@article {697, title = {Cardiovascular disease risk status in elderly persons with renal insufficiency.}, journal = {Kidney Int}, volume = {62}, year = {2002}, month = {2002 Sep}, pages = {997-1004}, abstract = {

BACKGROUND: Renal insufficiency has been independently associated with incident cardiovascular disease events in some, but not all, prospective studies. We determined the prevalence of elevated cardiovascular disease risk status among elderly persons with renal insufficiency.

METHODS: This study is a cross-sectional analysis using data collected at the baseline visit of the Cardiovascular Health Study, which enrolled 5888 community dwelling adults aged 65 years or older from four clinical centers in the United States. Renal insufficiency was defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men. The outcomes of this study included prevalent cardiovascular disease [prior coronary heart disease (CHD) or stroke], subclinical cardiovascular disease (abnormal values of ankle-arm index, carotid ultrasound, and echocardiography) and elevated cardiovascular risk based upon a diagnosis of diabetes and the Framingham equations. The association between renal insufficiency and cardiovascular risk status was estimated with and without adjustment for other cardiovascular predictors.

RESULTS: Among the 5808 participants with creatinine levels measured at entry, 15.9\% of men (N = 394), and 7.6\% of women (N = 254) had renal insufficiency. The prevalence of either clinical or subclinical cardiovascular disease was 64\% in persons with renal insufficiency compared with 43\% in those without it [odds ratio (OR) 2.34; 95\% confidence interval (95\% CI), 1.96, 2.80]. After adjustment for other cardiovascular risk factors, renal insufficiency remained significantly associated with clinical and subclinical cardiovascular disease (adjusted OR 1.43; 95\% CI, 1.18, 1.75), but the magnitude of association was substantially reduced. After combining clinical and subclinical cardiovascular disease, diabetes, and an estimated risk>20\% by the Framingham equations, 78\% of men and 61\% of women with renal insufficiency had elevated cardiovascular risk status.

CONCLUSIONS: Renal insufficiency is a marker for elevated cardiovascular disease risk in community dwelling elderly adults.

}, keywords = {Age Distribution, Aged, Cholesterol, HDL, Cholesterol, LDL, Coronary Disease, Creatinine, Cross-Sectional Studies, Female, Humans, Kidney Failure, Chronic, Male, Prevalence, Prospective Studies, Risk Factors}, issn = {0085-2538}, doi = {10.1046/j.1523-1755.2002.00522.x}, author = {Shlipak, Michael G and Fried, Linda F and Crump, Casey and Bleyer, Anthony J and Manolio, Teri A and Tracy, Russell P and Furberg, Curt D and Psaty, Bruce M} } @article {735, title = {Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals.}, journal = {J Am Coll Cardiol}, volume = {41}, year = {2003}, month = {2003 Apr 16}, pages = {1364-72}, abstract = {

OBJECTIVES: This study was designed to evaluate the relationship between elevated creatinine levels and cardiovascular events.

BACKGROUND: End-stage renal disease is associated with high cardiovascular morbidity and mortality. The association of mild to moderate renal insufficiency with cardiovascular outcomes remains unclear.

METHODS: We analyzed data from the Cardiovascular Health Study, a prospective population-based study of subjects, aged >65 years, who had a serum creatinine measured at baseline (n = 5,808) and were followed for a median of 7.3 years. Proportional hazards models were used to examine the association of creatinine to all-cause mortality and incident cardiovascular mortality and morbidity. Renal insufficiency was defined as a creatinine level > or =1.5 mg/dl in men or > or =1.3 mg/dl in women.

RESULTS: An elevated creatinine level was present in 648 (11.2\%) participants. Subjects with elevated creatinine had higher overall (76.7 vs. 29.5/1,000 years, p < 0.001) and cardiovascular (35.8 vs. 13.0/1,000 years, p < 0.001) mortality than those with normal creatinine levels. They were more likely to develop cardiovascular disease (54.0 vs. 31.8/1,000 years, p < 0.001), stroke (21.1 vs. 11.9/1,000 years, p < 0.001), congestive heart failure (38.7 vs. 17/1,000 years, p < 0.001), and symptomatic peripheral vascular disease (10.6 vs. 3.5/1,000 years, p < 0.001). After adjusting for cardiovascular risk factors and subclinical disease measures, elevated creatinine remained a significant predictor of all-cause and cardiovascular mortality, total cardiovascular disease (CVD), claudication, and congestive heart failure (CHF). A linear increase in risk was observed with increasing creatinine.

CONCLUSIONS: Elevated creatinine levels are common in older adults and are associated with increased risk of mortality, CVD, and CHF. The increased risk is apparent early in renal disease.

}, keywords = {Aged, Cardiovascular Diseases, Confidence Intervals, Creatinine, Female, Heart Failure, Humans, Intermittent Claudication, Kidney Failure, Chronic, Male, Odds Ratio, Predictive Value of Tests, Survival Analysis}, issn = {0735-1097}, doi = {10.1016/s0735-1097(03)00163-3}, author = {Fried, Linda F and Shlipak, Michael G and Crump, Casey and Bleyer, Anthony J and Gottdiener, John S and Kronmal, Richard A and Kuller, Lewis H and Newman, Anne B} } @article {775, title = {The presence of frailty in elderly persons with chronic renal insufficiency.}, journal = {Am J Kidney Dis}, volume = {43}, year = {2004}, month = {2004 May}, pages = {861-7}, abstract = {

BACKGROUND: Frailty has been defined as a tool to define individuals who lack functional reserve and are at risk for functional decline. We hypothesized that chronic renal insufficiency (CRI) would be associated with a greater prevalence of frailty and disability in the elderly.

METHODS: This cross-sectional analysis used baseline data collected from the Cardiovascular Health Study, which enrolled 5,888 community-dwelling adults aged 65 years or older from 4 clinical centers in the United States. Renal insufficiency is defined as a serum creatinine level of 1.3 mg/dL or greater (> or =115 micromol/L) in women and 1.5 mg/dL or greater (> or =133 micromol/L) in men. Frailty is defined by the presence of 3 of the following abnormalities: unintentional weight loss, self-reported exhaustion, measured weakness, slow walking speed, and low physical activity. Disability is defined as any self-reported difficulty with activities of daily living.

RESULTS: Among 5,808 participants with creatinine levels measured at entry, 15.9\% of men (n = 394) and 7.6\% of women (n = 254) had CRI. Prevalences of frailty (15\% versus 6\%; P < 0.001) and disability (12\% versus 7\%; P = 0.001) were greater in participants with CRI compared with those with normal renal function. After multivariate adjustment for comorbidity, CRI remained significantly associated with frailty (odds ratio, 1.76; 95\% confidence interval, 1.28 to 2.41), but not disability (odds ratio, 1.26; 95\% confidence interval, 0.94 to 1.69).

CONCLUSION: Elderly persons with CRI have a high prevalence of frailty, which may signal their risk for progression to adverse health outcomes. If confirmed in other studies, identification of frailty in patients with CRI may warrant special interventions to preserve their independence, quality of life, and survival.

}, keywords = {Activities of Daily Living, Aged, Cross-Sectional Studies, Female, Frail Elderly, Humans, Kidney Failure, Chronic, Male, United States}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2003.12.049}, author = {Shlipak, Michael G and Stehman-Breen, Catherine and Fried, Linda F and Song, Xiao and Siscovick, David and Fried, Linda P and Psaty, Bruce M and Newman, Anne B} } @article {865, title = {Kidney function as a predictor of noncardiovascular mortality.}, journal = {J Am Soc Nephrol}, volume = {16}, year = {2005}, month = {2005 Dec}, pages = {3728-35}, abstract = {

