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1.  Urinary sodium is a potent correlate of proteinuria: Lessons from the CRIC Study 
American journal of nephrology  2012;36(5):397-404.
Background
While higher blood pressure is known to increase proteinuria, whether increased dietary sodium as estimated from 24-hour urinary excretion correlates with increased proteinuria in patients with chronic kidney disease (CKD) is not well studied.
Methods
We measured 24-hour urine sodium, potassium, and protein excretion in 3,680 participants in the Chronic Renal Insufficiency Cohort (CRIC) study, to determine the relationship between urinary sodium and potassium and urinary protein excretion in patients with CKD. We stratified our data based on the presence or absence of diabetes given the absence of any data on this relationship, and evidence that diabetics had greater urinary protein excretion at nearly every level of urinary sodium excretion. Multiple linear regressions were used with a stepwise inclusion of covariates such as systolic blood pressure (SBP), demographics, hemoglobin A1C, and type of antihypertensive medications to evaluate the relationship between urinary electrolyte excretion and proteinuria.
Results
Our data demonstrated that urinary sodium (+1SD above the mean), as a univariate variable, explained 12% of the variation in proteinuria (β=0.29, p<.0001) with rising urinary sodium excretion associated with increasing proteinuria. The significance of that relationship was only partially attenuated with adjustment for demographic and clinical factors and the addition of 24-hour urinary potassium to the model (β=0.13, R2=0.35, p<.0001).
Conclusions
An understanding of the relationship between these clinical factors and dietary sodium may allow a more tailored approach for dietary salt restriction in patients with CKD.
doi:10.1159/000342966
PMCID: PMC4448958  PMID: 23076013
proteinuria; sodium; potassium; blood pressure
2.  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
3.  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
4.  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
5.  Response of Pediatric Uveitis to Tumor Necrosis Factor-α Inhibitors 
The Journal of rheumatology  2013;40(8):1394-1403.
Objectives
To evaluate the outcome of TNF-alpha inhibition (anti-TNFα) for pediatric uveitis.
Methods
We retrospectively assessed children (≤18 years) with non-infectious uveitis receiving anti-TNFα at five uveitis centers and one pediatric-rheumatology center. Incident treatment success was defined as minimal or no uveitis activity at ≥2 consecutive ophthalmological exams ≥28 days apart while taking no oral and ≤2 eyedrops/day of corticosteroids. Eligible children had active uveitis and/or were taking higher corticosteroid doses.
Results
Among 56 eligible children followed over 33.73 person-years, 52% had juvenile idiopathic arthritis (JIA) and 75% had anterior uveitis (AU). The Kaplan-Meier estimated proportion achieving treatment success within 12 months was 75% (95% confidence interval [95% CI]: 62–87%). Complete absence of inflammatory signs with discontinuation of all corticosteroids was observed in an estimated 64% by 12 months (95% CI: 51–76%). Diagnoses of JIA or AU were associated with greater likelihood of success, as was the oligoarticular subtype amongst JIA cases. In a multivariable model, compared to those with JIA-associated AU, those with neither or with JIA or AU alone had a 75–80% lower rate of achieving quiescence under anti-TNFα - independent of the number of immunomodulators previously or concomitantly prescribed. Uveitis re-activated within 12 months of achieving quiescence in 14% of those continuing anti-TNFα (95% CI: 6–31%). The incidence of discontinuation for adverse effects was 8%/year (95% CI: 1–43%).
Conclusion
Treatment with anti-TNFα was successful and sustained in a majority of children with non-infectious uveitis and treatment-limiting toxicity was infrequent. JIA-associated AU may be especially responsive to anti-TNFα.
doi:10.3899/jrheum.121180
PMCID: PMC3802519  PMID: 23818712
uveitis; tumor necrosis factor-alpha antagonist; juvenile idiopathic arthritis
7.  CAUSAL INFERENCE FOR CONTINUOUS-TIME PROCESSES WHEN COVARIATES ARE OBSERVED ONLY AT DISCRETE TIMES 
Annals of statistics  2011;39(1):10.1214/10-AOS830.
