BACKGROUND/RATIONALE:
The incidence of cardiovascular disease (CVD) is 3 times higher in patients with chronic kidney disease (CKD) compared to the general population. CKD disproportionally affects African Americans, who make up a third of the population that needs renal replacement therapy. There are several novel cardiovascular risk factors whose profile worsens as CKD progresses, such as proteinuria, elevated lipoprotein (a) [Lp(a)], and homocysteine. Because CKD patients are at high risk for cardiovascular disease, it is important to screen for CVD. Carotid intima-media thickness (IMT) measured by ultrasound has been shown to assess the extent and severity of atherosclerosis.

OBJECTIVE(S):
The study examined prospectively patients with CKD to determine if traditional and non-traditional risk factors were independent risk factors for subclinical CVD as measured by IMT.

Specific Aim #1: To identify predictors of the degree of subclinical CVD as measured by carotid IMT at baseline, such as duration and characteristics of CKD and measures of homocysteine, Lipoprotein (a) [Lp (a)] and high sensitivity C-reactive protein (hs-CRP) in patients with CKD, adjusting for other known cardiovascular risk factors.

Specific Aim #2: To determine the relationship between progression of subclinical CVD as measured by carotid IMT and concurrent measures of homocysteine, Lp (a) and hs-CRP over a 36-month interval, adjusting for other known cardiovascular risk factors.

METHODS:
The study population included patients 18 to 74 years of age who came in to Philadelphia Veterans Administration Medical Center (PVAMC) for their primary or nephrology care during the study's recruitment period. The subjects were recruited as part of an ancillary study to the Chronic Renal Insufficiency Cohort (CRIC) that will determine associations between IMT and chronic kidney disease. This award allowed us to perform baseline and follow-up IMT in the VA subjects, to assess progression and determine risk factors for progression in this high-risk population. Patients were eligible to participate if they presented an estimated glomerular filtration rate (eGFR) between 20 and 70 ml/min/1.73 m2. The tool of analysis was multiple linear regression for baseline associations. A change was measured by the difference in IMT measurements. Models using standard mixed effects growth curves were used to allow both the estimation of individual subjects' slopes and intercepts and for the comparison of groups defined by baseline or time-varying covariates. In addition, we evaluated the robustness of our findings in the non-CKD cohort of the Multi-Ethnic Subclinical Atherosclerosis Study.

FINDINGS/RESULTS:
Recruitment for this ancillary study to the CRIC study was completed in December 2006. There were 507 subjects participating in the CRIC study at the University of Pennsylvania/Philadelphia VA Medical Center. We obtained consent from 464 participants at our site, and performed 447 carotid IMTs. An additional 5 CRIC subjects were ineligible, and 11 subjects refused participation in the ancillary study. The subjects were predominantly male (66.7%) and African-American (53.5%). There were 99 veterans in this cohort. The mean (SD) age was 60.4 (10.5). One-third of subjects had a history of cardiovascular disease, and over half (52.1%) had diabetes mellitus. The mean eGFR was 47.1 (15.6). The mean IMT for the cohort was 0.80 (0.19) with a median of 0.77. The mean IMT was 0.74 (0.16) for participants with eGFR greater than 60 ml/min. IMT was higher in patients with eGFR less than 60 ml/min, at 0.81 (0.20). IMT was higher in diabetics compared to non-diabetics [0.83 (0.18) vs. 0.77 (0.19), p=0.003], in subjects with hypertension [0.82 (0.19) vs. 0.7 (0.15), p<0.001], and in subjects with a history of CVD [0.84 (0.18) vs. 0.78 (0.18), p=0.0003]. Smokers had higher IMT compared to non-smokers [0.82 (0.19) vs. 0.77 (0.18), p=0.005]. Patients with proteinuria >3 grm/24 hr had higher IMT compared to proteinuria <3 grm/24 hr [0.91 (0.24)vs. 0.79 (0.18), p=0.005].

Plaques were very common (56%). Increasing age, calcium, and systolic blood pressure, as well as a history of smoking, were associated with presence of plaque. There was an inverse relationship between eGFR, body mass index (BMI), and serum albumin with presence of plaque. There was a borderline association with phosphorus levels (p=0.058).