Chronic kidney disease is associated with a higher risk for cardiovascular mortality, as well as all-cause mortality. Whether chronic kidney disease is a predictor of noncardiovascular mortality is less clear. To further explore the latter, the association of kidney function with total noncardiovascular mortality and cause-specific mortality was assessed in the Cardiovascular Health Study, a community-based cohort of older individuals. Kidney disease was assessed using cystatin C and estimated GFR in 4637 participants in 1992 to 1993. Participants were followed until June 30, 2001. Deaths were adjudicated as cardiovascular or noncardiovascular disease by committee, and an underlying cause of death was assigned. The associations of kidney function with total noncardiovascular mortality and cause-specific mortality were analyzed by proportional hazards regression. Noncardiovascular mortality rates increased with higher cystatin C quartiles (16.8, 17.1, 21.6, and 50.0 per 1000 person-years). The association of cystatin C with noncardiovascular mortality persisted after adjustment for demographic factors; the presence of diabetes, C-reactive protein, hemoglobin, and prevalent cardiovascular disease; and measures of atherosclerosis (hazard ratio 1.69; 95\% confidence interval 1.33 to 2.15, for the fourth quartile versus the first quartile). Results for estimated GFR were similar. The risk for noncardiac deaths attributed to pulmonary disease, infection, cancer, and other causes was similarly associated with cystatin C levels. Kidney function predicts noncardiovascular mortality from multiple causes in the elderly. Further research is needed to understand the mechanisms and evaluate interventions to reduce the high mortality rate in chronic kidney disease.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Cardiovascular Diseases, Cause of Death, Cohort Studies, Confidence Intervals, Creatinine, Cystatin C, Cystatins, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Kidney Function Tests, Longitudinal Studies, Male, Probability, Proportional Hazards Models, Risk Assessment, Severity of Illness Index, Survival Analysis, United States}, issn = {1046-6673}, doi = {10.1681/ASN.2005040384}, author = {Fried, Linda F and Katz, Ronit and Sarnak, Mark J and Shlipak, Michael G and Chaves, Paulo H M and Jenny, Nancy Swords and Stehman-Breen, Catherine and Gillen, Dan and Bleyer, Anthony J and Hirsch, Calvin and Siscovick, David and Newman, Anne B} } @article {926, title = {Sleep apnea in patients on conventional thrice-weekly hemodialysis: comparison with matched controls from the Sleep Heart Health Study.}, journal = {J Am Soc Nephrol}, volume = {17}, year = {2006}, month = {2006 Dec}, pages = {3503-9}, abstract = {

Sleep-disordered breathing (SDB) has been noted commonly in hemodialysis (HD) patients, but it is not known whether this is related directly to the treatment of kidney failure with HD or to the higher prevalence of obesity and older age. Forty-six HD patients were compared with 137 participants from the Sleep Heart Health Study (SHHS) who were matched for age, gender, body mass index (BMI), and race. Home unattended polysomnography was performed and scored using similar protocols. The study sample was 62.7 +/- 10.1 yr, was predominantly male (72\%) and white (63\%), and had an average BMI of 28 +/- 5.3 kg/m(2). The HD sample had a higher systolic BP (137 versus 121 mmHg; P < 0.01) and a higher prevalence of diabetes (33 versus 9\%; P < 0.01) and cardiovascular disease (33 versus 13\%; P < 0.01) compared with the SHHS sample. The HD group had significantly less sleep time (320 versus 379 min; P < 0.0001) but similar sleep efficiency. HD patients had a higher frequency of arousals per hour (25.1 versus 17.1; P < 0.0001) and apnea-hypopneas per hour (27.2 versus 15.2; P < 0.0001) and greater percentage of the total sleep time below an oxygen saturation of 90\% (7.2 versus 1.8; P < 0.0001). HD patients were more likely to have severe SDB (>30 respiratory events per hour) compared with the SHHS sample (odds ratio 4.07; 95\% confidence interval 1.83 to 9.07). There was a strong association of HD with severe SDB and nocturnal hypoxemia independent of age, BMI, and the higher prevalence of chronic disease. The potential mechanisms for the higher likelihood of SDB in the HD population must be identified to provide specific prevention and therapy.

}, keywords = {Blood Pressure, Body Mass Index, Cardiovascular Diseases, Case-Control Studies, Cross-Sectional Studies, Diabetes Mellitus, Female, Humans, Kidney Failure, Chronic, Male, Middle Aged, Prevalence, Renal Dialysis, Severity of Illness Index, Sleep Apnea Syndromes}, issn = {1046-6673}, doi = {10.1681/ASN.2006060659}, author = {Unruh, Mark L and Sanders, Mark H and Redline, Susan and Piraino, Beth M and Umans, Jason G and Hammond, Terese C and Sharief, Imran and Punjabi, Naresh M and Newman, Anne B} } @article {933, title = {Association of kidney function with incident hip fracture in older adults.}, journal = {J Am Soc Nephrol}, volume = {18}, year = {2007}, month = {2007 Jan}, pages = {282-6}, abstract = {

Kidney dysfunction is associated with bone loss, and patients with ESRD have an increased risk for hip fracture. However, the association of mild to moderate kidney disease with hip fracture has not been studied previously. The association of kidney function with incident hip fracture was examined among participants in the Cardiovascular Health Study, a community-based cohort of older individuals. The primary measure of kidney function was serum cystatin C, a measure that does not depend on lean mass. Hip fractures were identified using International Classification of Diseases, Ninth Revision codes for hospitalizations. A total of 4699 individuals had cystatin C measured in 1992 to 1993 and did not have a hip fracture before cystatin C measurement. The association of kidney function with hip fracture was analyzed with Cox proportional hazards models. Analyses were conducted separately for men and women. After a mean follow-up of 7.1 yr, 195 incident hip fractures occurred in women and 79 occurred in men. Higher cystatin C levels were associated with a higher risk for fracture in women (hazard ratio [HR] 1.26; 95\% confidence interval [CI] 1.14 to 1.38 per SD) and in men (HR 1.27; 95\% CI 1.11 to 1.46). After multivariable adjustment, higher cystatin C levels were significantly associated with hip fracture in women (HR 1.16; 95\% CI 1.01, 1.33) but not in men (HR 1.14; 95\% CI 0.86 to 1.52), although the magnitude of the association was similar. Kidney dysfunction, as assessed by cystatin C, is associated with an increased risk for hip fracture. Further studies are needed to evaluate potential mediators of this relationship and to assess whether interventions can decrease this risk.

}, keywords = {Aged, Aged, 80 and over, Cystatin C, Cystatins, Female, Hip Fractures, Humans, Kidney, Kidney Failure, Chronic, Longitudinal Studies, Male, Osteoporosis, Prospective Studies, Risk Factors, Sex Factors}, issn = {1046-6673}, doi = {10.1681/ASN.2006050546}, author = {Fried, Linda F and Biggs, Mary Louise and Shlipak, Michael G and Seliger, Stephen and Kestenbaum, Bryan and Stehman-Breen, Catherine and Sarnak, Mark and Siscovick, David and Harris, Tamara and Cauley, Jane and Newman, Anne B and Robbins, John} } @article {964, title = {Individual and neighborhood socioeconomic status and progressive chronic kidney disease in an elderly population: The Cardiovascular Health Study.}, journal = {Soc Sci Med}, volume = {65}, year = {2007}, month = {2007 Aug}, pages = {809-21}, abstract = {

Few studies have focused on the association between socioeconomic status (SES) and progressive chronic kidney disease (pCKD) in an elderly population. We conducted a cohort study of 4735 Cardiovascular Health Study participants, ages 65 and older and living in 4 US communities, to examine the independent risk of pCKD associated with income, education and living in a low SES area. pCKD was defined as creatinine elevation 0.4 mg/dL (35 micromol/L) over a 4-7 year follow-up or CKD hospitalization. Area SES was characterized using measures of income, wealth, education and occupation for 1990 (corresponding to time of enrollment) US Census block groups of residence. Age and study site-adjusted incidence rates (per 1000 person years) of pCKD by quartiles of area-level SES score, income and education showed decreasing rates with increasing SES. Cox proportional hazards models showed that living in the lowest SES area quartile, as opposed to the highest, was associated with 50\% greater risk of pCKD, after adjusting for age, gender, study site, baseline creatinine, and individual-level SES. This increased risk and trend persisted after adjusting for lifestyle risk factors, diabetes and hypertension. We found no significant independent associations between pCKD and individual-level income or education (after adjusting for all other SES factors). As such, living in a low SES area is associated with greater risk of pCKD in an elderly US population.

