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1.  Physical Performance and Frailty in Chronic Kidney Disease 
American journal of nephrology  2013;38(4):307-315.
Background
Poor physical performance and frailty are associated with elevated risks of death and disability. Chronic kidney disease (CKD) is also strongly associated with these outcomes. The risks of poor physical performance and frailty among CKD patients, however, are not well established.
Methods
We measured the Short Physical Performance Battery (SPPB, a summary test of gait speed, chair-raises and balance; range 0–12) and the five elements of frailty among 1111 Chronic Renal Insufficiency Cohort participants. Adjusting for demographics and multiple comorbidities, we fit a linear regression model for the outcome of SPPB score and an ordinal logistic regression model for frailty status.
Results
Median (interquartile range [IQR]) age was 65 (57–71) years, median estimated glomerular filtration rate (eGFR) for non-dialysis patients was 49 (36–62) ml/min/1.73m2, and median SPPB score was 9 (7–10). Seven percent of participants were frail and 43% were pre-frail. Compared with the SPPB score for eGFR >60 ml/min/1.73m2, the SPPB was 0.51 points lower for eGFR 30 – 59; 0.61 points lower for eGFR 15 – 29; and 1.75 points lower for eGFR <15; (p<0.01 for all comparisons). eGFR 30 – 59 (OR 1.45; p=0.024), eGFR 15 – 29 (OR 2.02; p=0.002) and eGFR <15 (OR 4.83, p<0.001) were associated with worse frailty status compared with eGFR >60 ml/min/1.73m2.
Conclusions
CKD severity was associated with poor physical performance and frailty in a graded fashion. Future trials should determine if outcomes for CKD patients with frailty and poor physical performance are improved by targeted interventions.
doi:10.1159/000355568
PMCID: PMC4019506  PMID: 24107579
Physical performance; frailty; chronic kidney disease
2.  Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort Study 
Objectives
To identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD).
Background
CKD is associated with increased CAC and subsequent coronary heart disease (CHD) but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD.
Methods
We performed a candidate gene study (~2,100 genes; ~50,000 SNPs) of CAC within the Chronic Renal Insufficiency Cohort (CRIC) Study (n=1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in PennCAC (n=2,560) and Amish Family Calcification Study (AFCS; n=784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the Pakistan Risk of Myocardial Infarction study (PROMIS) (n=14,885).
Results
Of 268 SNPs reaching P <5×10−4 for CAC in CRIC, 28 SNPs in 23 loci had nominal support (P <0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported GWAS association with hypertension (e.g., ATP2B1). In PROMIS, four of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1 and ABCA4) had significant associations with MI consistent with their direction of effect on CAC.
Conclusions
We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.
doi:10.1016/j.jacc.2013.01.103
PMCID: PMC3953823  PMID: 23727086
Coronary artery calcification (CAC); chronic kidney disease (CKD); Chronic Renal Insufficiency Cohort Study (CRIC); myocardial infarction (MI); risk factors; candidate genes; single nucleotide polymorphisms (SNPs)
3.  Burden of chronic kidney disease in resource-limited settings from Peru: a population-based study 
BMC Nephrology  2015;16:114.
Background
The silent progression of chronic kidney diseases (CKD) and its association with other chronic diseases, and high treatment costs make it a great public health concern worldwide. The population burden of CKD in Peru has yet to be fully described.
Methods
We completed a cross sectional study of CKD prevalence among 404 participants (total study population median age 54.8 years, 50.2 % male) from two sites, highly-urbanized Lima and less urbanized Tumbes, who were enrolled in the population-based CRONICAS Cohort Study of cardiopulmonary health in Peru. Factors potentially associated with the presence of CKD were explored using Poisson regression, a statistical methodology used to determine prevalence ratios.
Results
In total, 68 participants (16.8 %, 95 % CI 13.5–20.9 %) met criteria for CKD: 60 (14.9%) with proteinuria, four (1%) with eGFR <60mL/min/1.73m2 , and four (1%) with both. CKD prevalence was higher in Lima (20.7 %, 95 % CI 15.8–27.1) than Tumbes (12.9 %, 95 % CI 9.0–18.5). Among participants with CKD, the prevalence of diabetes and hypertension was 19.1 % and 42.7 %, respectively. After multivariable adjustment, CKD was associated with older age, female sex, greater wealth tertile (although all wealth strata were below the poverty line), residence in Lima, and presence of diabetes and hypertension.
Conclusions
The high prevalence rates of CKD identified in Lima and Tumbes are similar to estimates from high-income settings. These findings highlight the need to identify occult CKD and implement strategies to prevent disease progression and secondary morbidity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12882-015-0104-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12882-015-0104-7
PMCID: PMC4512019  PMID: 26205002
Chronic kidney disease; Prevalence; Chronic diseases
4.  SERUM ALDOSTERONE AND DEATH, END STAGE RENAL DISEASE AND CARDIOVASCULAR EVENTS IN BLACKS AND WHITES: FINDINGS FROM THE CRIC STUDY 
Hypertension  2014;64(1):103-110.
