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The association of cell cycle checkpoint 2 variants and kidney function: findings of the Family Blood Pressure Program and the Atherosclerosis Risk In Communities study.

ABSTRACT: Recent experimental evidence suggests that DNA damage and cell cycle regulatory proteins are involved in kidney injury and apoptosis. The checkpoint 2 gene (CHEK2) is an important transducer in DNA damage signaling pathways in response to injury, and therefore, CHEK2 variants may affect susceptibility to kidney disease.We used tag-single-nucleotide polymorphisms (tag-SNPs) to evaluate the association of the CHEK2 with kidney function (estimated glomerular filtration rate, eGFR) in 1,549 African-American and 1,423 white Hypertension Genetic Epidemiology Network (HyperGEN) participants. We performed replication analyses in the Genetic Epidemiology Network of Arteriopathy (GENOA) participants (1,746 African Americans and 1,418 whites), GenNet participants (706 whites), and Atherosclerosis Risk in Communities (ARIC) study participants (3,783 African Americans and 10,936 whites). All analyses were race-stratified and used additive genetic models with adjustments for covariates and for family structure, if needed.One tag-SNP, rs5762764, was associated with eGFR in HyperGEN (P = 0.003) and GENOA white participants (P = 0.009), and it was significantly associated with eGFR in meta-analyses (P = 0.002). The associations were independent of type 2 diabetes.These results suggest that CHEK2 variants may influence eGFR in the context of hypertension.

SUBMITTER: Franceschini N

PROVIDER: S-EPMC2727134 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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The association of cell cycle checkpoint 2 variants and kidney function: findings of the Family Blood Pressure Program and the Atherosclerosis Risk In Communities study.

Franceschini Nora N North Kari E KE Arnett Donna D Pankow James S JS Chung Jay H JH Baird Lisa L Leppert Mark F MF Eckfeldt John H JH Boerwinkle Eric E Gu C Charles CC Lewis Cora E CE Myers Richard H RH Turner Stephen T ST Weder Alan A Kao W H Linda WH Mosley Thomas H TH Chakravarti Aravinda A Kramer Holly H Zhang Jinghui J Hunt Steven C SC

American journal of hypertension 20090305 5

<h4>Background</h4>Recent experimental evidence suggests that DNA damage and cell cycle regulatory proteins are involved in kidney injury and apoptosis. The checkpoint 2 gene (CHEK2) is an important transducer in DNA damage signaling pathways in response to injury, and therefore, CHEK2 variants may affect susceptibility to kidney disease.<h4>Methods</h4>We used tag-single-nucleotide polymorphisms (tag-SNPs) to evaluate the association of the CHEK2 with kidney function (estimated glomerular filtr ...[more]

PMID: 19265784

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Project description:Rationale & Objective Novel metabolite biomarkers of kidney failure with replacement therapy (KFRT) may help identify people at high risk for adverse kidney outcomes and implicated pathways may aid in developing targeted therapeutics. Study Design Prospective cohort. Setting & Participants The cohort included 3,799 Atherosclerosis Risk in Communities study participants with serum samples available for measurement at visit 1 (1987-1989). Exposure Baseline serum levels of 318 metabolites. Outcomes Incident KFRT, kidney failure (KFRT, estimated glomerular filtration rate <15 mL/min/1.73 m2, or death from kidney disease). Analytical Approach Because metabolites are often intercorrelated and represent shared pathways, we used a high dimension reduction technique called Netboost to cluster metabolites. Longitudinal associations between clusters of metabolites and KFRT and kidney failure were estimated using a Cox proportional hazards model. Results Mean age of study participants was 53 years, 61% were African American, and 13% had diabetes. There were 160 KFRT cases and 357 kidney failure cases over a mean of 23 years. The 314 metabolites were grouped in 43 clusters. Four clusters were significantly associated with risk of KFRT and 6 were associated with kidney failure (including 3 shared clusters). The 3 shared clusters suggested potential pathways perturbed early in kidney disease: cluster 5 (15 metabolites involved in alanine, aspartate, and glutamate metabolism as well as 5-oxoproline and several gamma-glutamyl amino acids), cluster 26 (6 metabolites involved in sugar and inositol phosphate metabolism), and cluster 34 (21 metabolites involved in glycerophospholipid metabolism). Several individual metabolites were also significantly associated with both KFRT and kidney failure, including glucose and mannose, which were associated with higher risk of both outcomes, and 5-oxoproline, gamma-glutamyl amino acids, linoleoylglycerophosphocholine, 1,5-anhydroglucitol, which were associated with lower risk of both outcomes. Limitations Inability to determine if the metabolites cause or are a consequence of changes in kidney function. Conclusions We identified several clusters of metabolites reproducibly associated with development of KFRT. Future experimental studies are needed to validate our findings as well as continue unraveling metabolic pathways involved in kidney function decline. Visual Abstract

