Valerie Teal

Chronic Renal Insufficiency Cohort (CRIC) Study: Baseline Characteristics and Associations with Kidney Function

BACKGROUND AND OBJECTIVES The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for the progression of chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with CKD. We examined baseline demographic and clinical characteristics. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Seven clinical centers recruited adults who were aged 21 to 74 yr and had CKD using age-based estimated GFR (eGFR) inclusion criteria. At baseline, blood and urine specimens were collected and information regarding health behaviors, diet, quality of life, and functional status was obtained. GFR was measured using radiolabeled iothalamate in one third of participants. RESULTS A total of 3612 participants were enrolled with mean age +/- SD of 58.2 +/- 11.0 yr; 46% were women, and 47% had diabetes. Overall, 45% were non-Hispanic white, 46% were non-Hispanic black, and 5% were Hispanic. Eighty-six percent reported hypertension, 22% coronary disease, and 10% heart failure. Mean body mass index was 32.1 +/- 7.9 kg/m(2), and 47% had a BP >130/80 mmHg. Mean eGFR was 43.4 +/- 13.5 ml/min per 1.73 m(2), and median (interquartile range) protein excretion was 0.17 g/24 h (0.07 to 0.81 g/24 h). Lower eGFR was associated with older age, lower socioeconomic and educational level, cigarette smoking, self-reported CVD, peripheral arterial disease, and elevated BP. CONCLUSIONS Lower level of eGFR was associated with a greater burden of CVD as well as lower socioeconomic and educational status. Long-term follow-up of participants will provide critical insights into the epidemiology of CKD and its relationship to adverse outcomes.

Relationship of Estimated GFR and Coronary Artery Calcification in the (CRIC) Chronic Renal Insufficiency Cohort Study

BACKGROUND Coronary artery calcification (CAC) is associated with increased mortality risk in the general population. Although individuals with chronic kidney disease (CKD) are at markedly increased mortality risk, the incidence, prevalence, and prognosis of CAC in CKD are not well understood. STUDY DESIGN Cross-sectional observational study. SETTING & PARTICIPANTS Analysis of 1,908 participants who underwent coronary calcium scanning as part of the multiethnic CRIC (Chronic Renal Insufficiency Cohort) Study. PREDICTOR Estimated glomerular filtration rate (eGFR) computed using the Modification of Diet in Renal Disease (MDRD) Study equation, stratified by race, sex, and diabetic status. eGFR was treated as a continuous and a categorical variable compared with the reference value of >60 mL/min/1.73 m(2). MEASUREMENTS CAC detected using computed tomography (CT) using either an Imatron C-300 electron beam computed tomography (CT) scanner or multidetector CT scanner. CAC was computed using Agatston score as a categorical variable. Analyses were performed using ordinal logistic regression. RESULTS We found a strong and graded relationship between lower eGFR and increasing CAC. In unadjusted models, ORs increased from 1.68 (95% CI, 1.23-2.31) for eGFR of 50-59 mL/min/1.73 m(2) to 2.82 (95% CI, 2.06-3.85) for eGFR <30 mL/min/1.73 m(2). Multivariable adjustment only partially attenuated the results (OR, 1.53; 95% CI, 1.07-2.20) for eGFR <30 mL/min/1.73 m(2). LIMITATIONS Use of eGFR rather than measured GFR. CONCLUSIONS We showed a graded relationship between severity of CKD and CAC independent of traditional risk factors. These findings support recent guidelines that state that if vascular calcification is present, it should be considered as a complementary component to be included in the decision making required for individualizing CKD treatment.

Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the Chronic Renal Insufficiency Cohort (CRIC) study.