Prior studies have demonstrated that elevated aldosterone concentrations are an independent risk factor for death in patients with cardiovascular disease. Limited studies, however, have evaluated systematically the association between serum aldosterone and adverse events in the setting of chronic kidney disease (CKD). We investigated the association between serum aldosterone and death and end-stage renal disease (ESRD) in 3,866 participants from the Chronic Renal Insufficiency Cohort. We also evaluated the association between aldosterone and incident congestive heart failure (CHF) and atherosclerotic events in participants without baseline cardiovascular disease. Cox proportional hazards models were used to evaluate independent associations between elevated aldosterone concentrations and each outcome. Interactions were hypothesized and explored between aldosterone and sex, race, and the use of loop diuretics and RAAS inhibitors. Over a median follow-up period of 5.4 years, 587 participants died, 743 developed ESRD, 187 developed CHF, and 177 experienced an atherosclerotic event. Aldosterone concentrations (per standard deviation of the log transformed aldosterone) were not an independent risk factor for death (adjusted HR 1.00, 95% CI [0.93–1.12]), ESRD (adjusted HR 1.07, 95% CI [0.99–1.17]), or atherosclerotic events (adjusted HR 1.04, 95% CI [0.85–1.18]). Aldosterone was associated with CHF (adjusted HR 1.21, 95% CI [1.02–1.35]). Among participants with CKD, higher aldosterone concentrations were independently associated with the development of CHF, but not for death, ESRD, or atherosclerotic events. Further studies should evaluate whether mineralocorticoid receptor antagonists may reduce adverse events in individuals with CKD since elevated cortisol levels may activate the mineralocorticoid receptor.
doi:10.1161/HYPERTENSIONAHA.114.03311
PMCID: PMC4089190  PMID: 24752431
Aldosterone; Chronic kidney disease; Outcomes; Death; Congestive Heart Failure
5.  Computed tomography-defined abdominal adiposity is associated with acute kidney injury in critically ill trauma patients 
Critical care medicine  2014;42(7):1619-1628.
Objective
Higher body mass index (BMI) is associated with increased risk of acute kidney injury (AKI) after major trauma. Since BMI is non-specific, reflecting lean, fluid, and adipose mass, we evaluated the use of computed tomography (CT) to determine if abdominal adiposity underlies the BMI-AKI association.
Design
Prospective cohort study.
Setting
Level I Trauma Center of a university hospital.
Patients
Patients older than 13 years with an Injury Severity Score ≥16 admitted to the trauma intensive care unit were followed for development of AKI over five days. Those with isolated severe head injury or on chronic dialysis were excluded.
Interventions
None
Measurements and Main Results
Clinical, anthropometric, and demographic variables were collected prospectively. CT images at the level of the L4-5 intervertebral disc space were extracted from the medical record and used by two operators to quantitate visceral and subcutaneous adipose tissue (VAT and SAT, respectively) areas. AKI was defined by Acute Kidney Injury Network (AKIN) creatinine and dialysis criteria. Of 400 subjects, 327 (81.8%) had CT scans suitable for analysis: 264/285 (92.6%) blunt trauma subjects, 63/115 (54.8%) penetrating trauma subjects. VAT and SAT areas were highly correlated between operators (ICC>0.999, p<0.001 for each) and within operator (ICC>0.999, p<0.001 for each). In multivariable analysis, the standardized risk of AKI was 15.1% (95% CI 10.6%,19.6%), 18.1% (14%,22.2%), and 23.1% (18.3%,27.9%) at the 25th, 50th, and 75th percentiles of VAT area, respectively (p=0.001), with similar findings when using SAT area as the adiposity measure.
Conclusions
Quantitation of abdominal adiposity using CT scans obtained for clinical reasons is feasible and highly reliable in critically ill trauma patients. Abdominal adiposity is independently associated with AKI in this population, confirming that excess adipose tissue contributes to the BMI-AKI association. Further studies of the potential mechanisms linking adiposity with AKI are warranted.
doi:10.1097/CCM.0000000000000306
PMCID: PMC4230013  PMID: 24776609
acute kidney injury; trauma; critical illness; obesity; adiposity; computed tomography
6.  Increasing Use of Vitamin D Supplementation in the Chronic Renal Insufficiency Cohort Study 
Objective
This study examined rates and determinants of vitamin D supplementation among Chronic Renal Insufficiency Cohort (CRIC) participants and determined the association between dose and 25-hydroxyvitamin D (25(OH)D) level. The 2010 Institute of Medicine Report noted a significant increase in vitamin D supplementation in the general population, but use in chronic kidney disease (CKD) is unknown.