Most of the work on the structural nested model and g-estimation for causal inference in longitudinal data assumes a discrete-time underlying data generating process. However, in some observational studies, it is more reasonable to assume that the data are generated from a continuous-time process and are only observable at discrete time points. When these circumstances arise, the sequential randomization assumption in the observed discrete-time data, which is essential in justifying discrete-time g-estimation, may not be reasonable. Under a deterministic model, we discuss other useful assumptions that guarantee the consistency of discrete-time g-estimation. In more general cases, when those assumptions are violated, we propose a controlling-the-future method that performs at least as well as g-estimation in most scenarios and which provides consistent estimation in some cases where g-estimation is severely inconsistent. We apply the methods discussed in this paper to simulated data, as well as to a data set collected following a massive flood in Bangladesh, estimating the effect of diarrhea on children’s height. Results from different methods are compared in both simulation and the real application.
doi:10.1214/10-AOS830
PMCID: PMC3857358  PMID: 24339454
Causal inference; continuous-time process; deterministic model; diarrhea; g-estimation; longitudinal data; structural nested model
8.  Carotid Plaque, Carotid Intima-Media Thickness, and Coronary Calcification Equally Discriminate Prevalent Cardiovascular Disease in Kidney Disease 
American journal of nephrology  2012;36(4):342-347.
Background
Despite the significant morbidity and mortality attributable to cardiovascular disease (CVD), risk stratification remains an important challenge in the chronic kidney disease(CKD) population. We examined the discriminative ability of non-invasive measures of atherosclerosis, including carotid intima-media thickness(cIMT), carotid plaque, coronary artery calcification(CAC) and ascending and descending thoracic aorta calcification(TCAC), and Framingham Risk Score (FRS) to predict self-reported prevalent CVD.
Methods and Results
Participants were enrolled in the cIMT ancillary study of the Chronic Renal Insufficiency Cohort(CRIC) Study and also had all of the above measures within an 18 month period. CVD was present in 21% of study participants. C-statistics were used to ascertain the discriminatory power of each measure of atherosclerosis. The study population (n=220) was 64% male; 51% black and 45% white. The proportion of individuals with estimated glomerular filtration rate ≥60, 45–59, 30–44, and <30ml/min/1.73m2 was 21%, 41%, 28%, and 11%, respectively. In multivariable analyses adjusting for demographic factors, we failed to find a difference between CAC, carotid plaque, and cIMT as predictors of self-reported prevalent CVD (c-statistic 0.70, 95% confidence interval [CI]: 0.62–0.78; c-statistic 0.68, 95% CI: 0.60–0.75, and c-statistic 0.64, CI: 0.56–0.72, respectively). CAC was statistically better than FRS. FRS was the weakest discriminator of self-reported prevalent CVD (c-statistic 0.58).
Conclusions
There was a significant burden of atherosclerosis among individuals with CKD, ascertained by several different imaging modalities. We were unable to find a difference in the ability of CAC, carotid plaque, and cIMT to predict self-reported prevalent CVD.
doi:10.1159/000342794
PMCID: PMC3538165  PMID: 23107930
carotid intima media thickness; coronary artery calcification; kidney; plaque
9.  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
10.  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
11.  Effects of Adjusting for Instrumental Variables on Bias and Precision of Effect Estimates 
American Journal of Epidemiology  2011;174(11):1213-1222.
Recent theoretical studies have shown that conditioning on an instrumental variable (IV), a variable that is associated with exposure but not associated with outcome except through exposure, can increase both bias and variance of exposure effect estimates. Although these findings have obvious implications in cases of known IVs, their meaning remains unclear in the more common scenario where investigators are uncertain whether a measured covariate meets the criteria for an IV or rather a confounder. The authors present results from two simulation studies designed to provide insight into the problem of conditioning on potential IVs in routine epidemiologic practice. The simulations explored the effects of conditioning on IVs, near-IVs (predictors of exposure that are weakly associated with outcome), and confounders on the bias and variance of a binary exposure effect estimate. The results indicate that effect estimates which are conditional on a perfect IV or near-IV may have larger bias and variance than the unconditional estimate. However, in most scenarios considered, the increases in error due to conditioning were small compared with the total estimation error. In these cases, minimizing unmeasured confounding should be the priority when selecting variables for adjustment, even at the risk of conditioning on IVs.