BACKGROUND The purpose of this study is to evaluate serum bicarbonate level as a risk factor for renal outcomes, cardiovascular events, and mortality in patients with chronic kidney disease (CKD). STUDY DESIGN Observational cohort study. SETTING & PARTICIPANTS 3,939 participants with CKD stages 2-4 who enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and December 2008. PREDICTOR Serum bicarbonate level. OUTCOMES Renal outcomes, defined as end-stage renal disease (either initiation of dialysis therapy or kidney transplantation) or 50% reduction in estimated glomerular filtration rate (eGFR); atherosclerotic events (myocardial infarction, stroke, or peripheral arterial disease); congestive heart failure events; and death. MEASUREMENTS Time to event. RESULTS Mean eGFR was 44.8 ± 16.8 (SD) mL/min/1.73 m(2), and median serum bicarbonate level was 24 (IQR, 22-26) mEq/L. During a median follow-up of 3.9 years, 374 participants died, 767 had a renal outcome, 332 experienced an atherosclerotic event, and 391 had a congestive heart failure event. In adjusted analyses, the risk of developing a renal end point was 3% lower per 1-mEq/L increase in serum bicarbonate level (HR, 0.97; 95% CI, 0.94-0.99; P = 0.01). The association was stronger for participants with eGFR >45 mL/min/1.73 m(2) (HR, 0.91; 95% CI, 0.85-0.97; P = 0.004). The risk of heart failure increased by 14% (HR, 1.14; 95% CI, 1.03-1.26; P = 0.02) per 1-mEq/L increase in serum bicarbonate level over 24 mEq/L. Serum bicarbonate level was not associated independently with atherosclerotic events (HR, 0.99; 95% CI, 0.95-1.03; P = 0.6) and all-cause mortality (HR, 0.98; 95% CI, 0.95-1.02; P = 0.3). LIMITATIONS Single measurement of sodium bicarbonate. CONCLUSIONS In a cohort of participants with CKD, low serum bicarbonate level was an independent risk factor for kidney disease progression, particularly for participants with preserved kidney function. The risk of heart failure was higher at the upper extreme of serum bicarbonate levels. There was no association between serum bicarbonate level and all-cause mortality or atherosclerotic events.

Vascular Risk Factors and Cognitive Impairment in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study

BACKGROUND AND OBJECTIVES Cognitive impairment is common among persons with chronic kidney disease, but the extent to which nontraditional vascular risk factors mediate this association is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted cross-sectional analyses of baseline data collected from adults with chronic kidney disease participating in the Chronic Renal Insufficiency Cohort study. Cognitive impairment was defined as a Modified Mini-Mental State Exam score>1 SD below the mean score. RESULTS Among 3591 participants, the mean age was 58.2±11.0 years, and the mean estimated GFR (eGFR) was 43.4±13.5 ml/min per 1.73 m2. Cognitive impairment was present in 13%. After adjustment for demographic characteristics, prevalent vascular disease (stroke, coronary artery disease, and peripheral arterial disease) and traditional vascular risk factors (diabetes, hypertension, smoking, and elevated cholesterol), an eGFR<30 ml/min per 1.73 m2 was associated with a 47% increased odds of cognitive impairment (odds ratio 1.47, 95% confidence interval 1.05, 2.05) relative to those with an eGFR 45 to 59 ml/min per 1.73 m2. This association was attenuated and no longer significant after adjustment for hemoglobin concentration. While other nontraditional vascular risk factors including C-reactive protein, homocysteine, serum albumin, and albuminuria were correlated with cognitive impairment in unadjusted analyses, they were not significantly associated with cognitive impairment after adjustment for eGFR and other confounders. CONCLUSIONS The prevalence of cognitive impairment was higher among those with lower eGFR, independent of traditional vascular risk factors. This association may be explained in part by anemia.

Association of Metabolic Syndrome with Development of New Onset Diabetes After Transplantation