}, keywords = {Age Factors, Aged, Cohort Studies, Female, Humans, Incidence, Kidney Failure, Chronic, Male, Proportional Hazards Models, Residence Characteristics, Risk Factors, Sex Factors, Social Class, United States}, issn = {0277-9536}, doi = {10.1016/j.socscimed.2007.04.011}, author = {Merkin, Sharon Stein and Diez Roux, Ana V and Coresh, Josef and Fried, Linda F and Jackson, Sharon A and Powe, Neil R} } @article {1001, title = {Chronic kidney disease increases risk for venous thromboembolism.}, journal = {J Am Soc Nephrol}, volume = {19}, year = {2008}, month = {2008 Jan}, pages = {135-40}, abstract = {

Chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease morbidity and mortality, but its association with incident venous thromboembolism (VTE) in non-dialysis-dependent patients has not been evaluated in a community-based population. With the use of data from the Longitudinal Investigation of Thromboembolism Etiology (LITE) study, 19,073 middle-aged and elderly adults were categorized on the basis of estimated GFR, and cystatin C (available in 4734 participants) was divided into quintiles. During a mean follow-up time of 11.8 yr, 413 participants developed VTE. Compared with participants with normal kidney function, relative risk for VTE was 1.28 (95\% confidence interval [CI] 1.02 to 1.59) for those with mildly decreased kidney function and 2.09 (95\% CI 1.47 to 2.96) for those with stage 3/4 CKD, when adjusted for age, gender, race, and center. After additional adjustment for cardiovascular disease risk factors, an increased risk for VTE was still observed in participants with stage 3/4 CKD, with a multivariable adjusted relative risk of 1.71 (95\% CI 1.18 to 2.49). There was no significant association between cystatin C and VTE. In conclusion, middle-aged and elderly patients with CKD (stages 3 through 4) are at increased risk for incident VTE, suggesting that VTE prophylaxis may be particularly important in this population.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Diabetic Nephropathies, Factor VIII, Female, Glomerular Filtration Rate, Humans, Hypertension, Kidney Failure, Chronic, Longitudinal Studies, Male, Middle Aged, Risk Factors, Thromboembolism, Venous Thrombosis}, issn = {1533-3450}, doi = {10.1681/ASN.2007030308}, author = {Wattanakit, Keattiyoat and Cushman, Mary and Stehman-Breen, Catherine and Heckbert, Susan R and Folsom, Aaron R} } @article {1041, title = {Subjective and objective sleep quality in patients on conventional thrice-weekly hemodialysis: comparison with matched controls from the sleep heart health study.}, journal = {Am J Kidney Dis}, volume = {52}, year = {2008}, month = {2008 Aug}, pages = {305-13}, abstract = {

BACKGROUND: Studies examining sleep in the hemodialysis (HD) population have largely lacked an adequate comparison group. It therefore is uncertain whether poor sleep quality in the HD population reflects age, chronic health conditions, or effects of conventional HD therapy.

STUDY DESIGN: Cross-sectional matched-group study.

SETTING \& PARTICIPANTS: Forty-six in-center HD patients were compared with 137 community participants participating in the Sleep Heart Health Study matched for age, sex, body mass index, and race.

PREDICTOR: HD patients compared with community-dwelling non-HD participants.

OUTCOMES \& MEASUREMENTS: Home unattended polysomnography was performed and scored by using similar protocols. Sleep habits and sleepiness were assessed by using the Sleep Habits Questionnaire and Epworth Sleepiness Scale.

RESULTS: Average age of study samples was 63 years, 72\% were white, and average body mass index was 28 +/- 5 kg/m(2). HD patients were significantly more likely than community participants to have short sleep (odds ratio, 3.27; 95\% confidence interval, 1.16 to 9.25) and decreased sleep efficiency (odds ratio, 5.5; 95\% confidence interval, 1.5 to 19.6). HD patients reported more difficulty getting back to sleep (odds ratio, 2.25; 95\% confidence interval, 1.11 to 4.60) and waking up too early (odds ratio, 2.39; 95\% confidence interval, 1.01 to 5.66). There was no association between polysomnography sleep time and self-reported sleep time (r = 0.09; P = 0.6) or between the Epworth Sleepiness Scale and severity of sleep apnea (r = 0.10; P = 0.5) in the HD population.

LIMITATIONS: The study was limited to participants older than 45 years.

CONCLUSIONS: Kidney failure treated with thrice-weekly HD is significantly associated with poor subjective and objective sleep quality.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cross-Sectional Studies, Disease Progression, Female, Follow-Up Studies, Heart Rate, Humans, Incidence, Kidney Failure, Chronic, Male, Middle Aged, Odds Ratio, Pennsylvania, Polysomnography, Prognosis, Renal Dialysis, Retrospective Studies, Risk Factors, Severity of Illness Index, Sleep, Sleep Apnea Syndromes, Surveys and Questionnaires}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2008.04.019}, author = {Unruh, Mark L and Sanders, Mark H and Redline, Susan and Piraino, Beth M and Umans, Jason G and Chami, Hassan and Budhiraja, Rohit and Punjabi, Naresh M and Buysse, Daniel and Newman, Anne B} } @article {1099, title = {Multiple loci associated with indices of renal function and chronic kidney disease.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Jun}, pages = {712-7}, abstract = {

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 {\texttimes} 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

}, keywords = {Chromosome Mapping, Cohort Studies, Genetic Variation, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Meta-Analysis as Topic, Mucoproteins, Netherlands, Polymorphism, Single Nucleotide, Prevalence, Uromodulin}, issn = {1546-1718}, doi = {10.1038/ng.377}, author = {K{\"o}ttgen, Anna and Glazer, Nicole L and Dehghan, Abbas and Hwang, Shih-Jen and Katz, Ronit and Li, Man and Yang, Qiong and Gudnason, Vilmundur and Launer, Lenore J and Harris, Tamara B and Smith, Albert V and Arking, Dan E and Astor, Brad C and Boerwinkle, Eric and Ehret, Georg B and Ruczinski, Ingo and Scharpf, Robert B and Chen, Yii-Der Ida and de Boer, Ian H and Haritunians, Talin and Lumley, Thomas and Sarnak, Mark and Siscovick, David and Benjamin, Emelia J and Levy, Daniel and Upadhyay, Ashish and Aulchenko, Yurii S and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Chasman, Daniel I and Par{\'e}, Guillaume and Ridker, Paul M and Kao, W H Linda and Witteman, Jacqueline C and Coresh, Josef and Shlipak, Michael G and Fox, Caroline S} } @article {1183, title = {New loci associated with kidney function and chronic kidney disease.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 May}, pages = {376-84}, abstract = {

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

}, keywords = {Cohort Studies, Creatinine, Cystatin C, Diet, Europe, Genetic Markers, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Models, Genetic, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.568}, author = {K{\"o}ttgen, Anna and Pattaro, Cristian and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Glazer, Nicole L and Parsa, Afshin and Gao, Xiaoyi and Yang, Qiong and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Li, Man and Schmidt, Helena and Tanaka, Toshiko and Isaacs, Aaron and Ketkar, Shamika and Hwang, Shih-Jen and Johnson, Andrew D and Dehghan, Abbas and Teumer, Alexander and Par{\'e}, Guillaume and Atkinson, Elizabeth J and Zeller, Tanja and Lohman, Kurt and Cornelis, Marilyn C and Probst-Hensch, Nicole M and Kronenberg, Florian and T{\"o}njes, Anke and Hayward, Caroline and Aspelund, Thor and Eiriksdottir, Gudny and Launer, Lenore J and Harris, Tamara B and Rampersaud, Evadnie and Mitchell, Braxton D and Arking, Dan E and Boerwinkle, Eric and Struchalin, Maksim and Cavalieri, Margherita and Singleton, Andrew and Giallauria, Francesco and Metter, Jeffrey and de Boer, Ian H and Haritunians, Talin and Lumley, Thomas and Siscovick, David and Psaty, Bruce M and Zillikens, M Carola and Oostra, Ben A and Feitosa, Mary and Province, Michael and de Andrade, Mariza and Turner, Stephen T and Schillert, Arne and Ziegler, Andreas and Wild, Philipp S and Schnabel, Renate B and Wilde, Sandra and Munzel, Thomas F and Leak, Tennille S and Illig, Thomas and Klopp, Norman and Meisinger, Christa and Wichmann, H-Erich and Koenig, Wolfgang and Zgaga, Lina and Zemunik, Tatijana and Kolcic, Ivana and Minelli, Cosetta and Hu, Frank B and Johansson, Asa and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and Schreiber, Stefan and Aulchenko, Yurii S and Felix, Janine F and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Hofman, Albert and Imboden, Medea and Nitsch, Dorothea and Brandst{\"a}tter, Anita and Kollerits, Barbara and Kedenko, Lyudmyla and M{\"a}gi, Reedik and Stumvoll, Michael and Kovacs, Peter and Boban, Mladen and Campbell, Susan and Endlich, Karlhans and V{\"o}lzke, Henry and Kroemer, Heyo K and Nauck, Matthias and V{\"o}lker, Uwe and Polasek, Ozren and Vitart, Veronique and Badola, Sunita and Parker, Alexander N and Ridker, Paul M and Kardia, Sharon L R and Blankenberg, Stefan and Liu, Yongmei and Curhan, Gary C and Franke, Andre and Rochat, Thierry and Paulweber, Bernhard and Prokopenko, Inga and Wang, Wei and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Shlipak, Michael G and van Duijn, Cornelia M and Borecki, Ingrid and Kr{\"a}mer, Bernhard K and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Witteman, Jacqueline C and Pramstaller, Peter P and Rettig, Rainer and Hastie, Nick and Chasman, Daniel I and Kao, W H and Heid, Iris M and Fox, Caroline S} } @article {1336, title = {Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Sep}, pages = {e1002292}, abstract = {