doi:10.1093/aje/kwr364
PMCID: PMC3254160  PMID: 22025356
bias (epidemiology); confounding factors (epidemiology); epidemiologic methods; instrumental variable; precision; simulation; variable selection
12.  Causal inference in longitudinal studies with history-restricted marginal structural models 
A new class of Marginal Structural Models (MSMs), History-Restricted MSMs (HRMSMs), was recently introduced for longitudinal data for the purpose of defining causal parameters which may often be better suited for public health research or at least more practicable than MSMs (6, 2). HRMSMs allow investigators to analyze the causal effect of a treatment on an outcome based on a fixed, shorter and user-specified history of exposure compared to MSMs. By default, the latter represent the treatment causal effect of interest based on a treatment history defined by the treatments assigned between the study’s start and outcome collection. We lay out in this article the formal statistical framework behind HRMSMs. Beyond allowing a more flexible causal analysis, HRMSMs improve computational tractability and mitigate statistical power concerns when designing longitudinal studies. We also develop three consistent estimators of HRMSM parameters under sufficient model assumptions: the Inverse Probability of Treatment Weighted (IPTW), G-computation and Double Robust (DR) estimators. In addition, we show that the assumptions commonly adopted for identification and consistent estimation of MSM parameters (existence of counterfactuals, consistency, time-ordering and sequential randomization assumptions) also lead to identification and consistent estimation of HRMSM parameters.
doi:10.1214/07-EJS050
PMCID: PMC3475192  PMID: 23087778
causal inference; counterfactual; marginal structural model; longitudinal study; IPTW; G-computation; Double Robust
13.  Principal Stratification and Attribution Prohibition: Good Ideas Taken Too Far 
Pearl’s article provides a useful springboard for discussing further the benefits and drawbacks of principal stratification and the associated discomfort with attributing effects to post-treatment variables. The basic insights of the approach are important: pay close attention to modification of treatment effects by variables not observable before treatment decisions are made, and be careful in attributing effects to variables when counterfactuals are ill-defined. These insights have often been taken too far in many areas of application of the approach, including instrumental variables, censoring by death, and surrogate outcomes. A novel finding is that the usual principal stratification estimand in the setting of censoring by death is by itself of little practical value in estimating intervention effects.
doi:10.2202/1557-4679.1367
PMCID: PMC3204670  PMID: 22049269
principal stratification; causal inference
15.  Metabolic Syndrome, Components, and Cardiovascular Disease Prevalence in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study 
American Journal of Nephrology  2011;33(6):477-484.
Background/Aims
Metabolic syndrome may increase the risk for incident cardiovascular disease (CVD) and all-cause mortality in the general population. It is unclear whether, and to what degree, metabolic syndrome is associated with CVD in chronic kidney disease (CKD). We determined metabolic syndrome prevalence among individuals with a broad spectrum of kidney dysfunction, examining the role of the individual elements of metabolic syndrome and their relationship to prevalent CVD.
Methods
We evaluated four models to compare metabolic syndrome or its components to predict prevalent CVD using prevalence ratios in the Chronic Renal Insufficiency Cohort (CRIC) Study.
Results
Among 3,939 CKD participants, the prevalence of metabolic syndrome was 65% and there was a significant association with prevalent CVD. Metabolic syndrome was more common in diabetics (87.5%) compared with non-diabetics (44.3%). Hypertension was the most prevalent component, and increased triglycerides the least prevalent. Using the bayesian information criterion, we found that the factors defining metabolic syndrome, considered as a single interval-scaled variable, was the best of four models of metabolic syndrome, both for CKD participants overall and for diabetics and non-diabetics separately.