Methods
CRIC is a multicenter prospective observational cohort study of 3,939 participants with a median baseline age of 60 and an estimated glomerular filtration rate (eGFR) of 42.1 mL/minute per 1.73 m2. Of the cohort, 54.9% was male, 42.1% were Black, and 48.4% were diabetic. Multivariable logistic generalized estimating equations were used to examine determinants of supplementation use assessed annually between 2003 and 2011. Cross-sectional linear regression models, based on a subset of 1,155 participants, assessed associations between supplement dose and 25(OH)D level, measured by high-performance liquid chromatography coupled with tandem mass spectrometry.
Results
The proportion of participants reporting supplement use increased (P < .0001), from 10% at baseline to 44% at 7-year follow-up visits. This was largely due to initiation of products containing only ergocalciferol or cholecalciferol. The odds of supplementation were greater in older, female, non-Black, married participants with greater education and lower body mass index. Among participants taking supplementation, dose was positively associated with 25(OH)D level, adjusted for race, season, diabetes, dietary intake, eGFR, and proteinuria. Only 3.8% of non-Black and 16.5% of Black participants taking a supplement were deficient (<20 ng/mL), whereas 22.7% of non-Black and 62.4% of Black participants not reporting supplement use were deficient.
Conclusions
Vitamin D supplementation rates rose significantly among CRIC participants over 7 years of follow-up and were associated with greater serum 25(OH)D levels. Studies of vitamin D levels on clinical outcomes in CKD and future vitamin D interventional studies should consider these changes in supplementation practices.
doi:10.1053/j.jrn.2014.01.015
PMCID: PMC4023561  PMID: 24613295
7.  Association between Inflammation and Cardiac Geometry in Chronic Kidney Disease: Findings from the CRIC Study 
PLoS ONE  2015;10(4):e0124772.
Background
Left ventricular hypertrophy (LVH) and myocardial contractile dysfunction are independent predictors of mortality in patients with chronic kidney disease (CKD). The association between inflammatory biomarkers and cardiac geometry has not yet been studied in a large cohort of CKD patients with a wide range of kidney function.
Methods
Plasma levels of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, high-sensitivity C-Reactive protein (hs-CRP), fibrinogen and serum albumin were measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Echocardiography was performed according to the recommendations of the American Society of Echocardiography and interpreted at a centralized core laboratory.
Results
LVH, systolic dysfunction and diastolic dysfunction were present in 52.3%, 11.8% and 76.3% of the study subjects, respectively. In logistic regression analysis adjusted for age, sex, race/ethnicity, diabetic status, current smoking status, systolic blood pressure, urinary albumin- creatinine ratio and estimated glomerular filtration rate, hs-CRP (OR 1.26 [95% CI 1.16, 1.37], p<0.001), IL-1RA (1.23 [1.13, 1.34], p<0.0001), IL-6 (1.25 [1.14, 1.36], p<0.001) and TNF-α (1.14 [1.04, 1.25], p = 0.004) were associated with LVH. The odds for systolic dysfunction were greater for subjects with elevated levels of hs-CRP (1.32 [1.18, 1.48], p<0.001) and IL-6 (1.34 [1.21, 1.49], p<0.001). Only hs-CRP was associated with diastolic dysfunction (1.14 [1.04, 1.26], p = 0.005).
Conclusion
In patients with CKD, elevated plasma levels of hs-CRP and IL-6 are associated with LVH and systolic dysfunction.
doi:10.1371/journal.pone.0124772
PMCID: PMC4409366  PMID: 25909952
8.  Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C 
BACKGROUND
Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR.
METHODS
Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials.
RESULTS
Mean measured GFRs were 68 and 70 ml per minute per 1.73 m2 of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine–cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m2 with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m2 with the creatinine equation and the cystatin C equation (P = 0.07 and P = 0.05), respectively. Precision was improved with the combined equation (inter-quartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m2, respectively [P = 0.001 and P<0.001]), and the results were more accurate (percentage of estimates that were >30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m2, the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m2 or greater than or equal to 60 ml per minute per 1.73 m2 (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m2 as having a GFR of 60 ml or higher per minute per 1.73 m2.
CONCLUSIONS
The combined creatinine–cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)
doi:10.1056/NEJMoa1114248
PMCID: PMC4398023  PMID: 22762315
9.  DNA methylation profile associated with rapid decline in kidney function: findings from the CRIC Study 
Background
Epigenetic mechanisms may be important in the progression of chronic kidney disease (CKD).
Methods
We studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate.
Results
The mean eGFR slope was 2.2 (1.4) and −5.1 (1.2) mL/min/1.73 m2 in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E−05 to 9.5E−05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E−03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD.
