Abstract
Background. This study was performed to identify the association of atherosclerotic coronary artery disease (CAD) and pulse pressure with renal disease progression in patients with mild chronic renal disease. Methods. Eligibility criteria for enrollment in this study included age 18 to 70 years, mild chronic renal disease (CRD), undergoing thallium SPECT and echocardiography and followed longer than three years. Mild CRD was defined as serum creatinine level of 1.5 to 3.0 mg/dL in men and 1.4 to 3.0 mg/dL in women. Patients with serious illness, history of kidney transplantation, ejection fraction less than 40% on echocardiography and development of acute renal failure during follow-up were excluded. Results. A total of 87 patients were included in this study. The underlying renal disease included diabetic nephropathy in 51 patients. Forty-five patients showed positive findings on thallium SPECT and they were classified as having CAD. Coronary angiography showed significant stenosis in 41 of 42 patients studied. Median duration of follow-up was 56 months. During the follow-up period, 40 patients required chronic dialysis therapy and 16 patients showed a doubling of baseline serum creatinine in three years. These 56 patients were classified as progressors. Comparison of clinical and laboratory parameters between progressors and nonprogressors showed a difference in the presence of diabetic nephropathy, mean arterial pressure, 24-h urine protein (p<0.001), pulse pressure (p<0.01), total cholesterol and presence of CAD (p<0.05). There was no association between the progression of CRD and the results of CAD or treatment of CAD. Multivariate logistic regression analysis showed that the presence of diabetic nephropathy and mean arterial pressure ≥100 mm Hg were independent predictors of CRD progression. Conclusion. Atherosclerotic coronary artery disease and pulse pressure were associated with renal disease progression.
Introduction
Patients with end-stage renal disease (ESRD) have a rate of coronary artery disease (CAD) far in excess of the nonuremic population. Even mild renal insufficiency is associated with angiographic coronary artery disease. It is controversial whether chronic renal disease (CRD) is a proatherogenic condition.Citation[[1]] There is a possibility that atherosclerosis may aggravate renal insufficiency, which increases the proportion of ESRD in patients with atherosclerosis.
Pulse pressure, which reflects arterial stiffness, has been implicated in the development and progression of large vessel atherosclerosis, small vessel disease, and in the occurrence of cardiovascular events.Citation[[2]] Pulse pressure is also significantly increased in patients with CRD.Citation[[3]]
There are several reasons to suspect that atherosclerotic CAD and pulse pressure may be associated with progression of CRD. First, atherosclerotic CAD and atherosclerotic vascular disease elsewhere, including the renal artery, commonly co-exist.Citation[[4]], Citation[[5]] Ischemic injury from renal artery disease may aggravate progression of CRD. Second, there are many similarities in the pathogenesis of atherosclerosis and glomerulosclerosis, such as smoking, lipid, hypertension, and diabetes.Citation[[6]], Citation[[7]] Third, there are several reports that inflammatory markers, such as ferritin, white blood cell count and serum albumin, are associated with renal disease progression.Citation[[8]] Because atherosclerosis is thought to be inflammatory disease,Citation[[9]] atherosclerosis may be associated with renal disease progression through inflammation. Increases in pulse pressure are also associated with elevated C-reactive protein levels among apparently healthy US adults.Citation[[10]] Fourth, pulse pressure is associated with the development of albuminuria in hypertensive, diabetic, and nondiabetic patients.Citation[[2]], Citation[[11]], Citation[[12]]
The purpose of this study was to identify the association of atherosclerotic CAD and pulse pressure with renal disease progression in patients with mild CRD.