Conclusion
The predictive value of this model for future CVD outcomes will subsequently be validated in longitudinal analyses.
doi:10.1159/000327618
PMCID: PMC3095834  PMID: 21525746
Cardiovascular disease; Chronic kidney disease; Chronic Renal Insufficiency Cohort (CRIC) Study; Metabolic syndrome
16.  Inflammation, Coronary Artery Calcification and Cardiovascular Events in Incident Renal Transplant Recipients 
Atherosclerosis  2010;212(2):589-594.
Objective
Coronary artery calcification (CAC) predicts cardiovascular events in the general population. We conducted a prospective study to determine if inflammatory markers were predictive of CAC and if CAC predicted cardiovascular events and mortality in incident renal transplant recipients.
Methods
A prospective cohort of 112 asymptomatic incident renal transplant recipients who had no prior history of coronary artery revascularization or myocardial infarction had coronary calcifications measured early post-transplant and at least 18 months later by Agatston score and volume method.
Results
The mean CAC score was 367.7 (682.3). Inflammatory markers such as WBC and CRP were predictive of CAC severity. Recipients with cardiovascular events (n=11) or death (n=12) during the follow-up period had higher mean [675.1 (669.3) vs. 296.8(669.0), p=0.02] and median [434.8 vs. 28.9, p=0.01] CAC score compared to those without them. Recipients with CAC score less than 100 had a better cumulative survival rate compared to the recipients with CAC score greater than 100 [95.1 vs. 82.3%, p=0.03]. We found a significant unadjusted and adjusted association between CAC score and cardiovascular events and mortality. A quarter (25.9%) of recipients had CAC progression. Coronary calcification progression also predicted cardiovascular events and mortality after adjustment for diabetes, age, dialysis vintage and presence of CAC at time of transplant.
Conclusion
CAC is prevalent in renal recipients and is predictive of cardiovascular events and mortality. Changes in coronary calcification are common and predict clinical outcomes. Inflammatory markers are predictive of CAC severity at time of transplant, but are not predictive of future cardiovascular event or mortality.
doi:10.1016/j.atherosclerosis.2010.05.016
PMCID: PMC2953547  PMID: 20934074
coronary calcification; EBCT; renal transplant; inflammation; C-reactive protein
17.  Central Pulse Pressure in Chronic Kidney Disease: A CRIC Ancillary Study 
Hypertension  2010;56(3):518-524.
Central pulse pressure can be non-invasively derived using the radial artery tonometric methods. Knowledge of central pressure profiles has predicted cardiovascular morbidity and mortality in several populations of patients, particularly those with known coronary artery disease and those receiving dialysis. Few data exist characterizing central pressure profiles in patients with mild-moderate chronic kidney disease who are not on dialysis. We measured central pulse pressure cross-sectionally in 2531 participants in the Chronic Renal Insufficiency Cohort study to determine correlates of the magnitude of central pulse pressure in the setting of chronic kidney disease. Tertiles of central pulse pressure (CPP) were < 36 mmHg, 36–51 mmHg and > 51 mmHg with an overall mean (± S.D.) of 46 ± 19 mmHg. Multivariable regression identified the following independent correlates of central pulse pressure: age, gender, diabetes mellitus, heart rate (negatively correlated), glycosylated hemoglobin, hemoglobin, glucose and PTH concentrations. Additional adjustment for brachial mean arterial pressure and brachial pulse pressure showed associations for age, gender, diabetes, weight and heart rate. Discrete intervals of brachial pulse pressure stratification showed substantial overlap within the associated central pulse pressure values. The large size of this unique chronic kidney disease cohort provides an ideal situation to study the role of brachial and central pressure measurements in kidney disease progression and cardiovascular disease incidence.
doi:10.1161/HYPERTENSIONAHA.110.153924
PMCID: PMC2941985  PMID: 20660819
Elasticity; epidemiology; diabetic nephropathies; hemodynamics; gender
18.  Variability of Creatinine Measurements in Clinical Laboratories: Results from the CRIC Study 
American Journal of Nephrology  2010;31(5):426-434.