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.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, Aged, Chronic Disease, Creatinine, European Continental Ancestry Group, Female, Follow-Up Studies, Genetic Association Studies, Humans, Kidney Diseases, Kidney Failure, Chronic, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptor, Epidermal Growth Factor, Uromodulin}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002292}, author = {B{\"o}ger, Carsten A and Gorski, Mathias and Li, Man and Hoffmann, Michael M and Huang, Chunmei and Yang, Qiong and Teumer, Alexander and Krane, Vera and O{\textquoteright}Seaghdha, Conall M and Kutalik, Zolt{\'a}n and Wichmann, H-Erich and Haak, Thomas and Boes, Eva and Coassin, Stefan and Coresh, Josef and Kollerits, Barbara and Haun, Margot and Paulweber, Bernhard and K{\"o}ttgen, Anna and Li, Guo and Shlipak, Michael G and Powe, Neil and Hwang, Shih-Jen and Dehghan, Abbas and Rivadeneira, Fernando and Uitterlinden, Andre and Hofman, Albert and Beckmann, Jacques S and Kr{\"a}mer, Bernhard K and Witteman, Jacqueline and Bochud, Murielle and Siscovick, David and Rettig, Rainer and Kronenberg, Florian and Wanner, Christoph and Thadhani, Ravi I and Heid, Iris M and Fox, Caroline S and Kao, W H} } @article {1230, title = {Chronic kidney disease and the risk of end-stage renal disease versus death.}, journal = {J Gen Intern Med}, volume = {26}, year = {2011}, month = {2011 Apr}, pages = {379-85}, abstract = {

BACKGROUND: Among older adults with chronic kidney disease (CKD), the comparative event rates of end-stage renal disease (ESRD) and cause-specific death are unknown.

OBJECTIVE: To compare the rates of ESRD, cardiovascular and non-cardiovascular death and examine risk factors for ESRD and all-cause mortality in Cardiovascular Health Study (CHS) participants.

DESIGN: The CHS is a longitudinal cohort study of community-dwelling adults aged 65 years and older.

PARTICIPANTS: 1,268 participants with an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m(2) were followed until the time of first event (ESRD, cardiovascular or non-cardiovascular death) or until March 31, 2003.

MAIN MEASURES: The outcomes were ESRD, cardiovascular- and non-cardiovascular death. Rates of each event were calculated, and a Cox Proportional Hazards Model with a competing risk framework was used to examine risk factors for ESRD as compared with death. Predictors included age, gender, race, BMI, hypertension, diabetes, cardiovascular disease, heart failure, tobacco use, eGFR, and total cholesterol.

KEY RESULTS: During 9.7 years of follow-up, 5\% of the cohort progressed to ESRD, and 61\% of the cohort died. The rate (per 100 person-years) was 0.5 for ESRD and 6.8 for all-cause mortality (3.0 for cardiovascular and 3.8 for non-cardiovascular mortality). In the competing risk framework, lower eGFR, male gender, African-American race, and higher BMI were associated with an increased risk of ESRD.

CONCLUSIONS: Older adults with CKD are 13-fold more likely to die from any cause than progress to ESRD and are 6-fold more likely to die from cardiovascular causes than develop ESRD.

}, keywords = {Aged, Aged, 80 and over, Cause of Death, Cohort Studies, Female, Follow-Up Studies, Humans, Kidney Failure, Chronic, Longitudinal Studies, Male, Prospective Studies, Renal Insufficiency, Chronic, Risk Factors, Treatment Outcome}, issn = {1525-1497}, doi = {10.1007/s11606-010-1511-x}, author = {Dalrymple, Lorien S and Katz, Ronit and Kestenbaum, Bryan and Shlipak, Michael G and Sarnak, Mark J and Stehman-Breen, Catherine and Seliger, Stephen and Siscovick, David and Newman, Anne B and Fried, Linda} } @article {1256, title = {Cystatin C identifies chronic kidney disease patients at higher risk for complications.}, journal = {J Am Soc Nephrol}, volume = {22}, year = {2011}, month = {2011 Jan}, pages = {147-55}, abstract = {

Although cystatin C is a stronger predictor of clinical outcomes associated with CKD than creatinine, the clinical role for cystatin C is unclear. We included 11,909 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) and assessed risks for death, cardiovascular events, heart failure, and ESRD among persons categorized into mutually exclusive groups on the basis of the biomarkers that supported a diagnosis of CKD (eGFR <60 ml/min per 1.73 m(2)): creatinine only, cystatin C only, both, or neither. We used CKD-EPI equations to estimate GFR from these biomarkers. In MESA, 9\% had CKD by the creatinine-based equation only, 2\% had CKD by the cystatin C-based equation only, and 4\% had CKD by both equations; in CHS, these percentages were 12, 4, and 13\%, respectively. Compared with those without CKD, the adjusted hazard ratios (HR) for mortality in MESA were: 0.80 (95\% CI 0.50 to 1.26) for CKD by creatinine only; 3.23 (95\% CI 1.84 to 5.67) for CKD by cystatin C only; and 1.93 (95\% CI 1.27 to 2.92) for CKD by both; in CHS, the adjusted HR were 1.09 (95\% CI 0.98 to 1.21), 1.78 (95\% CI 1.53 to 2.08), and 1.74 (95\% CI 1.58 to 1.93), respectively. The pattern was similar for cardiovascular disease (CVD), heart failure, and kidney failure outcomes. In conclusion, among adults diagnosed with CKD using the creatinine-based CKD-EPI equation, the adverse prognosis is limited to the subset who also have CKD according to the cystatin C-based equation. Cystatin C may have a role in identifying persons with CKD who have the highest risk for complications.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Chronic Disease, Creatinine, Cystatin C, Disease Progression, Female, Glomerular Filtration Rate, Heart Failure, Humans, Kidney Diseases, Kidney Failure, Chronic, Male, Middle Aged, Predictive Value of Tests, Retrospective Studies, Risk Factors}, issn = {1533-3450}, doi = {10.1681/ASN.2010050483}, author = {Peralta, Carmen A and Katz, Ronit and Sarnak, Mark J and Ix, Joachim and Fried, Linda F and de Boer, Ian and Palmas, Walter and Siscovick, David and Levey, Andrew S and Shlipak, Michael G} } @article {1327, title = {Genetic association for renal traits among participants of African ancestry reveals new loci for renal function.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Sep}, pages = {e1002264}, abstract = {

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-value = 5.3{\texttimes}10(-7)) and FNDC1 (p-value = 3.0{\texttimes}10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6{\texttimes}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.