Patients and Methods
Subjects
Eligibility criteria for enrollment in this study included age 18 to 70 years, mild CRD, performance of thallium SPECT and echocardiography between January 1995 and June 1999 in Asian Medical Center and follow-up longer than three years. Mild CRD was defined as serum creatinine level of 1.5 to 3.0 mg/dL in men and 1.4 to 3.0 mg/dL in women.Citation[[13]] Patients with serious illness, history of kidney transplantation, ejection fractions less than 40% on echocardiography and development of acute renal failure during follow-up were excluded. A total of 87 patients were included in this study. All patients were followed at least once every three months. Blood pressure assessment and laboratory parameters were repeated at every visit.
We selected 20 baseline covariates as possible predictors of progression, including age, gender, current smoking, body mass index, history of hypertension, mean arterial pressure, pulse pressure, presence of diabetic nephropathy, initial creatinine, initial estimated creatinine clearance, 24-h urine protein, total cholesterol, HDL-cholesterol, LDL-cholesterol, albumin, uric acid, calcium × phosphorus, ejection fraction of the left ventricle, left ventricular mass index and presence of coronary artery disease. A current smoker was defined as one who smoked at least daily. Estimated creatinine clearance was calculated using the Cockcroft-Gault formula, including a correction factor of 0.85 for women and adjustment for body surface area. Left ventricular mass index (LVMI) was calculated as left ventricular mass on echocardiography divided by body surface area. Blood pressure assessment and laboratory parameters represent mean value during the follow-up period except initial creatinine and estimated creatinine clearance. Progression of renal disease was defined as the combined endpoint of a doubling of the baseline serum creatinine or initiation of chronic dialysis therapy.Citation[[14]]
Thallium-SPECT and Coronary Angiography
After an overnight fast, dipyridamole (0.14 mg/kg/min) was infused over 4 min with a monitoring of symptoms using electrocardiogram, heart rate, and blood pressure. Three minutes after infusion, 2 mCi of thallium was injected and stress images were obtained. Four hours later, three or four redistribution images were obtained while the patients were at rest.
Coronary angiography was performed in patients with positive thallium SPECT. Significant stenosis was defined as a narrowing of the diameter of more than 50%, and was classified into three categories; one-vessel, two-vessel, and three-vessel or left main artery disease.
Statistical Analysis
The data were expressed as a mean value ± S.D. or median values with their ranges. The significance of differences in clinical and laboratory data between the groups was tested by Student's t test, Mann-Whitney U test, and Fisher's exact test. Based on the factors that were found to be of significance on univariate analysis, multivariate logistic regression analysis was performed to identify independent variables predictive of renal disease progression. For the multivariate logistic regression analysis, we subdivided the patients into two groups according to each continuous variable. A mean arterial pressure 100 mm Hg means that of the target blood pressure (130/85) in patients with CRD. Hypercholesterolemia can be defined as a total cholesterol level of ≥200 mg/dL. Pulse pressure greater than 65 mm Hg was reported to be associated with higher long-term cardiovascular mortality.Citation[[15]] All statistical analyses were performed using a two-tailed test and were considered statistically significant at P<0.05.
Results
The mean age was 61 ± 9 years; the male to female ratio was 1.6:1 (54:33). Median duration of follow-up was 56 months (range, 36 to 90 months). Underlying renal diseases included diabetic nephropathy (n = 51), chronic glomerulonephritis (n = 15), polycystic kidney disease (n = 3), lupus nephritis (n = 1), and small kidneys of unknown etiology (n = 17). Seventy-four patients (85%) had a history of hypertension and 18 patients (21%) were current smokers. Mean initial creatinine and creatinine clearance were 1.9 ± 0.4 mg/dL and 32 ± 9 mL/min/1.73 m2, respectively.
Forty-five patients had positive findings on thallium SPECT and they were classified as having coronary artery disease. Three patients refused to undergo coronary angiography. Coronary angiography showed significant stenosis in 41 of 42 patients studied; one-vessel disease in five, two-vessel disease in 10, and 3-vessel, or left main disease in 26 patients. One patient did not show significant stenosis. Management for angiographically confirmed CAD patients was as follows; coronary artery bypass graft in 11, angioplasty with or without stent in 13 and medical treatment only in 17.