Background. New-onset diabetes after transplantation (NODAT) is a major posttransplant complication associated with lower allograft and recipient survival. Our objective was to determine whether metabolic syndrome pretransplant is independently associated with NODAT development. Methods. We recruited 640 consecutive incident nondiabetic renal transplant recipients from three academic centers between 1999 and 2004. NODAT was defined as the use of hypoglycemic medication, a random plasma glucose level more than 200 mg/dL, or two fasting glucose levels more than or equal to 126 mg/dL beyond 30 days posttransplant. Results. Metabolic syndrome was common pretransplant (57.2%). NODAT developed in 31.4% of recipients 1 year posttransplant. Participants with metabolic syndrome were more likely to develop NODAT compared with recipients without metabolic syndrome (34.4% vs. 27.4%, P=0.057). Recipients with increasing number of positive metabolic syndrome components were more likely to develop NODAT (metabolic syndrome score prevalence at 1 year: 0 components-0.0%, 1-24.2%, 2-29.3%, 3-31.0%, 4-34.8%, and 5-73.7%, P=0.001). After adjustment for demographics, age by decade (hazard ratio [HR] 1.34 [1.20-1.50], P<0.0001), African American race (HR 1.35 [1.01-1.82], P=0.043), cumulative prednisone dosage (HR 1.18 [1.07-1.30], P=0.001), and metabolic syndrome (HR 1.34 [1.00-1.79], P=0.047) were independent predictors of development of NODAT at 1 year posttransplant. In a multivariable analysis incorporating the individual metabolic syndrome components themselves as covariates, the only pretransplant metabolic syndrome component to remain an independent predictor of NODAT was low high-density lipoprotein (hazard ratio [HR] 1.37 [1.01-1.85], P=0.042). Conclusions. Metabolic syndrome is an independent predictor for NODAT and is a possible target for intervention to prevent NODAT. Future studies to evaluate whether modification of metabolic syndrome factors pretransplant reduces NODAT development are needed.

Relation of Serum Lipids and Lipoproteins with Progression of CKD: The CRIC Study

BACKGROUND AND OBJECTIVES Hyperlipidemia is common in patients with CKD. The objective of this study was to evaluate whether measures of plasma lipids and lipoproteins predict progression of kidney disease in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Prospective cohort study in adults (n=3939) with CKD aged 21-74 years recruited between 2003 and 2008 and followed for a median of 4.1 years. At baseline, total cholesterol, triglycerides, very-low-density lipoprotein cholesterol (VLDL-C), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), apoA-I , apoB, and lipoprotein(a) [Lp(a)] were measured. The outcomes were composite end point of ESRD or 50% decline in eGFR from baseline (rate of change of GFR). RESULTS Mean age of the study population was 58.2 years, and the mean GFR was 44.9 ml/min per 1.73 m(2); 48% of patients had diabetes. None of the lipid or lipoprotein measures was independently associated with risk of the composite end point or rate of change in GFR. However, there were significant (P=0.01) interactions by level of proteinuria. In participants with proteinuria<0.2 g/d, 1-SD higher LDL-C was associated with a 26% lower risk of the renal end point (hazard ratio [HR], 0.74; 95% confidence interval [95% CI], 0.59 to 0.92; P=0.01), and 1-SD higher total cholesterol was associated with a 23% lower risk of the renal end point (HR, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In participants with proteinuria>0.2 g/d, neither LDL-C (HR, 0.98; 95% CI, 0.98 to 1.05) nor total cholesterol levels were associated with renal outcomes. Treatment with statins was reported in 55% of patients and was differential across lipid categories. CONCLUSIONS In this large cohort of patients with CKD, total cholesterol, triglycerides, VLDL-C, LDL-C, HDL-C, apoA-I, apoB, and Lp(a) were not independently associated with progression of kidney disease. There was an inverse relationship between LDL-C and total cholesterol levels and kidney disease outcomes in patients with low levels of proteinuria.

Relationship Between Adherence to Hepatitis C Virus Therapy and Virologic Outcomes: A Cohort Study