Conclusions
Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.
doi:10.1093/ndt/gft537
PMCID: PMC3967834  PMID: 24516231
chronic renal disease; chronic renal disease progression; DNA methylation; epigenetics
10.  Race modifies the association between adiposity and inflammation in patients with chronic kidney disease: findings from the CRIC study 
Obesity (Silver Spring, Md.)  2014;22(5):1359-1366.
Objective
To examine the race-specific association of inflammation with adiposity and muscle mass in subjects with chronic kidney disease (CKD).
Design and Methods
Plasma concentration of IL-1β, IL-Receptor antagonist (IL-1RA), IL-6, IL-10, TNF-α, TGF-β, hs-CRP, fibrinogen, and serum albumin were measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Bioelectric impedance analysis was used to determine body fat mass (BFM) and fat free mass (FFM).
Results
Plasma levels of hs-CRP, fibrinogen, IL-1RA, IL-6, and TNF-α increased and serum albumin decreased across the quartiles of body mass index. In multivariable analysis, BFM and FFM were positively associated with hs-CRP, fibrinogen, IL-1β, IL-1RA and IL-6. One standard deviation (SD) increase in BFM and FFM was associated with 0.36 (95% CI 0.33, 0.39) and 0.26 (95% CI 0.22, 0.30) SD increase in log transformed hs-CRP, respectively (p<0.001). Race stratified analysis showed that the association between biomarkers and BFM and FFM differed by race, with Caucasians demonstrating a stronger association with markers of inflammation than African Americans.
Conclusion
BFA and FFM are positively associated with markers of inflammation in patients with CKD. Race stratified analysis showed that Caucasians have a stronger association with markers of inflammation compared to African Americans.
doi:10.1002/oby.20692
PMCID: PMC4327849  PMID: 24415732
Bioelectric impedance analysis; cytokines; acute phase proteins; muscle mass; Body mass index; African Americans
11.  Functional status and survival after kidney transplantation1–12 
Transplantation  2014;97(2):189-195.
Background
Older patients constitute a growing proportion of U.S. kidney transplant recipients and often have a high burden of comorbidities. A summary measure of health such as functional status might enable transplant professionals to better evaluate and counsel these patients about their prognosis after transplant.
Methods
We linked UNOS registry data about post-transplant survival with pre-transplant functional status data (physical function [PF] scale of the Medical Outcomes Study Short Form-36) among individuals undergoing kidney transplant from 6/1/2000 – 5/31/2006. We examined the relationship between survival and functional status with multivariable Cox regression, adjusted for age. Using logistic regression models for three-year survival, we also estimated the reduction in deaths in the hypothetical scenario that recipients with poor functional status in this cohort experienced modest improvements in function.
Results
The cohort comprised 10,875 kidney transplant recipients (KTRs) with a mean age of 50 years; 14% were ≥65. Differences in three-year mortality between highest and lowest PF groups ranged from 3% among recipients <35 years to 14% among recipients ≥65 years. In multivariable Cox regression, worse PF was associated with higher mortality (HR 1.66 for lowest versus highest PF quartiles; p<0.001). Interactions between PF and age were non-significant. We estimated that 11% fewer deaths would occur if KTRs with the lowest functional status experienced modest improvements in function.
Conclusions
Across a wide age range, functional status was an independent predictor of post-transplant survival. Functional status assessment may be a useful tool with which to counsel patients about post-transplant outcomes.
doi:10.1097/TP.0b013e3182a89338
PMCID: PMC3946985  PMID: 24113514
Older age; functional status; kidney transplant; survival
12.  A New Equation to Estimate Glomerular Filtration Rate 
Annals of internal medicine  2009;150(9):604-612.
Background
Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher levels.
Objective
To develop a new estimating equation (CKD-EPI creatinine equation).
Design
Cross-sectional analysis. Separate pooled databases for equation development and validation. Representative U.S. population for prevalence estimates.
Setting
Research studies and clinical populations (“studies”) with measured GFR. National Health and Nutrition Examination Survey (NHANES) 1999-2006.
Patients
Equation development in 10 studies (8254 people) and validation in 16 studies (3896 people). Prevalence estimates based on 16,032 people.
Measurements
GFR measured as the clearance of exogenous filtration markers (iothalamate in the development dataset; iothalamate and other markers in the validation dataset). Linear regression to estimate the logarithm of measured GFR from standardized creatinine, sex, race and age.