Objectives
Estimating equations using serum creatinine (SCr) are often used to assess glomerular filtration rate (GFR). Such creatinine (Cr)-based formulae may produce biased estimates of GFR when using Cr measurements that have not been calibrated to reference laboratories. In this paper, we sought to examine the degree of this variation in Cr assays in several laboratories associated with academic medical centers affiliated with the Chronic Renal Insufficiency Cohort (CRIC) Study; to consider how best to correct for this variation, and to quantify the impact of such corrections on eligibility for participation in CRIC. Variability of Cr is of particular concern in the conduct of CRIC, a large multicenter study of subjects with chronic renal disease, because eligibility for the study depends on Cr-based assessment of GFR.
Methods
A library of 5 large volume plasma specimens from apheresis patients was assembled, representing levels of plasma Cr from 0.8 to 2.4 mg/dl. Samples from this library were used for measurement of Cr at each of the 14 CRIC laboratories repetitively over time. We used graphical displays and linear regression methods to examine the variability in Cr, and used linear regression to develop calibration equations. We also examined the impact of the various calibration equations on the proportion of subjects screened as potential participants who were actually eligible for the study.
Results
There was substantial variability in Cr assays across laboratories and over time. We developed calibration equations for each laboratory; these equations varied substantially among laboratories and somewhat over time in some laboratories. The laboratory site contributed the most to variability (51% of the variance unexplained by the specimen) and variation with time accounted for another 15%. In some laboratories, calibration equations resulted in differences in eligibility for CRIC of as much as 20%.
Conclusions
The substantial variability in SCr assays across laboratories necessitates calibration of SCr measures to a common standard. Failing to do so may substantially affect study eligibility and clinical interpretations when they are determined by Cr-based estimates of GFR.
doi:10.1159/000296250
PMCID: PMC2883847  PMID: 20389058
Chronic renal disease; Creatinine measurements, variability; Chronic Renal Insufficiency Cohort (CRIC) Study; Glomerular filtration rate
19.  Design and Analysis of Multiple Events Case-Control Studies 
Biometrics  2010;66(4):1220-1229.
Summary
In case-control research where there are multiple case groups, standard analyses fail to make use of all available information. Multiple events case-control (MECC) studies provide a new approach to sampling from a cohort and are useful when it is desired to study multiple types of events in the cohort. In this design, subjects in the cohort who develop any event of interest are sampled, as well as a fraction of the remaining subjects. We show that a simple case-control analysis of data arising from MECC studies is biased and develop three general estimating-equation based approaches to analyzing data from these studies. We conduct simulation studies to compare the efficiency of the various MECC analyses with each other and with the corresponding conventional analyses. It is shown that the gain in efficiency by using the new design is substantial in many situations. We demonstrate the application of our approach to a nested case-control study of the effect of oral sodium phosphate use on chronic kidney injury with multiple case definitions.
doi:10.1111/j.1541-0420.2009.01369.x
PMCID: PMC2980800  PMID: 20002403
Multiple events case-control study; case-cohort study; nested case-control study; sampling from a cohort; semi-parametric efficient estimator
20.  Predictors of having a potential live donor: a prospective cohort study of kidney transplant candidates 
The barriers to live donor transplantation are poorly understood. We performed a prospective cohort study of individuals undergoing renal transplant evaluation. Participants completed a questionnaire that assessed clinical characteristics as well as knowledge and beliefs about transplantation. A participant satisfied the primary outcome if anyone contacted the transplant center to be considered as a live donor for that participant. The final cohort comprised 203 transplant candidates, among whom 80 (39.4%) had a potential donor contact the center and 19 (9.4%) underwent live donor transplantation. In multivariable logistic regression, younger candidates (OR 1.65 per 10 fewer years, p<0.01) and those with annual income >=$15,000 (OR 4.22, p=0.03) were more likely to attract a potential live donor. Greater self-efficacy, a measure of the participant’s belief in his or her ability to attract a donor, was a predictor of having a potential live donor contact the center (OR 2.73 per point, p<0.01), while knowledge was not (p=0.56). The lack of association between knowledge and having a potential donor suggests that more intensive education of transplant candidates will not increase live donor transplantation. On the other hand, self-efficacy may be an important target in designing interventions to help candidates find live donors.
doi:10.1111/j.1600-6143.2009.02848.x
PMCID: PMC2864790  PMID: 19845584
live donor; kidney transplantation; health disparities
21.  Aortic PWV in Chronic Kidney Disease: A CRIC Ancillary Study 
American journal of hypertension  2009;23(3):282-289.