BACKGROUND Adherence to therapy with pegylated interferon and ribavirin for hepatitis C virus (HCV) infection has been incompletely examined. OBJECTIVE To evaluate the relationship between adherence to HCV therapy and early and sustained virologic response, assess changes in adherence over time, and examine risk factors for nonadherence. DESIGN Retrospective cohort study. SETTING National Veterans Affairs Hepatitis C Clinical Case Registry. PATIENTS 5706 HCV-infected patients (genotypes 1, 2, 3, or 4) with at least 1 prescription for both pegylated interferon and ribavirin between 2003 and 2006 and HCV RNA results before and after treatment initiation. MEASUREMENTS Adherence was calculated over 12-week intervals by using pharmacy refill data. End points included early virologic response (decrease of ≥2 log(10) HCV RNA at 12 weeks) and sustained virologic response (undetectable HCV RNA 24 weeks after the end of treatment). RESULTS Early virologic response increased with higher levels of adherence to ribavirin therapy over the initial 12 weeks (patients with HCV genotype 1 or 4, 25 of 68 [37%] with ≤40% adherence vs. 1367 of 2187 [63%] with 91% to 100% adherence [P < 0.001]; patients with HCV genotype 2 or 3, 12 of 18 [67%] with ≤40% adherence vs. 651 of 713 [91%] with 91% to 100% adherence [P < 0.001]). Among patients with HCV genotype 1 or 4, sustained response increased with higher adherence to ribavirin therapy over the second, third, and fourth 12-week intervals. Results were similar for adherence to interferon therapy. Mean adherence to therapy with interferon and ribavirin decreased by 3.4 and 6.6 percentage points per 12-week interval, respectively (P for trend < 0.001 for each drug). Patients who received growth factors or thyroid medications during treatment had higher mean adherence to antiviral therapy. LIMITATION This was an observational study without standardized timing for outcome measurements. CONCLUSION Early and sustained virologic responses increased with higher levels of adherence to interferon and ribavirin therapy. Adherence to therapy with both antivirals decreased over time, but more so for ribavirin.

Adherence to Hepatitis C Virus Therapy and Early Virologic Outcomes

BACKGROUND Suboptimal drug exposure attributable to physician-directed dosage reductions of pegylated interferon and/or ribavirin are associated with decreased sustained virologic response rates. However, data are limited with regard to suboptimal drug exposure that is attributable to missed doses by patients with chronic hepatitis C virus (HCV) infection. We examined the relationship between adherence to pegylated interferon and ribavirin therapy, measured by pharmacy refill, and HCV suppression during the initial 12 weeks of therapy. METHODS We conducted a cohort study involving 188 patients with chronic HCV infection who were treated with pegylated interferon plus ribavirin. Adherence was calculated using pharmacy refill data and could exceed 100%. The primary outcome was decrease in HCV load at 12 weeks; early virologic response was a secondary outcome. Mixed-effects regression models estimated the association between adherence and HCV suppression during the initial 12 weeks. Subanalyses were performed among patients who received optimal weight-based dosages. RESULTS The mean decrease in HCV load at 12 weeks was 0.66 log IU/mL greater for patients with > or =85% adherence than for those with <85% adherence (3.23 vs. 2.57 log IU/mL; P = .04). When patients who received a suboptimal ribavirin dosage were excluded, the decrease in viral load was 1.00 log IU/mL greater for persons with > or =85% adherence (3.32 vs. 2.32 log IU/mL; P = .01). Early virologic response was more common among patients with > or =85% adherence than it was among those with <85% adherence to treatment with pegylated interferon (73% vs. 29%; P = .02) and ribavirin (73% vs. 55%; P = .08). CONCLUSIONS Adherence of > or =85% to pegylated interferon and ribavirin treatment was associated with increased HCV suppression. Decreases in HCV load became greater when patients with > or =85% adherence to their regimen continued to receive their recommended weight-based ribavirin dosage.

Arterial Stiffness, Central Pressures, and Incident Hospitalized Heart Failure in the Chronic Renal Insufficiency Cohort Study