}, keywords = {Adaptor Proteins, Vesicular Transport, Adult, African Continental Ancestry Group, Aged, Animals, Female, Gene Knockdown Techniques, Genetic Association Studies, Genetic Loci, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, KCNQ1 Potassium Channel, Kidney, Kidney Failure, Chronic, Male, Middle Aged, Neoplasm Proteins, Phenotype, Polymorphism, Single Nucleotide, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002264}, author = {Liu, Ching-Ti and Garnaas, Maija K and Tin, Adrienne and K{\"o}ttgen, Anna and Franceschini, Nora and Peralta, Carmen A and de Boer, Ian H and Lu, Xiaoning and Atkinson, Elizabeth and Ding, Jingzhong and Nalls, Michael and Shriner, Daniel and Coresh, Josef and Kutlar, Abdullah and Bibbins-Domingo, Kirsten and Siscovick, David and Akylbekova, Ermeg and Wyatt, Sharon and Astor, Brad and Mychaleckjy, Josef and Li, Man and Reilly, Muredach P and Townsend, Raymond R and Adeyemo, Adebowale and Zonderman, Alan B and de Andrade, Mariza and Turner, Stephen T and Mosley, Thomas H and Harris, Tamara B and Rotimi, Charles N and Liu, Yongmei and Kardia, Sharon L R and Evans, Michele K and Shlipak, Michael G and Kramer, Holly and Flessner, Michael F and Dreisbach, Albert W and Goessling, Wolfram and Cupples, L Adrienne and Kao, W Linda and Fox, Caroline S} } @article {6301, title = {Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts.}, journal = {Kidney Int}, volume = {80}, year = {2011}, month = {2011 Jul}, pages = {93-104}, abstract = {

Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for end-stage renal disease (ESRD). To determine their joint contribution to ESRD and other kidney outcomes, we performed a meta-analysis of nine general population cohorts with 845,125 participants and an additional eight cohorts with 173,892 patients, the latter selected because of their high risk for chronic kidney disease (CKD). In the general population, the risk for ESRD was unrelated to eGFR at values between 75 and 105 ml/min per 1.73 m(2) but increased exponentially at lower levels. Hazard ratios for eGFRs averaging 60, 45, and 15 were 4, 29, and 454, respectively, compared with an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log ESRD risk without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 30, 300, and 1000 mg/g were 5, 13, and 28, respectively, compared with an albumin-to-creatinine ratio of 5. Albuminuria and eGFR were associated with ESRD, without evidence for multiplicative interaction. Similar associations were found for acute kidney injury and progressive CKD. In high-risk cohorts, the findings were generally comparable. Thus, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive CKD in both general and high-risk populations, independent of each other and of cardiovascular risk factors.

}, keywords = {Aged, Albuminuria, Cohort Studies, Creatinine, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Prognosis, Proportional Hazards Models, Risk Factors}, issn = {1523-1755}, doi = {10.1038/ki.2010.531}, author = {Gansevoort, Ron T and Matsushita, Kunihiro and van der Velde, Marije and Astor, Brad C and Woodward, Mark and Levey, Andrew S and de Jong, Paul E and Coresh, Josef} } @article {7380, title = {Age and association of kidney measures with mortality and end-stage renal disease.}, journal = {JAMA}, volume = {308}, year = {2012}, month = {2012 Dec 12}, pages = {2349-60}, abstract = {

CONTEXT: Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial.

OBJECTIVE: To evaluate possible effect modification (interaction) by age of the association of eGFR and albuminuria with clinical risk, examining both relative and absolute risks.

DESIGN, SETTING, AND PARTICIPANTS: Individual-level meta-analysis including 2,051,244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD cohorts from Asia, Australasia, Europe, and North/South America, conducted in 1972-2011 with a mean follow-up time of 5.8 years (range, 0-31 years).

MAIN OUTCOME MEASURES: Hazard ratios (HRs) of mortality and end-stage renal disease (ESRD) according to eGFR and albuminuria were meta-analyzed across age categories after adjusting for sex, race, cardiovascular disease, diabetes, systolic blood pressure, cholesterol, body mass index, and smoking. Absolute risks were estimated using HRs and average incidence rates.

RESULTS: Mortality (112,325 deaths) and ESRD (8411 events) risks were higher at lower eGFR and higher albuminuria in every age category. In general and high-risk cohorts, relative mortality risk for reduced eGFR decreased with increasing age; eg, adjusted HRs at an eGFR of 45 mL/min/1.73 m2 vs 80 mL/min/1.73 m2 were 3.50 (95\% CI, 2.55-4.81), 2.21 (95\% CI, 2.02-2.41), 1.59 (95\% CI, 1.42-1.77), and 1.35 (95\% CI, 1.23-1.48) in age categories 18-54, 55-64, 65-74, and >=75 years, respectively (P <.05 for age interaction). Absolute risk differences for the same comparisons were higher at older age (9.0 [95\% CI, 6.0-12.8], 12.2 [95\% CI, 10.3-14.3], 13.3 [95\% CI, 9.0-18.6], and 27.2 [95\% CI, 13.5-45.5] excess deaths per 1000 person-years, respectively). For increased albuminuria, reduction of relative risk with increasing age was less evident, while differences in absolute risk were higher in older age categories (7.5 [95\% CI, 4.3-11.9], 12.2 [95\% CI, 7.9-17.6], 22.7 [95\% CI, 15.3-31.6], and 34.3 [95\% CI, 19.5-52.4] excess deaths per 1000 person-years, respectively by age category, at an albumin-creatinine ratio of 300 mg/g vs 10 mg/g). In CKD cohorts, adjusted relative hazards of mortality did not decrease with age. In all cohorts, ESRD relative risks and absolute risk differences at lower eGFR or higher albuminuria were comparable across age categories.

CONCLUSIONS: Both low eGFR and high albuminuria were independently associated with mortality and ESRD regardless of age across a wide range of populations. Mortality showed lower relative risk but higher absolute risk differences at older age.

}, keywords = {Adolescent, Adult, Age Factors, Aged, Albuminuria, Cohort Studies, Female, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Male, Middle Aged, Risk, Young Adult}, issn = {1538-3598}, doi = {10.1001/jama.2012.16817}, author = {Hallan, Stein I and Matsushita, Kunihiro and Sang, Yingying and Mahmoodi, Bakhtawar K and Black, Corri and Ishani, Areef and Kleefstra, Nanne and Naimark, David and Roderick, Paul and Tonelli, Marcello and Wetzels, Jack F M and Astor, Brad C and Gansevoort, Ron T and Levin, Adeera and Wen, Chi-Pang and Coresh, Josef} } @article {6086, title = {Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis.}, journal = {Lancet}, volume = {380}, year = {2012}, month = {2012 Nov 10}, pages = {1662-73}, abstract = {

BACKGROUND: Chronic kidney disease is characterised by low estimated glomerular filtration rate (eGFR) and high albuminuria, and is associated with adverse outcomes. Whether these risks are modified by diabetes is unknown.

METHODS: We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and end-stage renal disease (ESRD) associated with eGFR and albuminuria in individuals with and without diabetes.

FINDINGS: We analysed data for 1,024,977 participants (128,505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts. In the combined general population and high-risk cohorts with data for all-cause mortality, 75,306 deaths occurred during a mean follow-up of 8{\textperiodcentered}5 years (SD 5{\textperiodcentered}0). In the 23 studies with data for cardiovascular mortality, 21,237 deaths occurred from cardiovascular disease during a mean follow-up of 9{\textperiodcentered}2 years (SD 4{\textperiodcentered}9). In the general and high-risk cohorts, mortality risks were 1{\textperiodcentered}2-1{\textperiodcentered}9 times higher for participants with diabetes than for those without diabetes across the ranges of eGFR and albumin-to-creatinine ratio (ACR). With fixed eGFR and ACR reference points in the diabetes and no diabetes groups, HR of mortality outcomes according to lower eGFR and higher ACR were much the same in participants with and without diabetes (eg, for all-cause mortality at eGFR 45 mL/min per 1{\textperiodcentered}73 m(2) [vs 95 mL/min per 1{\textperiodcentered}73 m(2)], HR 1{\textperiodcentered}35; 95\% CI 1{\textperiodcentered}18-1{\textperiodcentered}55; vs 1{\textperiodcentered}33; 1{\textperiodcentered}19-1{\textperiodcentered}48 and at ACR 30 mg/g [vs 5 mg/g], 1{\textperiodcentered}50; 1{\textperiodcentered}35-1{\textperiodcentered}65 vs 1{\textperiodcentered}52; 1{\textperiodcentered}38-1{\textperiodcentered}67). The overall interactions were not significant. We identified much the same findings for ESRD in the chronic kidney disease cohorts.

INTERPRETATION: Despite higher risks for mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and ACR are much the same irrespective of the presence or absence of diabetes, emphasising the importance of kidney disease as a predictor of clinical outcomes.

