system in progressive renal disease.<h4>Methods</h4>We used the African-American Study of Kidney Disease to probe whether beta2-adrenergic receptor (ADRB2) predicts glomer ...[more]

PMID: 20484896

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Project description:A progressive trajectory toward renal failure is common in patients with Alport syndrome. Genotype-phenotype correlations have been well described; however, the natural history of the trajectory toward renal failure is not well described.The objective of this study is to describe the natural history of renal function decline in a cohort of Alport syndrome patients.Retrospective observational cohort study.British Columbia, Canada, chronic renal disease registry 1995-2012.37 biopsy proven Alport syndrome or hematuria with family history of Alport syndrome.Serial estimated glomerular filtration rate (eGFR) Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient's eGFR measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2 /y decline), stable state (0-2 mL/min/1.73 m2 /y decline), and regressors (>2 mL/min/1.73 m2 /y incline).In this retrospective observational cohort study, participants were identified through a chronic renal disease registry in British Columbia, Canada, from 1995 to 2012. Inclusion criteria were biopsy proven or hematuria with a family history of Alport syndrome. Individual patients and family group members were studied. Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient's serial estimated glomerular filtration rate (eGFR) measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2/y decline), stable state (0-2 mL/min/1.73 m2/y decline), and regressors (>2 mL/min/1.73 m2/y incline).Histological or genetic evidence of Alport syndrome is not available in all patients.Median follow-up time was 48.2 months of 37 patients (78% male), with a median age of 36 (interquartile range [IQR], 18-47) and a median age of renal replacement therapy commencement (n = 23) of 38 (IQR = 20-52). Renal function changes were found to be heterogeneous overall, intra-individual and within families. Portion of progressors in eGFR 45-60 mL/min/1.73 m2 was 73.7% (SD, 10.3), whereas 23.6% (SD, 11.0) remained stable. Within eGFR 30-45 mL/min/1.73 m2, 45.6% (SD, 7.0) were progressors, whereas 53.4% (SD, 7.4) remained stable. A large portion of eGFR 15-30 mL/min/1.73 m2 patients were stable (54.8%; SD, 8.4), whereas 25.7% (SD, 7.1) progressed and 19.5% (SD, 5.6) regressed.The renal decline in Alport syndrome patients is heterogeneous which has implications for designing clinical trials of interventions.

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Progression of chronic kidney disease: Adrenergic genetic influence on glomerular filtration rate decline in hypertensive nephrosclerosis.

Publications

Progression of chronic kidney disease: Adrenergic genetic influence on glomerular filtration rate decline in hypertensive nephrosclerosis.

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