Conall Seaghdha - Academia.edu (original) (raw)

Papers by Conall Seaghdha

Nephron Clinical Practice, 2011

The current review collates what is already known of the genetics of chronic kidney disease (CKD)... more The current review collates what is already known of the genetics of chronic kidney disease (CKD), and focuses on new trends in genome-wide assessment of the inherited component of susceptibility to this condition. Early efforts to identify kidney disease susceptibility genetic loci using linkage and candidate gene strategies proved disappointing. More recently, genome-wide association studies have yielded highly promising results suggesting a number of potential candidate genes and genomic regions that may contribute to the pathogenesis of CKD. Renal failure susceptibility genes identified by these methods, such as MYH9, have yielded novel insights into the pathogenesis of CKD. Genome-wide association studies of CKD are beginning to define the genomic architecture of kidney disease and will impact our understanding of how genetic variation influences susceptibility to this condition.

American Journal of Kidney Diseases, 2011

This review discusses how the internet currently is being used to provide medical education in th... more This review discusses how the internet currently is being used to provide medical education in the nephrology community and addresses some of the issues and dilemmas unique to using this media. It focuses on how blogs, wikis, podcasts/YouTube, social bookmarking/media, and mobile devices are used to deliver e-learning in nephrology.

PLoS Genetics, 2011

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and en... more Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR ,60ml/min/1.73m 2 at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

Journal of the American Society of Nephrology, 2013

Whether novel biomarkers improve the assessment of incident kidney disease and related adverse ou... more Whether novel biomarkers improve the assessment of incident kidney disease and related adverse outcomes remains to be tested in longitudinal observational studies. We tested 14 urinary biomarkers for association with incident kidney, cardiovascular, and mortality outcomes in 2948 Framingham Heart Study participants. Baseline examinations were performed between 1995 and 1998; mean follow-up was 10.1 years for renal outcomes and 11.2 years for survival analyses. Primary outcomes were incident CKD, incident albuminuria, incident cardiovascular disease, and all-cause mortality. Secondary analyses assessed incident congestive heart failure (CHF) and mortality with coexistent kidney disease. Biomarkers were tested for association with renal end points using logistic regression and incident cardiovascular and mortality outcomes in proportional hazards models; a1-microglobulin, Kim-1, and TFF-3 predicted allcause mortality (hazard ratio per SD increase in log-transformed biomarker [HR] range, 1.15 to 1.21; 95% confidence interval [CI] range, 1.04 to 1.34; P values=0.007 to ,0.001), whereas a1-microglobulin, b2-microglobulin, KIM-1, and TFF-3 associated with death with coexistent kidney disease (HR range, 1.72-2.25; 95% CI, 1.17 to 3.24; P values,0.01). KIM-1 also associated with the risk of incident CHF (HR, 1.32; 95% CI, 1.07 to 1.63; P=0.008). CTGF associated nominally with CKD (HR, 0.83; 95% CI, 0.71 to 0.98; P=0.03), but no other biomarkers associated with incident CKD or albuminuria. Addition of a1-microglobulin and TFF-3 resulted in a nonsignificant net reclassification index (NRI) of 3% for all-cause mortality beyond clinical risk factors. In conclusion, components of a panel of 14 subclinical biomarkers of kidney injury were associated with important clinical outcomes and merit additional investigation.