Results
In the validation dataset, the CKD-EPI performed better than the MDRD Study equation (p<0.001 for all subsequent comparisons), especially at higher GFR: lesser bias (median difference between measured and estimated GFR of 2.5 vs. 5.5 mL/min/1.73 m2, respectively); improved precision (interquartile range of the differences of 16.6 vs. 18.3 mL/min/1.73 m2, respectively); and greater accuracy (percent of estimated GFR within 30% of measured GFR of 84.1 vs. 80.6%, respectively. In NHANES, median (interquartile range) estimated GFR was 94.5 (79.7 – 108.1) vs. 85.0 (72.9 – 98.5) mL/min/1.73 m2, and the prevalence (95% confidence interval) of CKD was 11.5 (10.6, 12.4) % vs. 13.1 (12.1, 14.0) %, respectively.
Limitations
Limited number of elderly people and racial and ethnic minorities with measured GFR.
Conclusions
The CKD-EPI creatinine equation is more accurate than the MDRD Study equation and could replace it for routine clinical use.
PMCID: PMC2763564  PMID: 19414839
13.  Objectives and Design of the Hemodialysis Fistula Maturation Study 
Background
A large proportion of newly created arteriovenous fistulas cannot be used for dialysis because they fail to mature adequately to support the hemodialysis blood circuit. The Hemodialysis Fistula Maturation (HFM) Study was designed to elucidate clinical and biological factors associated with fistula maturation outcomes.
Study Design
Multicenter prospective cohort study.
Setting & Participants
Approximately 600 patients undergoing creation of a new hemodialysis fistula will be enrolled at 7 centers in the United States and followed up for as long as 4 years.
Predictors
Clinical, anatomical, biological, and process-of-care attributes identified pre-operatively, intra-operatively, or post-operatively.
Outcomes
The primary outcome is unassisted clinical maturation defined as successful use of the fistula for dialysis for four weeks without any maturation-enhancing procedures. Secondary outcomes include assisted clinical maturation, ultrasound-based anatomical maturation, fistula procedures, fistula abandonment, and central venous catheter use.
Measurements
Pre-operative ultrasound arterial and venous mapping, flow-mediated and nitroglycerin-mediated brachial artery dilation, arterial pulse wave velocity, and venous distensibility; intra-operative vein tissue collection for histopathological and molecular analyses; post-operative ultrasounds at 1 day, 2 weeks, 6 weeks, and prior to fistula intervention and initial cannulation.
Results
Assuming complete data, no covariate adjustment, and unassisted clinical maturation of 50%, there will be 80% power to detect ORs of 1.83 and 1.61 for dichotomous predictor variables with exposure prevalences of 20% and 50%, respectively.
Limitations
Exclusion of two-stage transposition fistulas limits generalizability. The requirement for study visits may result in a cohort that is healthier than the overall population of patients undergoing fistula creation.
Conclusions
The HFM Study will be of sufficient size and scope to 1) evaluate a broad range of mechanistic hypotheses, 2) identify clinical practices associated with maturation outcomes, 3) assess the predictive utility of early indicators of fistula outcome, and 4) establish targets for novel therapeutic interventions to improve fistula maturation.
doi:10.1053/j.ajkd.2013.06.024
PMCID: PMC4134933  PMID: 23992885
14.  APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease 
The New England journal of medicine  2013;369(23):2183-2196.
BACKGROUND
Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients.
METHODS
In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline.
RESULTS
In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons).
CONCLUSIONS
Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)
doi:10.1056/NEJMoa1310345
PMCID: PMC3969022  PMID: 24206458
16.  The impact of documentation of severe acute kidney injury on mortality 
Clinical nephrology  2013;80(6):417-425.
Aims
Modification of the mortality risk associated with acute kidney injury (AKI) necessitates recognition of AKI when it occurs. We sought to determine whether formal documentation of AKI in the medical record, assessed by billing codes for AKI, would be associated with improved clinical outcomes.
Methods
Retrospective cohort study conducted at three hospitals within a single university health system. Adults without severe underlying kidney disease who suffered in-hospital AKI as defined by a doubling of baseline creatinine (n = 5,438) were included. Those whose AKI was formally documented according to discharge billing codes were compared to those without such documentation in terms of 30-day mortality.
Results
Formal documentation of AKI occurred in 2,325 patients (43%). Higher baseline creatinine, higher peak creatinine, medical admission status, and higher Sequential Organ Failure Assessment (SOFA) score were strongly associated with documentation of AKI. After adjustment for severity of disease, formal AKI documentation was associated with reduced 30-day mortality – OR 0.81 (0.68 – 0.96, p = 0.02). Patients with formal documentation were more likely to receive a nephrology consultation (31% vs. 6%, p < 0.001) and fluid boluses (64% vs. 45%, p < 0.001), and had a more rapid discontinuation of angiotensin-converting enzyme inhibitor and angiotensin-receptor blocker medications (HR 2.04, CI 1.69 – 2.46, p < 0.001).