Project description:People with end-stage renal disease are at high risk for bone fracture. Less is known about fracture risk in milder chronic kidney disease and whether chronic kidney disease-associated fracture risk varies by sex or assessment with alternative kidney markers.Prospective cohort study.10,955 participants from the Atherosclerosis Risk in Communities (ARIC) Study followed up from 1996 to 2011.Kidney function as assessed by creatinine-based estimated glomerular filtration rate (eGFRcr), urine albumin-creatinine ratio, and alternative filtration markers.Fracture-related hospitalizations determined by diagnostic code.Baseline kidney markers; hospitalizations identified by self-report during annual telephone contact and active surveillance of local hospital discharge lists.Mean age of participants was 63 years, 56% were women, and 22% were black. During a median follow-up of 13 years, there were 722 incident fracture-related hospitalizations. Older age, female sex, and white race were associated with higher risk for fracture (P<0.001). The relationship between eGFRcr and fracture risk was nonlinear: <60mL/min/1.73m(2), lower eGFRcr was associated with higher fracture risk (adjusted HR per 10mL/min/1.73m(2) lower, 1.24; 95% CI, 1.05-1.47); there was no statistically significant association for ?60mL/min/1.73m(2) in the primary analysis. In contrast, there was a graded association between other markers of kidney function and subsequent fracture, including albumin-creatinine ratio (HR per doubling, 1.10; 95% CI, 1.06-1.14), cystatin C-based eGFR (HR per 1-SD decrease, 1.15; 95% CI, 1.06-1.25), and 1/?2-microglobulin (HR per 1-SD decrease, 1.26, 95% CI, 1.15-1.37).No bone mineral density assessment; one-time measurement of kidney function.Both low eGFR and higher albuminuria were significant risk factors for fracture in this community-based population. The shape of the association in the upper ranges of eGFR varied by the filtration marker used in estimation.

Project description:BackgroundFrail individuals are at increased risk for poor outcomes, including adverse drug events. Kidney function is often compromised in frailty and is a key consideration in medication choice and dosing; however, creatinine-based measures of kidney function may be biased in frail individuals.Study designObservational study.Setting & participants4,987 community-dwelling older men and women with complete data who participated in visit 5 of the Atherosclerosis Risk in Communities (ARIC) Study (2011-2013).PredictorsKidney measures included glomerular filtration rate (GFR) estimated using serum creatinine (eGFRcr) and serum cystatin C level (eGFRcys) and urine albumin-creatinine ratio.OutcomeFrailty, defined using established criteria of 3 or more frailty characteristics (weight loss, slowness, exhaustion, weakness, and low physical activity).Results341 (7%) participants were classified as frail, 1,475 (30%) had eGFRcr<60mL/min/1.73m2, 2,480 (50%) had eGFRcys<60mL/min/1.73m2, and 1,006 (20%) had albuminuria with albumin excretion ≥ 30mg/g. Among frail participants, prevalences of eGFRcr and eGFRcys<60mL/min/1.73m2 were 45% and 77%, respectively. Adjusted for covariates, frailty showed a moderate association with eGFRcr and a strong association with eGFRcys and albumin-creatinine ratio. Frail individuals with eGFRcr of 60 to <75mL/min/1.73m2 were frequently reclassified to lower eGFR categories using eGFRcys (49% to 45-<60, 32% to 30-<45, and 3% to <30mL/min/1.73m2). Hyperpolypharmacy (taking ≥10 classes of medications) was more common in frail individuals (54% vs 38% of nonfrail), including classes requiring kidney clearance (eg, digoxin) and associated with falls and subsequent complications (eg, hypnotic/sedatives and anticoagulants).LimitationsCross-sectional study design.ConclusionsFrail individuals had a high prevalence of reduced kidney function, with large discrepancies when reduced kidney function was classified by eGFRcys versus eGFRcr. Given the substantial medication burden and uncertainty in chronic kidney disease classification, confirmation of kidney function with alternative biomarkers may be warranted to ensure careful prescribing practices in this vulnerable population.