FUNDING: US National Kidney Foundation.

}, keywords = {Aged, Albuminuria, Cardiovascular Diseases, Cause of Death, Diabetic Nephropathies, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Risk Factors}, issn = {1474-547X}, doi = {10.1016/S0140-6736(12)61350-6}, author = {Fox, Caroline S and Matsushita, Kunihiro and Woodward, Mark and Bilo, Henk J G and Chalmers, John and Heerspink, Hiddo J Lambers and Lee, Brian J and Perkins, Robert M and Rossing, Peter and Sairenchi, Toshimi and Tonelli, Marcello and Vassalotti, Joseph A and Yamagishi, Kazumasa and Coresh, Josef and de Jong, Paul E and Wen, Chi-Pang and Nelson, Robert G} } @article {1385, title = {Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate.}, journal = {JAMA}, volume = {307}, year = {2012}, month = {2012 May 09}, pages = {1941-51}, abstract = {

CONTEXT: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation more accurately estimates glomerular filtration rate (GFR) than the Modification of Diet in Renal Disease (MDRD) Study equation using the same variables, especially at higher GFR, but definitive evidence of its risk implications in diverse settings is lacking.

OBJECTIVE: To evaluate risk implications of estimated GFR using the CKD-EPI equation compared with the MDRD Study equation in populations with a broad range of demographic and clinical characteristics.

DESIGN, SETTING, AND PARTICIPANTS: A meta-analysis of data from 1.1 million adults (aged >= 18 years) from 25 general population cohorts, 7 high-risk cohorts (of vascular disease), and 13 CKD cohorts. Data transfer and analyses were conducted between March 2011 and March 2012.

MAIN OUTCOME MEASURES: All-cause mortality (84,482 deaths from 40 cohorts), cardiovascular mortality (22,176 events from 28 cohorts), and end-stage renal disease (ESRD) (7644 events from 21 cohorts) during 9.4 million person-years of follow-up; the median of mean follow-up time across cohorts was 7.4 years (interquartile range, 4.2-10.5 years).

RESULTS: Estimated GFR was classified into 6 categories (>=90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m(2)) by both equations. Compared with the MDRD Study equation, 24.4\% and 0.6\% of participants from general population cohorts were reclassified to a higher and lower estimated GFR category, respectively, by the CKD-EPI equation, and the prevalence of CKD stages 3 to 5 (estimated GFR <60 mL/min/1.73 m(2)) was reduced from 8.7\% to 6.3\%. In estimated GFR of 45 to 59 mL/min/1.73 m(2) by the MDRD Study equation, 34.7\% of participants were reclassified to estimated GFR of 60 to 89 mL/min/1.73 m(2) by the CKD-EPI equation and had lower incidence rates (per 1000 person-years) for the outcomes of interest (9.9 vs 34.5 for all-cause mortality, 2.7 vs 13.0 for cardiovascular mortality, and 0.5 vs 0.8 for ESRD) compared with those not reclassified. The corresponding adjusted hazard ratios were 0.80 (95\% CI, 0.74-0.86) for all-cause mortality, 0.73 (95\% CI, 0.65-0.82) for cardiovascular mortality, and 0.49 (95\% CI, 0.27-0.88) for ESRD. Similar findings were observed in other estimated GFR categories by the MDRD Study equation. Net reclassification improvement based on estimated GFR categories was significantly positive for all outcomes (range, 0.06-0.13; all P < .001). Net reclassification improvement was similarly positive in most subgroups defined by age (<65 years and >=65 years), sex, race/ethnicity (white, Asian, and black), and presence or absence of diabetes and hypertension. The results in the high-risk and CKD cohorts were largely consistent with the general population cohorts.

CONCLUSION: The CKD-EPI equation classified fewer individuals as having CKD and more accurately categorized the risk for mortality and ESRD than did the MDRD Study equation across a broad range of populations.

}, keywords = {African Continental Ancestry Group, Aged, Algorithms, Asian Continental Ancestry Group, Cardiovascular Diseases, Cohort Studies, Decision Support Techniques, European Continental Ancestry Group, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Models, Theoretical, Risk Assessment, Sex Factors}, issn = {1538-3598}, doi = {10.1001/jama.2012.3954}, author = {Matsushita, Kunihiro and Mahmoodi, Bakhtawar K and Woodward, Mark and Emberson, Jonathan R and Jafar, Tazeen H and Jee, Sun Ha and Polkinghorne, Kevan R and Shankar, Anoop and Smith, David H and Tonelli, Marcello and Warnock, David G and Wen, Chi-Pang and Coresh, Josef and Gansevoort, Ron T and Hemmelgarn, Brenda R and Levey, Andrew S} } @article {1377, title = {Genome-wide association and functional follow-up reveals new loci for kidney function.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002584}, abstract = {

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

}, keywords = {African Americans, Aged, Animals, Caspase 9, Cyclin-Dependent Kinases, DEAD-box RNA Helicases, DNA Helicases, European Continental Ancestry Group, Female, Follow-Up Studies, Gene Knockdown Techniques, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Male, Middle Aged, Phosphoric Diester Hydrolases, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002584}, author = {Pattaro, Cristian and K{\"o}ttgen, Anna and Teumer, Alexander and Garnaas, Maija and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Taliun, Daniel and Li, Man and Gao, Xiaoyi and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and O{\textquoteright}Seaghdha, Conall M and Glazer, Nicole and Isaacs, Aaron and Liu, Ching-Ti and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Johnson, Andrew D and Gierman, Hinco J and Feitosa, Mary and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, Asa and T{\"o}njes, Anke and Dehghan, Abbas and Chouraki, Vincent and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Kollerits, Barbara and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Cavalieri, Margherita and Rao, Madhumathi and Hu, Frank B and Demirkan, Ayse and Oostra, Ben A and de Andrade, Mariza and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Koenig, Wolfgang and Illig, Thomas and D{\"o}ring, Angela and Wichmann, H-Erich and Kolcic, Ivana and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Endlich, Karlhans and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Ketkar, Shamika and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Giulianini, Franco and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Metzger, Marie and Mitchell, Paul and Ciullo, Marina and Kim, Stuart K and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Siscovick, David S and van Duijn, Cornelia M and Borecki, Ingrid and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline C M and Hayward, Caroline and Ridker, Paul and Parsa, Afshin and Bochud, Murielle and Heid, Iris M and Goessling, Wolfram and Chasman, Daniel I and Kao, W H Linda and Fox, Caroline S} } @article {7377, title = {Cystatin C versus creatinine in determining risk based on kidney function.}, journal = {N Engl J Med}, volume = {369}, year = {2013}, month = {2013 Sep 05}, pages = {932-43}, abstract = {

BACKGROUND: Adding the measurement of cystatin C to that of serum creatinine to determine the estimated glomerular filtration rate (eGFR) improves accuracy, but the effect on detection, staging, and risk classification of chronic kidney disease across diverse populations has not been determined.

METHODS: We performed a meta-analysis of 11 general-population studies (with 90,750 participants) and 5 studies of cohorts with chronic kidney disease (2960 participants) for whom standardized measurements of serum creatinine and cystatin C were available. We compared the association of the eGFR, as calculated by the measurement of creatinine or cystatin C alone or in combination with creatinine, with the rates of death (13,202 deaths in 15 cohorts), death from cardiovascular causes (3471 in 12 cohorts), and end-stage renal disease (1654 cases in 7 cohorts) and assessed improvement in reclassification with the use of cystatin C.

RESULTS: In the general-population cohorts, the prevalence of an eGFR of less than 60 ml per minute per 1.73 m(2) of body-surface area was higher with the cystatin C-based eGFR than with the creatinine-based eGFR (13.7\% vs. 9.7\%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes, and reclassification to a lower eGFR was associated with an increased risk. The net reclassification improvement with the measurement of cystatin C, as compared with creatinine, was 0.23 (95\% confidence interval [CI], 0.18 to 0.28) for death and 0.10 (95\% CI, 0.00 to 0.21) for end-stage renal disease. Results were generally similar for the five cohorts with chronic kidney disease and when both creatinine and cystatin C were used to calculate the eGFR.

CONCLUSIONS: The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations. (Funded by the National Kidney Foundation and others.).