Conclusions
Formal documentation of AKI is associated with improved survival after adjustment for illness severity among patients with creatinine-defined AKI.
doi:10.5414/CN108072
PMCID: PMC4018223  PMID: 24075024
acute kidney injury; documentation; mortality; cohort studies; international classification of diseases
17.  Effect of Dipyridamole plus Aspirin on Hemodialysis Graft Patency 
The New England journal of medicine  2009;360(21):2191-2201.
BACKGROUND
Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates.
RESULTS
At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole–aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups.
CONCLUSIONS
Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)
doi:10.1056/NEJMoa0805840
PMCID: PMC3929400  PMID: 19458364
18.  The impact of documentation of severe acute kidney injury on mortality  
Clinical Nephrology  2013;80(6):417-425.
Aims: Modification of the mortality risk associated with acute kidney injury (AKI) necessitates recognition of AKI when it occurs. We sought to determine whether formal documentation of AKI in the medical record, assessed by billing codes for AKI, would be associated with improved clinical outcomes. Methods: Retrospective cohort study conducted at three hospitals within a single university health system. Adults without severe underlying kidney disease who suffered in-hospital AKI as defined by a doubling of baseline creatinine (n = 5,438) were included. Those whose AKI was formally documented according to discharge billing codes were compared to those without such documentation in terms of 30-day mortality. Results: Formal documentation of AKI occurred in 2,325 patients (43%). Higher baseline creatinine, higher peak creatinine, medical admission status, and higher Sequential Organ Failure Assessment (SOFA) score were strongly associated with documentation of AKI. After adjustment for severity of disease, formal AKI documentation was associated with reduced 30-day mortality – OR 0.81 (0.68 – 0.96, p = 0.02). Patients with formal documentation were more likely to receive a nephrology consultation (31% vs. 6%, p < 0.001) and fluid boluses (64% vs. 45%, p < 0.001), and had a more rapid discontinuation of angiotensin-converting enzyme inhibitor and angiotensin-receptor blocker medications (HR 2.04, CI 1.69 – 2.46, p < 0.001). Conclusions: Formal documentation of AKI is associated with improved survival after adjustment for illness severity among patients with creatinine-defined AKI.
doi:10.5414/CN108072
PMCID: PMC4018223  PMID: 24075024
acute kidney injury; documentation; mortality; cohort studies; international classification of diseases
19.  Urine neutrophil gelatinase-associated lipocalin levels do not improve risk prediction of progressive chronic kidney disease 
Kidney international  2013;83(5):909-914.
Novel biomarkers may improve our ability to predict which patients with chronic kidney disease (CKD) are at higher risk for progressive loss of renal function. Here we assessed the performance of urine neutrophil gelatinase-associated lipocalin (NGAL) for outcome prediction in a diverse cohort of 3386 patients with CKD in the CRIC study. In this cohort, the baseline mean estimated glomerular filtration rate (eGFR) was 42.4 ml/min/1.73m2; the median 24-hour urine protein was 0.2 gm/day; and the median urine NGAL concentration was 17.2 ng/mL. Over an average follow-up of 3.2 years, there were 689 cases in which the eGFR was decreased by half or incident end-stage renal disease developed. Even after accounting for eGFR, proteinuria and other known CKD progression risk factors, urine NGAL remained a significant independent risk factor (Cox model hazard ratio 1.70 highest to lowest quartile). The association between baseline urine NGAL levels and risk of CKD progression was strongest in the first two years of biomarker measurement. Within this time frame, adding urine NGAL to a model which included eGFR, proteinuria and other CKD progression risk factors led to net reclassification improvement of 24.7%; but the C-statistic remained nearly identical. Thus, while urine NGAL was an independent risk factor of progression among patients with established CKD of diverse etiology, it did not substantially improve prediction of outcome events.
doi:10.1038/ki.2012.458
PMCID: PMC3642209  PMID: 23344473
20.  African American race, obesity, and blood product transfusion are risk factors for acute kidney injury in critically ill trauma patients 
Journal of critical care  2012;27(5):496-504.
Purpose
Acute kidney injury (AKI) is a common source of morbidity after trauma. We sought to determine novel risk factors for AKI, by Acute Kidney Injury Network (AKIN) criteria, in critically ill trauma patients.
Materials and Methods
Prospective cohort study of 400 patients admitted to the ICU of a level one trauma center, followed for development of AKI over five days.
Results
AKI developed in 147/400 (36.8%) patients. In multivariable regression analysis, independent risk factors for AKI included African American race (OR 1.86; 95% CI 1.08,3.18; p=0.024), body mass index ≥30 (OR 4.72 versus normal BMI, 95% CI 2.59, 8.61, p<0.001), diabetes mellitus (OR 3.26; 95% CI 1.30,8.20; p=0.012), abdominal Abbreviated Injury Scale score ≥4 (OR 3.78; 95% CI 1.79,7.96; p<0.001), and unmatched packed red blood cells administered during resuscitation (OR 1.13 per unit; 95% CI 1.04,1.23; p=0.004). AKIN stages 1, 2, and 3 were associated with hospital mortality rates of 9.8%, 13.7%, and 30.4%, respectively, compared with 3.8% for those without AKI (p<0.001).