Chronic kidney disease (CKD) is independently associated with an increased risk of cardiovascular disease1;2. Patients with CKD are also at an increased risk of heart failure (HF), which is a major cause of morbidity and mortality in this population 3-6. Whereas several studies have been performed regarding predictors of overall cardiovascular risk in CKD (assessed using composite cardiovascular endpoints), the predictors of HF as a specific endpoint have not been adequately characterized in subjects with CKD. Of note, composite cardiovascular endpoints usually include several atherosclerotic and non-atherosclerotic events, for which risk factors may differ. HF in CKD has been proposed to be largely independent of atherosclerotic occlusive disease and more closely related to structural myocardial disease 3. Elevated blood pressure is a well-known risk factor for HF in the general population and a candidate mechanism for increased HF risk in CKD 7. However, a recent study reported that moderate CKD increases the risk of HF even in the absence of hypertension (defined from brachial pressure measurements) or diabetes mellitus at baseline 4. Central pressure profiles have been investigated in the prediction of cardiovascular risk in patients with end-stage kidney disease 8, but the relationship between central pressures and incident HF has never been examined in earlier stages of CKD. Similarly, increased large artery stiffness has been proposed as a major contributor to HF risk in CKD 3 due to its well-known effects on left ventricular pulsatile afterload 9, which promote left ventricular hypertrophy and myocardial dysfunction. Despite these important physiologic considerations, the relationship between large artery stiffness, central pressures and incident HF in CKD has not been investigated. In this study, we aimed to evaluate the role of large artery stiffness, brachial and central blood pressure as predictors of incident hospitalized HF in the Chronic Renal Insufficiency Cohort (CRIC), a multi-ethnic multi-center prospective observational study of patients with CKD10.Background—Chronic kidney disease is associated with an increased risk of heart failure (HF). We aimed to evaluate the role of large artery stiffness, brachial, and central blood pressure as predictors of incident hospitalized HF in the Chronic Renal Insufficiency Cohort (CRIC), a multiethnic, multicenter prospective observational study of patients with chronic kidney disease. Methods and Results—We studied 2602 participants who were free of HF at baseline. Carotid-femoral pulse wave velocity (CF-PWV; the gold standard index of large artery stiffness), brachial, and central pressures (estimated via radial tonometry and a generalized transfer function) were assessed at baseline. Participants were prospectively followed up to assess the development of new-onset hospitalized HF. During 3.5 years of follow-up, 154 participants had a first hospital admission for HF. CF-PWV was a significant independent predictor of incident hospitalized HF. When compared with the lowest tertile, the hazard ratios among subjects in the middle and top CF-PWV tertiles were 2.33 (95% confidence interval, 1.37–3.97; P=0.002) and 5.24 (95% confidence interval, 3.22–8.53; P<0.0001), respectively. After adjustment for multiple confounders, the hazard ratios for the middle and top CF-PWV tertiles were 1.95 (95% confidence interval, 0.92–4.13; P=0.079) and 3.01 (95% confidence interval, 1.45–6.26; P=0.003), respectively. Brachial systolic and pulse pressure were also independently associated with incident hospitalized HF, whereas central pressures were less consistently associated with this end point. The association between CF-PWV and incident HF persisted after adjustment for systolic blood pressure. Conclusions—Large artery stiffness is an independent predictor of incident HF in chronic kidney disease, an association with strong biological plausibility given the known effects of large artery stiffening of left ventricular pulsatile load.

Gender differences in achieving optimal lipid goals in patients with coronary artery disease.

To investigate gender differences in lipid goal attainment, we conducted a retrospective analysis of outpatient electronic health records from a large cardiology practice from September 2008 to September 2009. The most recent lipid profile and lipid-lowering medications and doses were extracted from electronic medical record. We identified 9,950 patients with coronary artery disease of whom 3,366 (34%) were women. Women were less likely to achieve a low-density lipoprotein (LDL) cholesterol goal of <70 mg/dl compared with men (30.6% vs 38.4%, p <0.001) and less likely to achieve a non-high-density lipoprotein cholesterol goal of <100 mg/dl (37.1% vs 48.2%, p <0.001). Irrespective of age, women were less likely to achieve their LDL cholesterol goals. Compared with men, women were more likely to be on no statin (16.9% vs 11.6%, p <0.001) or any lipid-lowering therapy (12.8% vs 7.8%, p <0.001) and less likely to be on high-potency statin (14.9% vs 18.0%, p <0.001) or combination therapy (22.2% vs 30.1%, p <0.001). There exists a major difference in the use of lipid-lowering therapy between men and women with coronary artery disease. In conclusion, women with coronary artery disease are prescribed insufficient doses of statins and combination lipid-lowering therapy and are less likely to achieve their optimal LDL and non-high-density lipoprotein cholesterol goals.