}, keywords = {Creatinine, Cystatin C, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Kidney Function Tests, Reference Standards, Renal Insufficiency, Chronic, Risk, Risk Assessment}, issn = {1533-4406}, doi = {10.1056/NEJMoa1214234}, author = {Shlipak, Michael G and Matsushita, Kunihiro and Arnl{\"o}v, Johan and Inker, Lesley A and Katz, Ronit and Polkinghorne, Kevan R and Rothenbacher, Dietrich and Sarnak, Mark J and Astor, Brad C and Coresh, Josef and Levey, Andrew S and Gansevoort, Ron T} } @article {6554, title = {Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality.}, journal = {JAMA}, volume = {311}, year = {2014}, month = {2014 Jun 25}, pages = {2518-2531}, abstract = {

IMPORTANCE: The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of -57\% or greater) is a late event.

OBJECTIVE: To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated.

DATA SOURCES AND STUDY SELECTION: Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data.

DATA EXTRACTION AND SYNTHESIS: Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012.

MAIN OUTCOMES AND MEASURES: End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR.

RESULTS: The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95\% CI, 22.3-46.3) for changes of -57\% in estimated GFR and 5.4 (95\% CI, 4.5-6.4) for changes of -30\%. However, changes of -30\% or greater (6.9\% [95\% CI, 6.4\%-7.4\%] of the entire consortium) were more common than changes of -57\% (0.79\% [95\% CI, 0.52\%-1.06\%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99\% (95\% CI, 95\%-100\%) for estimated GFR change of -57\%, was 83\% (95\% CI, 71\%-93\%) for estimated GFR change of -40\%, and was 64\% (95\% CI, 52\%-77\%) for estimated GFR change of -30\% vs 18\% (95\% CI, 15\%-22\%) for estimated GFR change of 0\%. Corresponding mortality risks were 77\% (95\% CI, 71\%-82\%), 60\% (95\% CI, 56\%-63\%), and 50\% (95\% CI, 47\%-52\%) vs 32\% (95\% CI, 31\%-33\%), showing a similar but weaker pattern.

CONCLUSIONS AND RELEVANCE: Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30\% reduction over 2 years) as an alternative end point for CKD progression.

}, keywords = {Adult, Aged, Aged, 80 and over, Cohort Studies, Creatinine, Disease Progression, Endpoint Determination, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Reference Values, Risk}, issn = {1538-3598}, doi = {10.1001/jama.2014.6634}, author = {Coresh, Josef and Turin, Tanvir Chowdhury and Matsushita, Kunihiro and Sang, Yingying and Ballew, Shoshana H and Appel, Lawrence J and Arima, Hisatomi and Chadban, Steven J and Cirillo, Massimo and Djurdjev, Ognjenka and Green, Jamie A and Heine, Gunnar H and Inker, Lesley A and Irie, Fujiko and Ishani, Areef and Ix, Joachim H and Kovesdy, Csaba P and Marks, Angharad and Ohkubo, Takayoshi and Shalev, Varda and Shankar, Anoop and Wen, Chi Pang and de Jong, Paul E and Iseki, Kunitoshi and Stengel, B{\'e}n{\'e}dicte and Gansevoort, Ron T and Levey, Andrew S} } @article {6340, title = {Estimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials.}, journal = {Am J Kidney Dis}, volume = {64}, year = {2014}, month = {2014 Aug}, pages = {187-97}, abstract = {

BACKGROUND: Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25[OH]D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25[OH]2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFRs.

STUDY DESIGN: Cross-sectional study.

SETTING \& PARTICIPANTS: 9,596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N=1,193), Multi-Ethnic Study of Atherosclerosis (N=6,470), Cardiovascular Health Study (N=932), Seattle Kidney Study (N=289), and Hemodialysis Study (N=712).

PREDICTOR: eGFR.

OUTCOME: Circulating 24,25(OH)2D3 concentration.

MEASUREMENTS: GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry.

RESULTS: Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64-0.88). This correlation was weaker with lower eGFRs. Moreover, the increment in 24,25(OH)2D3 concentration associated with higher 25(OH)D3 concentration (slope) was lower with lower eGFRs: 2.06 (95\% CI, 2.01-2.10), 1.77 (95\% CI, 1.74-1.81), 1.55 (95\% CI, 1.48-1.62), 1.17 (95\% CI, 1.05-1.29), 0.92 (95\% CI, 0.74-1.10), 0.61 (95\% CI, 0.22-1.00), and 0.37 (95\% CI, 0.35-0.39) ng/mL of 24,25(OH)2D3 per 10 ng/mL of 25(OH)D3 for eGFRs>=90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2 and end-stage renal disease treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2D3 concentrations were 2.92 (95\% CI, 2.87-2.96), 2.68 (95\% CI, 2.64-2.72), 2.35 (95\% CI, 2.26-2.45), 1.92 (95\% CI, 1.74-2.10), 1.69 (95\% CI, 1.43-1.95), 1.14 (95\% CI, 0.62-1.66), and 1.04 (95\% CI,1.02-1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and circulating parathyroid hormone and fibroblast growth factor 23 concentrations more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3.

LIMITATIONS: Lack of direct pharmacokinetic measurements of vitamin D catabolism.

CONCLUSIONS: Lower eGFR is associated strongly with reduced vitamin D catabolism, as measured by circulating 24,25(OH)2D3 concentration.

}, keywords = {24,25-Dihydroxyvitamin D 3, Adult, Aged, Aged, 80 and over, Biomarkers, Cohort Studies, Cross-Sectional Studies, Diabetes Mellitus, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Observational Studies as Topic, Randomized Controlled Trials as Topic, Young Adult}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2014.02.015}, author = {de Boer, Ian H and Sachs, Michael C and Chonchol, Michel and Himmelfarb, Jonathan and Hoofnagle, Andrew N and Ix, Joachim H and Kremsdorf, Robin A and Lin, Yvonne S and Mehrotra, Rajnish and Robinson-Cohen, Cassianne and Siscovick, David S and Steffes, Michael W and Thummel, Kenneth E and Tracy, Russell P and Wang, Zhican and Kestenbaum, Bryan} } @article {6295, title = {Relative risks of chronic kidney disease for mortality and end-stage renal disease across races are similar.}, journal = {Kidney Int}, volume = {86}, year = {2014}, month = {2014 Oct}, pages = {819-27}, abstract = {

Some suggest race-specific cutpoints for kidney measures to define and stage chronic kidney disease (CKD), but evidence for race-specific clinical impact is limited. To address this issue, we compared hazard ratios of estimated glomerular filtration rates (eGFR) and albuminuria across races using meta-regression in 1.1 million adults (75\% Asians, 21\% Whites, and 4\% Blacks) from 45 cohorts. Results came mainly from 25 general population cohorts comprising 0.9 million individuals. The associations of lower eGFR and higher albuminuria with mortality and end-stage renal disease (ESRD) were largely similar across races. For example, in Asians, Whites, and Blacks, the adjusted hazard ratios (95\% confidence interval) for eGFR 45-59 versus 90-104 ml/min per 1.73 m(2) were 1.3 (1.2-1.3), 1.1 (1.0-1.2), and 1.3 (1.1-1.7) for all-cause mortality, 1.6 (1.5-1.7), 1.4 (1.2-1.7), and 1.4 (0.7-2.9) for cardiovascular mortality, and 27.6 (11.1-68.7), 11.2 (6.0-20.9), and 4.1 (2.2-7.5) for ESRD, respectively. The corresponding hazard ratios for urine albumin-to-creatinine ratio 30-299 mg/g or dipstick 1+ versus an albumin-to-creatinine ratio under 10 or dipstick negative were 1.6 (1.4-1.8), 1.7 (1.5-1.9), and 1.8 (1.7-2.1) for all-cause mortality, 1.7 (1.4-2.0), 1.8 (1.5-2.1), and 2.8 (2.2-3.6) for cardiovascular mortality, and 7.4 (2.0-27.6), 4.0 (2.8-5.9), and 5.6 (3.4-9.2) for ESRD, respectively. Thus, the relative mortality or ESRD risks of lower eGFR and higher albuminuria were largely similar among three major races, supporting similar clinical approach to CKD definition and staging, across races.