Conclusions
AKI in critically ill trauma patients is associated with substantial mortality. The findings of African American race, obesity, and blood product administration as independent risk factors for AKI deserve further study to elucidate underlying mechanisms.
doi:10.1016/j.jcrc.2012.02.002
PMCID: PMC3472045  PMID: 22591570
acute kidney injury; trauma; critical illness; race; obesity; transfusion; epidemiology; risk factors
21.  Estimating GFR Among Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study 
Background
Glomerular filtration rate (GFR) is considered the best measure of kidney function, but repeated assessment is not feasible in most research studies.
Study Design
Cross-sectional study of 1,433 participants from the Chronic Renal Insufficiency Cohort (CRIC) Study (i.e., the GFR subcohort) to derive an internal GFR estimating equation using a split sample approach.
Setting & Participants
Adults from 7 US metropolitan areas with mild to moderate chronic kidney disease; 48% had diabetes and 37% were black.
Index Test
CRIC GFR estimating equation
Reference Test or Outcome
Urinary 125I-iothalamate clearance testing (measured GFR)
Other Measurements
Laboratory measures including serum creatinine and cystatin C, and anthropometrics
Results
In the validation dataset, the model that included serum creatinine, serum cystatin C, age, gender, and race was the most parsimonious and similarly predictive of mGFR compared to a model additionally including bioelectrical impedance analysis phase angle, CRIC clinical center, and 24-hour urinary creatinine excretion. Specifically, the root mean square errors for the separate model were 0.207 vs. 0.202, respectively. The performance of the CRIC GFR estimating equation was most accurate among the subgroups of younger participants, men, non-blacks, non-Hispanics, those without diabetes, those with body mass index <30 kg/m2, those with higher 24-hour urine creatinine excretion, those with lower levels of high-sensitivity C-reactive protein, and those with higher mGFR.
Limitations
Urinary clearance of 125I-iothalamate is an imperfect measure of true GFR; cystatin C is not standardized to certified reference material; lack of external validation; small sample sizes limit analyses of subgroup-specific predictors.
Conclusions
The CRIC GFR estimating equation predicts measured GFR accurately in the CRIC cohort using serum creatinine and cystatin C, age, gender, and race. Its performance was best among younger and healthier participants.
doi:10.1053/j.ajkd.2012.04.012
PMCID: PMC3565578  PMID: 22658574
glomerular filtration rate (GFR); kidney function; GFR estimation
22.  Electronically-measured adherence to immunosuppressive medications and kidney function after deceased donor kidney transplantation* 
Clinical transplantation  2010;25(2):E124-E131.
Background
Non-adherence with immunosuppressive medications can result in allograft rejection and eventually allograft loss.
Methods
In a racially diverse population, we utilized microelectronic cap monitors to determine the association of adherence with a single immunosuppressive medication and kidney allograft outcomes post-transplantation. This prospective cohort study enrolled 243 patients from eight transplant centers to provide adherence and kidney allograft outcomes data. To determine the association of adherence with change in estimated glomerular filtration rate (eGFR), we fit mixed effects models with the outcome being change in eGFR over time. We also fit Cox proportional hazards models to determine the association of adherence with time to persistent 25% and 50% decline in eGFR.
Results
The distribution of adherence post-transplant was as follows: 164 (68%), 49 (20%) and 30 (12%) had >85–100%, 50–85% and <50% adherence, respectively. 79 (33%) and 36 (15%) of the subjects experienced a persistent 25% decline in eGFR or allograft loss and 50% decline in eGFR or allograft loss during follow-up. Adherence was not associated with acute rejection or 25% decline or 50% decline in eGFR. In the adjusted and unadjusted model, adherence and black race were not associated with change in eGFR over time.
Conclusions
Non-adherence with a single immunosuppressive medication, was not associated with kidney allograft outcomes.
doi:10.1111/j.1399-0012.2010.01340.x
PMCID: PMC3566245  PMID: 20977496
kidney transplant; adherence; renal function
23.  Synthetic vascular hemodialysis access vs native arteriovenous fistula: A cost-utility analysis 
Annals of surgery  2012;255(1):181-186.
Objective
To determine the cost-effectiveness of two different vascular access strategies among incident dialysis patients.
Summary Background Data
Vascular access is a principal cause of morbidity and cost in hemodialysis patients. Recent guidelines and initiatives are intended to increase the proportion of patients with a fistula. However, there is growing awareness of the high prevalence of fistula failures and attendant complications.