We found that patients with worse renal function (eGFR <30) had more rapid IMT progression compared to those with better kidney function (p=0.04). There was a borderline association between IMT progression with gender and diabetes (p=0.13 and p=0.10, respectively). We found no association between Lp(a), hs-CRP or homocysteine and progression of IMT.


IMPACT:
Because half of all cardiovascular events occur in patients without any known traditional risk factors, it is important to screen for CVD in an effort to identify high-risk individuals. Carotid IMT measured by ultrasound has been shown to assess the extent and severity of atherosclerosis in the general population. We have found that plaque is very common in the CKD population in mild to moderate disease. Kidney function was associated with presence of plaque after multivariable adjustment for traditional risk factors. We also found an association between calcium and phosphate with plaque that was confirmed in a non-CKD cohort. Confirmation of this finding by others may lead to dietary guideline changes. Identifying modifiable risk factors for the progression of cardiovascular disease may lead to targeted medical interventions for easily identifiable high-risk groups to decrease disease progression.

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External Links for this Project

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PUBLICATIONS:

Journal Articles

1. DeLoach SS, Appel LJ, Chen J, Joffe MM, Gadegbeku CA, Mohler ER, Parsa A, Perumal K, Rafey MA, Steigerwalt SP, Teal V, Townsend RR, Rosas SE. Aortic pulse pressure is associated with carotid IMT in chronic kidney disease: report from Chronic Renal Insufficiency Cohort. American journal of hypertension. 2009 Dec 1; 22(12):1235-41. [view]
2. Kamoun M, Israni AK, Joffe MM, Hoy T, Kearns J, Mange KC, Feldman D, Goodman N, Rosas SE, Abrams JD, Brayman KL, Feldman HI. Assessment of differences in HLA-A, -B, and -DRB1 allele mismatches among African-American and non-African-American recipients of deceased kidney transplants. Transplantation proceedings. 2007 Jan 1; 39(1):55-63. [view]
3. Israni AK, Li N, Sidhwani S, Rosas S, Kong X, Joffe M, Rebbeck T, Feldman HI. Association of hypertension genotypes and decline in renal function after kidney transplantation. Transplantation. 2007 Nov 27; 84(10):1240-7. [view]
4. Schankel K, Robinson J, Bloom RD, Guerra C, Rader D, Joffe M, Rosas SE. Determinants of coronary artery calcification progression in renal transplant recipients. American Journal of Transplantation. 2007 Sep 1; 7(9):2158-64. [view]
5. Robinson J, Tan AU, Wilensky RL, Matthai W, Munoz M, Rosas SE. Electron-beam computerized tomography correlates with coronary angiogram in chronic kidney disease patients. American Journal of Nephrology. 2007 Jan 1; 27(3):247-52. [view]
6. Imoagene-Oyedeji AE, Rosas SE, Doyle AM, Goral S, Bloom RD. Posttransplantation anemia at 12 months in kidney recipients treated with mycophenolate mofetil: risk factors and implications for mortality. Journal of the American Society of Nephrology : JASN. 2006 Nov 1; 17(11):3240-7. [view]
7. Rubin MF, Rosas SE, Chirinos JA, Townsend RR. Surrogate markers of cardiovascular disease in CKD: what's under the hood? American journal of kidney diseases : the official journal of the National Kidney Foundation. 2011 Mar 1; 57(3):488-97. [view]

Conference Presentations

1. Rosas SE. Chronic kidney disease in individuals with cardiovascular disease. Paper presented at: National Hispanic Medical Association Annual Conference; 2011 Mar 1; Washington, DC. [view]
2. Rosas SE. Vascular calcification in chronic kidney disease. Paper presented at: Johns Hopkins University Renal Grand Rounds; 2011 May 1; Baltimore, MD. [view]

DRA: Aging, Older Veterans' Health and Care
DRE: Diagnosis
Keywords: Cardiovasc’r disease, Chronic disease (other & unspecified), Risk factors
MeSH Terms: none