Journal of the American Society of Nephrology, 2013

Galectin-3, a profibrotic mediator, is linked to the development of renal fibrosis in animal mode... more Galectin-3, a profibrotic mediator, is linked to the development of renal fibrosis in animal models and inversely correlates with GFR in humans, but whether galectin-3 predicts incident kidney disease is unknown. Here, we assessed renal outcomes for 2450 Framingham Offspring participants who attended examination 6 (1995-1998) and had follow-up data at examination 8 (2005)(2006)(2007)(2008). Renal outcomes of interest included rapid decline in renal function ($3 ml/min per 1.73 m 2 per year decline in estimated GFR [eGFR]), CKD (eGFR , 60 ml/min per 1.73 m 2 ), and albuminuria (albumin-to-creatinine ratio 17mg/ginmenor17 mg/g in men or 17mg/ginmenor25 mg/g in women). We used multivariable logistic regression models to evaluate associations between galectin-3 with incident renal outcomes at examination 8. During a mean follow-up of 10.1 years, GFR declined rapidly in 241 (9.2%) participants, incident CKD developed in 277 (11.3%), and albuminuria developed in 194 (10.1%). Higher plasma levels of galectin-3 were associated with rapid decline in eGFR (per 1-SD log-galectin-3; adjusted odds ratio [OR], 1.49; 95% confidence interval [CI], 1.28 to 1.73]) and a higher risk of incident CKD (OR, 1.47; 95% CI, 1.27 to 1.71), but not with the risk of incident albuminuria. The addition of galectin-3 to clinical predictors improved the C-statistic (0.837-0.845; P=0.02) but did not reach predefined thresholds for clinically significant improvements to risk prediction based on reclassification indices. In conclusion, elevated levels of plasma galectin-3 are associated with increased risks of rapid GFR decline and of incident CKD in the community, which calls for further study in higher-risk groups.

American Journal of Nephrology, 2012

Cardiovascular risk factors are associated with the development of chronic kidney disease (CKD), ... more Cardiovascular risk factors are associated with the development of chronic kidney disease (CKD), and CKD and vascular disease are etiologically linked. Evidence suggests deficiencies of vitamins D and K may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. We hypothesized that deficiencies of vitamins D and K may be associated with incident CKD and/or incident albuminuria amongst members of the general population. We analyzed 1,442 Framingham Heart Study participants (mean age 58 years; 50.5% women), free of CKD (eGFR <60 ml/min/1.73 m(2)), with a mean follow-up of 7.8 years in 2005-2008. Incident albuminuria was defined using sex-specific cut-offs of urine albumin-to-creatinine ratio (≥17 mg/g men and ≥25 mg/g women). Baseline log plasma phylloquinone (vitamin K(1)) and 25(OH)D levels, analyzed as continuous variables and by quartile, were related to risk of incident CKD (n = 108) and incident albuminuria (n = 106) using logistic regression models adjusted for standard risk factors. Participants in the highest phylloquinone quartile (≥1.78 nmol/l) had an increased risk of CKD (multivariable-adjusted OR Q(4) vs. Q(1) 2.39; p = 0.006) and albuminuria at follow-up (multivariable-adjusted OR Q(4) vs. Q(1) 1.95; p = 0.05), whereas no association was observed with continuous phylloquinone levels for either endpoint. Deficiency of 25(OH)D was not associated with incident CKD or albuminuria in either analysis. Contrary to our hypothesis, higher plasma phylloquinone levels are associated with an increased risk of incident CKD. Whether plasma phylloquinone is a marker for another unmeasured risk factor requires further study. External validation is necessary given the unexpected nature of these results.

The American Journal of Medicine, 2012

American Journal of Kidney Diseases, 2010

Background-Predictors for incident albuminuria are not well-known in population based cohorts. Th... more Background-Predictors for incident albuminuria are not well-known in population based cohorts. The purpose of this study was to identify predictors of incident albuminuria in an unselected, middle-aged population.

American Journal of Kidney Diseases, 2011

Background: Connective tissue growth factor (CTGF) is involved in the development and progression... more Background: Connective tissue growth factor (CTGF) is involved in the development and progression of kidney diseases, including diabetic nephropathy and kidney fibrosis, but also may have a role in mesangial repair after injury. It is unknown whether, in the general population, urinary CTGF levels are associated with a decrease in estimated glomerular filtration rate (eGFR) to Ͻ60 mL/min/1.73 m 2 (ie, development of chronic kidney disease [CKD] stage 3).

American journal of kidney diseases : the official journal of the National Kidney Foundation, Jan 1, 2011

This review discusses how the internet currently is being used to provide medical education in th... more This review discusses how the internet currently is being used to provide medical education in the nephrology community and addresses some of the issues and dilemmas unique to using this media. It focuses on how blogs, wikis, podcasts/YouTube, social bookmarking/media, and mobile devices are used to deliver e-learning in nephrology. Am J Kidney Dis. 58(4):512-518.