Background
Aortic PWV is a measure of arterial stiffness and has proved useful in predicting cardiovascular morbidity and mortality in several populations of patients, including the healthy elderly, hypertensives and those with end stage renal disease receiving hemodialysis. Little data exist characterizing aortic stiffness in patients with chronic kidney disease who are not receiving dialysis, and in particular the effect of reduced kidney function on aortic PWV.
Methods
We performed measurements of aortic PWV in a cross-sectional cohort of participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study to determine factors which predict increased aortic PWV in chronic kidney disease.
Results
PWV measurements were obtained in 2564 participants. The tertiles of aortic PWV (adjusted for waist circumference) were < 7.7 m/sec, 7.7–10.2 m/sec and > 10.2 m/sec with an overall mean (± S.D.) value of 9.48 ± 3.03 m/sec [95% CI = 9.35–9.61 m/sec]. Multivariable regression identified significant independent positive associations of age, blood glucose concentrations, race, waist circumference, mean arterial blood pressure, gender, and presence of diabetes with aortic PWV and a significant negative association with the level of kidney function.
Conclusions
The large size of this unique cohort, and the targeted enrollment of chronic kidney disease participants provides an ideal situation to study the role of reduced kidney function as a determinant of arterial stiffness. Arterial stiffness may be a significant component of the enhanced cardiovascular risk associated with kidney failure.
doi:10.1038/ajh.2009.240
PMCID: PMC2822073  PMID: 20019670
22.  Aortic calcification predicts cardiovascular events and all-cause mortality in renal transplantation 
Nephrology Dialysis Transplantation  2009;24(4):1314-1319.
Background. Cardiovascular disease is a leading cause of death among renal transplant recipients. Aortic calcification is associated with increased mortality in dialysis subjects. The significance of aortic calcification among renal transplant recipients is unknown. Our objective was to prospectively examine the association of aortic calcification with cardiovascular events and all-cause mortality among asymptomatic incident renal transplant recipients.
Methods. One hundred and twelve renal transplant recipients underwent electron beam computed tomography. Aortic calcification was scored by the Agatston method. The mean follow-up time was 5.1 years. Cardiovascular events (heart failure, coronary artery disease, peripheral arterial disease and stroke) and all-cause mortality were recorded.
Results. The cohort consisted of 62% Caucasians, 38% African Americans and 62% male gender. The mean age was 49.0 ± 12.5 years. Thirty-four percent had aortic calcification. During follow-up, 12 cardiovascular events and 10 deaths were recorded. Subjects with aortic calcification had more cardiovascular events compared to those without aortic calcification (23.7 versus 4.1%, P = 0.001). Recipients with aortic calcification had higher mortality compared to those without aortic calcification but it did not reach statistical significance (15.8 versus 5.4%, P = 0.07). The univariate hazard ratio of aortic calcification score in a proportional hazard Cox model to assess event-free survival was 1.15 (1.04–1.27, P = 0.01). Diabetes and aortic calcification score were independently associated with survival. In addition to the predictors above, dialysis vintage was an independent predictor for combined future cardiovascular event and mortality.
Conclusions. In conclusion, aortic calcification is prevalent among renal transplant recipients and is predictive of future cardiovascular events. Aortic calcification is easily identified by non-invasive testing, and should be considered when assessing cardiovascular risk in asymptomatic renal transplant recipients.
doi:10.1093/ndt/gfn753
PMCID: PMC2721431  PMID: 19164320
cardiovascular events; renal transplantation; vascular calcification
23.  Metabolic Syndrome and Coronary Artery Calcification in Renal Transplant Recipients 
Transplantation  2008;86(5):728-732.