}, keywords = {Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Albuminuria, Asian Continental Ancestry Group, Cardiovascular Diseases, Cohort Studies, Creatinine, European Continental Ancestry Group, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Odds Ratio, Renal Insufficiency, Chronic, Risk Factors}, issn = {1523-1755}, doi = {10.1038/ki.2013.553}, author = {Wen, Chi Pang and Matsushita, Kunihiro and Coresh, Josef and Iseki, Kunitoshi and Islam, Muhammad and Katz, Ronit and McClellan, William and Peralta, Carmen A and Wang, Haiyan and de Zeeuw, Dick and Astor, Brad C and Gansevoort, Ron T and Levey, Andrew S and Levin, Adeera} } @article {6796, title = {A Meta-analysis of the Association of Estimated GFR, Albuminuria, Diabetes Mellitus, and Hypertension With Acute Kidney Injury.}, journal = {Am J Kidney Dis}, volume = {66}, year = {2015}, month = {2015 Oct}, pages = {602-12}, abstract = {

BACKGROUND: Diabetes mellitus and hypertension are risk factors for acute kidney injury (AKI). Whether estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (ACR) remain risk factors for AKI in the presence and absence of these conditions is uncertain.

STUDY DESIGN: Meta-analysis of cohort studies.

SETTING \& POPULATION: 8 general-population (1,285,045 participants) and 5 chronic kidney disease (CKD; 79,519 participants) cohorts.

SELECTION CRITERIA FOR STUDIES: Cohorts participating in the CKD Prognosis Consortium.

PREDICTORS: Diabetes and hypertension status, eGFR by the 2009 CKD Epidemiology Collaboration creatinine equation, urine ACR, and interactions.

OUTCOME: Hospitalization with AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results.

RESULTS: During a mean follow-up of 4 years, there were 16,480 episodes of AKI in the general-population and 2,087 episodes in the CKD cohorts. Low eGFRs and high ACRs were associated with higher risks of AKI in individuals with or without diabetes and with or without hypertension. When compared to a common reference of eGFR of 80mL/min/1.73m(2) in nondiabetic patients, HRs for AKI were generally higher in diabetic patients at any level of eGFR. The same was true for diabetic patients at all levels of ACR compared with nondiabetic patients. The risk gradient for AKI with lower eGFRs was greater in those without diabetes than with diabetes, but similar with higher ACRs in those without versus with diabetes. Those with hypertension had a higher risk of AKI at eGFRs>60mL/min/1.73m(2) than those without hypertension. However, risk gradients for AKI with both lower eGFRs and higher ACRs were greater for those without than with hypertension.

LIMITATIONS: AKI identified by diagnostic code.

CONCLUSIONS: Lower eGFRs and higher ACRs are associated with higher risks of AKI among individuals with or without either diabetes or hypertension.

}, keywords = {Acute Kidney Injury, Adult, Aged, Comorbidity, Diabetes Mellitus, Disease Progression, Female, Glomerular Filtration Rate, Humans, Hypertension, Incidence, Kidney Failure, Chronic, Male, Middle Aged, Prognosis, Renal Insufficiency, Chronic}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2015.02.338}, author = {James, Matthew T and Grams, Morgan E and Woodward, Mark and Elley, C Raina and Green, Jamie A and Wheeler, David C and de Jong, Paul and Gansevoort, Ron T and Levey, Andrew S and Warnock, David G and Sarnak, Mark J} } @article {6770, title = {Urinary uromodulin, kidney function, and cardiovascular disease in elderly adults.}, journal = {Kidney Int}, volume = {88}, year = {2015}, month = {2015 Nov}, pages = {1126-34}, abstract = {

Urinary uromodulin (uUMOD) is the most common secreted tubular protein in healthy adults. However, the relationship between uUMOD and clinical outcomes is still unclear. Here we measured uUMOD in 192 participants of the Cardiovascular Health Study with over a 30\% decline in estimated glomerular filtration rate (eGFR) over 9 years, 54 with incident end-stage renal disease (ESRD), and in a random subcohort of 958 participants. The association of uUMOD with eGFR decline was evaluated using logistic regression and with incident ESRD, cardiovascular disease, heart failure, and mortality using Cox proportional regression. Mean age was 78 years and median uUMOD was 25.8 μg/ml. In a case-control study evaluating eGFR decline (192 cases and 231 controls), each 1-s.d. higher uUMOD was associated with a 23\% lower odds of eGFR decline (odds ratio 0.77 (95\% CI 0.62-0.96)) and a 10\% lower risk of mortality (hazard ratio 0.90 (95\% CI 0.83-0.98)) after adjusting for demographics, eGFR, albumin/creatinine ratio, and other risk factors. There was no risk association of uUMOD with ESRD, cardiovascular disease, or heart failure after multivariable adjustment. Thus, low uUMOD levels may identify persons at risk of progressive kidney disease and mortality above and beyond established markers of kidney disease, namely eGFR and the albumin/creatinine ratio. Future studies need to confirm these results and evaluate whether uUMOD is a marker of tubular health and/or whether it plays a causal role in preserving kidney function.

}, keywords = {Aged, Aged, 80 and over, Albuminuria, Biomarkers, Cardiovascular Diseases, Case-Control Studies, Creatinine, Disease Progression, Female, Glomerular Filtration Rate, Heart Failure, Humans, Incidence, Kidney Failure, Chronic, Male, Proportional Hazards Models, Uromodulin}, issn = {1523-1755}, doi = {10.1038/ki.2015.192}, author = {Garimella, Pranav S and Biggs, Mary L and Katz, Ronit and Ix, Joachim H and Bennett, Michael R and Devarajan, Prasad and Kestenbaum, Bryan R and Siscovick, David S and Jensen, Majken K and Shlipak, Michael G and Chaves, Paulo H M and Sarnak, Mark J} } @article {6660, title = {Urine Collagen Fragments and CKD Progression-The Cardiovascular Health Study.}, journal = {J Am Soc Nephrol}, volume = {26}, year = {2015}, month = {2015 Oct}, pages = {2494-503}, abstract = {

Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged >=65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30\% decline in eGFR over 9 years, n=192) or incident ESRD (n=54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age ({\textpm}SD) was 78{\textpm}5 years, mean eGFR was 63{\textpm}18 ml/min per 1.73 m(2), and median urine PIIINP was 2.6 (interquartile range, 1.4-4.2) μg/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22\% higher odds of CKD progression (adjusted odds ratio, 1.22; 95\% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals.

}, keywords = {Aged, Cardiovascular Diseases, Case-Control Studies, Disease Progression, Female, Heart Failure, Humans, Kidney Failure, Chronic, Male, Peptide Fragments, Procollagen, Prospective Studies, Renal Insufficiency, Chronic}, issn = {1533-3450}, doi = {10.1681/ASN.2014070696}, author = {Ix, Joachim H and Biggs, Mary L and Mukamal, Kenneth and Djouss{\'e}, Luc and Siscovick, David and Tracy, Russell and Katz, Ronit and Delaney, Joseph A and Chaves, Paulo and Rifkin, Dena E and Hughes-Austin, Jan M and Garimella, Pranav S and Sarnak, Mark J and Shlipak, Michael G and Kizer, Jorge R} } @article {9254, title = {Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease.}, journal = {Diabetes}, volume = {71}, year = {2022}, month = {2022 Dec 01}, pages = {2664-2676}, abstract = {

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40\% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.

}, keywords = {Angiopoietin-1, Angiopoietin-2, Angiopoietins, Biomarkers, Cohort Studies, Diabetes Mellitus, Diabetic Nephropathies, Disease Progression, Endothelial Cells, Humans, Kidney Failure, Chronic, Receptor, TIE-2, Signal Transduction}, issn = {1939-327X}, doi = {10.2337/db22-0169}, author = {Liu, Jiahao and Nair, Viji and Zhao, Yi-Yang and Chang, Dong-Yuan and Limonte, Christine and Bansal, Nisha and Fermin, Damian and Eichinger, Felix and Tanner, Emily C and Bellovich, Keith A and Steigerwalt, Susan and Bhat, Zeenat and Hawkins, Jennifer J and Subramanian, Lalita and Rosas, Sylvia E and Sedor, John R and Vasquez, Miguel A and Waikar, Sushrut S and Bitzer, Markus and Pennathur, Subramaniam and Brosius, Frank C and de Boer, Ian and Chen, Min and Kretzler, Matthias and Ju, Wenjun} }