Nephron Clinical Practice, 2011

The current review collates what is already known of the genetics of chronic kidney disease (CKD)... more The current review collates what is already known of the genetics of chronic kidney disease (CKD), and focuses on new trends in genome-wide assessment of the inherited component of susceptibility to this condition. Early efforts to identify kidney disease susceptibility genetic loci using linkage and candidate gene strategies proved disappointing. More recently, genome-wide association studies have yielded highly promising results suggesting a number of potential candidate genes and genomic regions that may contribute to the pathogenesis of CKD. Renal failure susceptibility genes identified by these methods, such as MYH9, have yielded novel insights into the pathogenesis of CKD. Genome-wide association studies of CKD are beginning to define the genomic architecture of kidney disease and will impact our understanding of how genetic variation influences susceptibility to this condition.

American Journal of Kidney Diseases, 2011

This review discusses how the internet currently is being used to provide medical education in th... more This review discusses how the internet currently is being used to provide medical education in the nephrology community and addresses some of the issues and dilemmas unique to using this media. It focuses on how blogs, wikis, podcasts/YouTube, social bookmarking/media, and mobile devices are used to deliver e-learning in nephrology.

PLoS Genetics, 2011

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and en... more Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR ,60ml/min/1.73m 2 at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

Journal of the American Society of Nephrology, 2013

Whether novel biomarkers improve the assessment of incident kidney disease and related adverse ou... more Whether novel biomarkers improve the assessment of incident kidney disease and related adverse outcomes remains to be tested in longitudinal observational studies. We tested 14 urinary biomarkers for association with incident kidney, cardiovascular, and mortality outcomes in 2948 Framingham Heart Study participants. Baseline examinations were performed between 1995 and 1998; mean follow-up was 10.1 years for renal outcomes and 11.2 years for survival analyses. Primary outcomes were incident CKD, incident albuminuria, incident cardiovascular disease, and all-cause mortality. Secondary analyses assessed incident congestive heart failure (CHF) and mortality with coexistent kidney disease. Biomarkers were tested for association with renal end points using logistic regression and incident cardiovascular and mortality outcomes in proportional hazards models; a1-microglobulin, Kim-1, and TFF-3 predicted allcause mortality (hazard ratio per SD increase in log-transformed biomarker [HR] range, 1.15 to 1.21; 95% confidence interval [CI] range, 1.04 to 1.34; P values=0.007 to ,0.001), whereas a1-microglobulin, b2-microglobulin, KIM-1, and TFF-3 associated with death with coexistent kidney disease (HR range, 1.72-2.25; 95% CI, 1.17 to 3.24; P values,0.01). KIM-1 also associated with the risk of incident CHF (HR, 1.32; 95% CI, 1.07 to 1.63; P=0.008). CTGF associated nominally with CKD (HR, 0.83; 95% CI, 0.71 to 0.98; P=0.03), but no other biomarkers associated with incident CKD or albuminuria. Addition of a1-microglobulin and TFF-3 resulted in a nonsignificant net reclassification index (NRI) of 3% for all-cause mortality beyond clinical risk factors. In conclusion, components of a panel of 14 subclinical biomarkers of kidney injury were associated with important clinical outcomes and merit additional investigation.