Project description:BACKGROUND:Reduced lung function is associated with clinical outcomes such as cardiovascular disease. However, little is known about its association with incident end-stage renal disease (ESRD) and chronic kidney disease (CKD). STUDY DESIGN:Prospective cohort study. SETTING & PARTICIPANTS:14,946 participants aged 45 to 64 years at baseline (1987-1989) in the Atherosclerosis Risk in Communities (ARIC) Study (45.0% men and 25.2% black), with follow-up through 2012. PREDICTORS:Race- and sex-specific quartiles of percent-predicted forced vital capacity (FVC) and the proportion of forced expiratory volume in 1 second of expiration to FVC (FEV1/FVC) at baseline determined with spirometry. OUTCOMES:Incident ESRD (defined here as renal replacement therapy or death due to CKD) as the primary outcome and incident CKD (defined here as ESRD, ?25% decline in estimated glomerular filtration rate to a level <60mL/min/1.73m2, or CKD-related hospitalizations/deaths) as the secondary outcome. RESULTS:During a median follow-up of 23.6 years, 526 (3.5%) participants developed ESRD. After adjusting for potential confounders, the cause-specific HR of incident ESRD for the lowest (vs highest) quartile was 1.72 (95% CI, 1.31-2.26) for percent-predicted FVC and 1.33 (95% CI, 1.03-1.73) for FEV1/FVC. Compared to a high-normal lung function pattern, a mixed pattern (ie, percent-predicted FVC<80% and FEV1/FVC<70%; 3.4% of participants) demonstrated the highest adjusted cause-specific HR of ESRD at 2.28 (95% CI, 1.50-3.45), followed by the restrictive pattern (ie, percent-predicted FVC<80% and FEV1/FVC?70%; 4.8% of participants) at 2.03 (95% CI, 1.47-2.81), obstructive pattern (ie, percent-predicted FVC?80% and FEV1/FVC<70%; 18.9% of participants) at 1.47 (95% CI, 1.09-1.99), and low-normal pattern (ie, percent-predicted FVC 80%-<100% and FEV1/FVC?70%, or percent-predicted FVC?80% and FEV1/FVC 70%-<75%; 44.3% of participants) at 1.21 (95% CI, 0.94-1.55). Similar associations were seen with incident CKD. LIMITATIONS:Limited number of participants with moderate/severe lung dysfunction and spirometry only at baseline. CONCLUSIONS:Reduced lung function, particularly lower percent-predicted FVC, is independently associated with CKD progression. Our findings suggest a potential pathophysiologic contribution of reduced lung function to the development of CKD and a need for monitoring kidney function in persons with reduced lung function.

Dataset Information

The association of cell cycle checkpoint 2 variants and kidney function: findings of the Family Blood Pressure Program and the Atherosclerosis Risk In Communities study.

Publications

The association of cell cycle checkpoint 2 variants and kidney function: findings of the Family Blood Pressure Program and the Atherosclerosis Risk In Communities study.

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