Methods
A decision analysis using a Markov model was implemented to compare two different vascular access strategies among incident dialysis patients: a) placing an arteriovenous fistula (AVF1st) as the initial access followed by a synthetic vascular access if the AVF did not mature compared to b) placing a synthetic vascular access (SVA1st) as the initial access device. The cost-utility was evaluated across a range of the risk of complications from temporary catheters and SVA.
Results
Under base case assumptions, the AVF1st strategy yielded 2.19 QALYs compared to 2.06 QALYs from the SVA1st strategy. The incremental cost-effectiveness was $9389/QALY for AVF1st compared to SVA1st and was less than $50,000 per QALY as long as the probability of maturation is 36% or greater. AVF1st was the dominant strategy when the AVF maturation rate was 69% or greater.
Conclusion
The high risk of complications of temporary catheters and the overall low AVF maturation rate explain why a universal policy of AVF 1st for all incident dialysis patients may not optimize clinical outcomes. Strong consideration should be given to a more patient-centered approach taking into account the likelihood of AVF maturation.
doi:10.1097/SLA.0b013e31822f4e9b
PMCID: PMC3243807  PMID: 21918428
24.  Assessment of variation in live donor kidney transplantation across transplant centers in the United States1 - 8 
Transplantation  2011;91(12):1357-1363.
Background
Transplant centers vary in the proportion of kidney transplants performed using live donors. Clinical innovations that facilitate live donation may drive this variation.
Methods
We assembled a cohort of renal transplant candidates at 194 US centers using registry data from 1999 – 2005. We measured magnitude of live donor transplant (LDKTx) through development of a standardized live donor transplant ratio (SLDTR) at each center that accounted for center population differences. We examined associations between center characteristics and the likelihood that individual transplant candidates underwent LDKTx. To identify practices through which centers increase LDKTx, we also examined center characteristics associated with consistently being in the upper three quartiles of SLDTR.
Results
The cohort comprised 148,168 patients, among whom 34,593 (23.3%) underwent LDKTx. In multivariable logistic regression, candidates had an increased likelihood of undergoing LDKTx at centers with greater use of “unrelated donors” (defined as non-spouses and non-first-degree family members of the recipient; OR 1.31 for highest versus lowest use, p=0.02) and at centers with programs to overcome donor-recipient incompatibility (OR 1.33, p=0.01.) Centers consistently in the upper three SLDTR quartiles were also more likely to use “unrelated” donors (OR 8.30 per tertile of higher use, p<0.01), to have incompatibility programs (OR 4.79, p<0.01), and to use laparoscopic nephrectomy (OR 2.53 per tertile of higher use, p=0.02).
Conclusion
Differences in center population do not fully account for differences in the use of LDKTx. To maximize opportunities for LDKTx, centers may accept more unrelated donors and adopt programs to overcome biological incompatibility.
doi:10.1097/TP.0b013e31821bf138
PMCID: PMC3462439  PMID: 21562451
Live donor transplantation; center variation
25.  Longer-term outcomes after kidney transplantation from seronegative deceased donors at increased risk for blood-borne viral infection 1 – 17 
Transplantation  2011;91(11):1211-1217.
Background
Transmission of human immunodeficiency virus (HIV) and hepatitis C to transplant recipients has drawn attention to the use of allografts from seronegative donors at increased risk for viral infection (DIRVI).
Methods
We performed a cohort study of 7,803 kidney transplant recipients whose kidneys were recovered through one of two organ procurement organizations (OPO) from 1996 to 2007. Detailed OPO data on donor risk factors were linked to recipient data from the Organ Procurement and Transplantation Network.
Results
Median recipient follow-up was 3.9 years. 368 (5%) patients received DIRVI kidneys, a third of which were procured from donors with a history of injection drug use or commercial sex work. Compared to standard criteria kidney recipients, DIRVI kidney recipients were more likely to be HIV-positive or Black. In multivariable Cox regression, using DIRVI recipients as the reference, recipients of standard criteria donor kidneys had lower mortality (HR 0.71, p<0.01) and no difference in death-censored allograft failure (HR 1.09, p=0.62), whereas recipients of expanded criteria donor kidneys had no significant difference in mortality (HR 0.98, p=0.83), but a higher allograft failure rate (HR 1.93, p<0.01). High-quality data on post-transplant recipient viral testing were not available.
Conclusions
DIRVI kidney recipients experienced higher mortality than standard criteria kidney recipients. This finding could be explained if sicker patients received DIRVI kidneys (i.e., residual confounding) or the less likely possibility of undetected transmission of viral infections. Given the limitations of registry data used in this analysis, prospective studies are needed to further elucidate these findings.
doi:10.1097/TP.0b013e318218d59a
PMCID: PMC3462444  PMID: 21527872
Kidney transplantation; Viral transmission; Human immunodeficiency virus; High Risk Donor

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