Journal of the American Society of Nephrology, 2013

Galectin-3, a profibrotic mediator, is linked to the development of renal fibrosis in animal mode... more Galectin-3, a profibrotic mediator, is linked to the development of renal fibrosis in animal models and inversely correlates with GFR in humans, but whether galectin-3 predicts incident kidney disease is unknown. Here, we assessed renal outcomes for 2450 Framingham Offspring participants who attended examination 6 (1995-1998) and had follow-up data at examination 8 (2005)(2006)(2007)(2008). Renal outcomes of interest included rapid decline in renal function ($3 ml/min per 1.73 m 2 per year decline in estimated GFR [eGFR]), CKD (eGFR , 60 ml/min per 1.73 m 2 ), and albuminuria (albumin-to-creatinine ratio 17mg/ginmenor17 mg/g in men or 17mg/ginmenor25 mg/g in women). We used multivariable logistic regression models to evaluate associations between galectin-3 with incident renal outcomes at examination 8. During a mean follow-up of 10.1 years, GFR declined rapidly in 241 (9.2%) participants, incident CKD developed in 277 (11.3%), and albuminuria developed in 194 (10.1%). Higher plasma levels of galectin-3 were associated with rapid decline in eGFR (per 1-SD log-galectin-3; adjusted odds ratio [OR], 1.49; 95% confidence interval [CI], 1.28 to 1.73]) and a higher risk of incident CKD (OR, 1.47; 95% CI, 1.27 to 1.71), but not with the risk of incident albuminuria. The addition of galectin-3 to clinical predictors improved the C-statistic (0.837-0.845; P=0.02) but did not reach predefined thresholds for clinically significant improvements to risk prediction based on reclassification indices. In conclusion, elevated levels of plasma galectin-3 are associated with increased risks of rapid GFR decline and of incident CKD in the community, which calls for further study in higher-risk groups.

American Journal of Nephrology, 2012

Cardiovascular risk factors are associated with the development of chronic kidney disease (CKD), ... more Cardiovascular risk factors are associated with the development of chronic kidney disease (CKD), and CKD and vascular disease are etiologically linked. Evidence suggests deficiencies of vitamins D and K may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. We hypothesized that deficiencies of vitamins D and K may be associated with incident CKD and/or incident albuminuria amongst members of the general population. We analyzed 1,442 Framingham Heart Study participants (mean age 58 years; 50.5% women), free of CKD (eGFR <60 ml/min/1.73 m(2)), with a mean follow-up of 7.8 years in 2005-2008. Incident albuminuria was defined using sex-specific cut-offs of urine albumin-to-creatinine ratio (≥17 mg/g men and ≥25 mg/g women). Baseline log plasma phylloquinone (vitamin K(1)) and 25(OH)D levels, analyzed as continuous variables and by quartile, were related to risk of incident CKD (n = 108) and incident albuminuria (n = 106) using logistic regression models adjusted for standard risk factors. Participants in the highest phylloquinone quartile (≥1.78 nmol/l) had an increased risk of CKD (multivariable-adjusted OR Q(4) vs. Q(1) 2.39; p = 0.006) and albuminuria at follow-up (multivariable-adjusted OR Q(4) vs. Q(1) 1.95; p = 0.05), whereas no association was observed with continuous phylloquinone levels for either endpoint. Deficiency of 25(OH)D was not associated with incident CKD or albuminuria in either analysis. Contrary to our hypothesis, higher plasma phylloquinone levels are associated with an increased risk of incident CKD. Whether plasma phylloquinone is a marker for another unmeasured risk factor requires further study. External validation is necessary given the unexpected nature of these results.

The American Journal of Medicine, 2012

American Journal of Kidney Diseases, 2010

Background-Predictors for incident albuminuria are not well-known in population based cohorts. Th... more Background-Predictors for incident albuminuria are not well-known in population based cohorts. The purpose of this study was to identify predictors of incident albuminuria in an unselected, middle-aged population.

American Journal of Kidney Diseases, 2011

Background: Connective tissue growth factor (CTGF) is involved in the development and progression... more Background: Connective tissue growth factor (CTGF) is involved in the development and progression of kidney diseases, including diabetic nephropathy and kidney fibrosis, but also may have a role in mesangial repair after injury. It is unknown whether, in the general population, urinary CTGF levels are associated with a decrease in estimated glomerular filtration rate (eGFR) to Ͻ60 mL/min/1.73 m 2 (ie, development of chronic kidney disease [CKD] stage 3).

American journal of kidney diseases : the official journal of the National Kidney Foundation, Jan 1, 2011

This review discusses how the internet currently is being used to provide medical education in th... more This review discusses how the internet currently is being used to provide medical education in the nephrology community and addresses some of the issues and dilemmas unique to using this media. It focuses on how blogs, wikis, podcasts/YouTube, social bookmarking/media, and mobile devices are used to deliver e-learning in nephrology. Am J Kidney Dis. 58(4):512-518.