Background
Coronary artery calcification (CAC) and Metabolic Syndrome (MS) have been associated with increased cardiovascular risk. The study objective was to examine the association of MS with CAC presence and progression in renal transplant recipients.
Methods
We measured CAC progression in asymptomatic recipients who had no prior history of coronary artery disease.
Results
MS was common (55.4%). Median CAC scores were 0, 33.1, 98, and 261.9 for patients with 1, 2, 3, and 4 or more positive components of the MS, respectively. Severe CAC scores were more common in recipients with MS (p=0.04). Although recipients with MS had higher mean CAC scores at baseline and significant CAC progression [483 (590.6) vs. 619(813.8), p=0.01 ], MS was not an independent predictor of annualized rate of CAC change in a multivariate model
Conclusion
Future studies to evaluate if MS treatment improves cardiovascular outcomes are imperative.
doi:10.1097/TP.0b013e3181826d12
PMCID: PMC2656432  PMID: 18791455
renal transplant; coronary calcification; metabolic syndrome
24.  Association of Donor Inflammation– and Apoptosis-Related Genotypes and Delayed Allograft Function after Kidney Transplantation 
Background
Delayed renal allograft survival (DGF) after a deceased donor kidney transplant is associated with an increased risk of allograft loss. Inflammatory response and apoptosis are associated with increased risk of DGF.
Study Design
Cross Sectional Study
Setting & Participants
We first recruited 616 recipients of kidneys from 512 deceased kidney donors and the donor DNA was genotyped. These recipients who were included in a prospective cohort study of 9 transplant centers in the Delaware Valley region, had their DGF outcome obtained through medical record abstraction. Then, we identified the recipient (n=349) of the contralateral deceased kidney donor, if not part of the cohort, through the USRDS registry. The final cohort consisted of 965 recipients of deceased donor kidneys from 512 donors.
Predictors
Donor single nucleotide polymorphisms (SNPs) in genes for tumor necrosis factor α (TNF), transforming growth factor β1 (TGFB1), interleukin 10 (IL10), p53 (TP53), and heme oxygenase 1 (HMOX1).
Outcomes
DGF, defined as need for dialysis in the first week post-transplant. Secondary outcomes included acute rejection and eGFR.
Measurements
Information on DGF, acute rejection and eGFR for recipients in the Delaware Valley Cohort was obtained through medical record abstraction. For other recipients, information on DGF was obtained from UNOS forms and CMS claims in the USRDS registry.
Results
The TGFB1, IL10, TP53 and HMOX1 genes were not associated with DGF. The G allele of TNF polymorphism rs3093662 was associated with DGF in an adjusted analysis (OR= 1.85 compared to A allele, 95% C.I.=1.16–2.96, p=0.01). However this association does not achieve statistical significance after adjusting for multiple comparisons.
Limitations
Inadequate sample size for infrequent genotypes and multiple comparisons.
Conclusion
Due to the low frequency of donor SNPs of interest, a larger sample size and replication are necessary for conclusive evidence for the association of donor genotypes with DGF.
doi:10.1053/j.ajkd.2008.05.006
PMCID: PMC2562522  PMID: 18640487
Kidney Transplant; Deceased Donor Genotypes; Delayed Graft Function
25.  Extended Instrumental Variables Estimation for Overall Effects* 
We consider a method for extending instrumental variables methods in order to estimate the overall effect of a treatment or exposure. The approach is designed for settings in which the instrument influences both the treatment of interest and a secondary treatment also influenced by the primary treatment. We demonstrate that, while instrumental variables methods may be used to estimate the joint effects of the primary and secondary treatments, they cannot by themselves be used to estimate the overall effect of the primary treatment. However, instrumental variables methods may be used in conjunction with approaches for estimating the effect of the primary on the secondary treatment to estimate the overall effect of the primary treatment. We consider extending the proposed methods to deal with confounding of the effect of the instrument, mediation of the effect of the instrument by other variables, failure-time outcomes, and time-varying secondary treatments. We motivate our discussion by considering estimation of the overall effect of the type of vascular access among hemodialysis patients.
PMCID: PMC2669310  PMID: 19381345
instrumental variables; causal inference

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