During the follow-up period, 40 patients required chronic dialysis therapy and 16 patients showed a doubling of baseline serum creatinine in three years. These 56 patients were classified as progressors. The remaining 31 patients were classified as nonprogressors.
Comparison of CRD progression between the patients who had coronary artery disease (n = 45) and those who had not (n = 42) showed a significant difference (76% vs. 52%, p<0.05, ).
Table 1. Association between the progression of chronic renal disease and the presence of coronary artery disease
Comparison of clinical and laboratory parameters between progressors (n = 56) and nonprogressors (n = 31) showed a difference in the mean arterial pressure, pulse pressure, presence of diabetic nephropathy, 24-h urine protein, total cholesterol, and the presence of CAD (). There was no association between the results of CAD and the progression of CRD. The difference in treatment of CAD did not affect the progression of CRD (). There was a significant association between the presence of CAD and pulse pressure ≥65 mm Hg (P<0.05).
Table 2. Comparison of clinical and laboratory parameters between progressors and nonprogressors
Table 3. Comparison of the results of coronary angiography and treatment for coronary artery disease between progressors and nonprogressors with angiographically proven coronary artery disease patients
Multivariate logistic regression analysis identified that the presence of diabetic nephropathy and mean arterial pressure (≥100 mmHg) were independent predictors of CRD progression (). Pulse pressure (≥65 mm Hg), 24-h urine protein (≥3.5 g), total cholesterol (≥200 mg/dL), and the presence of CAD did not reach statistical significance.
Table 4. Multivariate analysis of risk factors for progression of chronic renal disease
Discussion
To the best of our knowledge, this is the first study to evaluate the association of atherosclerotic CAD and pulse pressure with renal disease progression. Although they were not independent predictors of renal disease progression, they were significantly associated with this progression. The prevalence of renal artery disease in patients being evaluated for CAD is about 30%.Citation[[16]], Citation[[17]] In elderly patients with myocardial infarction or symptomatic peripheral vascular disease, the incidence of renal artery stenosis can be up to 40%.Citation[[5]] In patients with renal artery stenosis, ischemic injury may aggravate renal disease progression. However, atherosclerosis may also have a noncausal association for renal disease progression through several risk factors, such as dyslipidemia, hypertension, and diabetes. This study also showed that the presence of diabetic nephropathy and mean arterial pressure ≥100 mm Hg were independent predictors of renal disease progression. Total cholesterol and 24-h urine protein have been reported as independent risk factors for renal disease progression.Citation[[18]], Citation[[19]] This study also identified that these factors were associated with renal disease progression, however, they were not significant in the multivariate analysis.
Comparison of serum albumin, a negative acute phase reactant, between progressors and nonprogressors did not show a difference in this study. Sarnak et al. showed that C-reactive protein was not associated with mean GFR slope in both univariate and multivariate analysis in the Modification of Diet in Renal Disease study.Citation[[20]] These findings suggest that inflammation may not be involved in the progression of CRD.
The severity of CAD may be a predictor of renal artery disease.Citation[[16]] In this study, however, there was no association between the results of coronary angiography and the progression of CRD.
Coronary angiography was not performed in patients with normal thallium scans, because the high sensitivity and specificity of thallium SPECT may preclude the routine use of this invasive procedure. Therefore, we subdivided the patients according to the results of a thallium scan that was performed in all patients. Generally, a dipyridamole thallium scan demonstrates a sensitivity and specificity of 80 to 90% in detecting CAD. One report demonstrated a sensitivity and specificity of 97 and 100%, respectively.Citation[[21]] In our study, coronary angiography showed significant stenosis in 41 (98%) of 42 patients with positive thallium scans.
Elevated pulse pressure is increasingly being recognized as a risk factor for cardiovascular, and particularly coronary disease.Citation[[22]] This study also showed significant relationship between atherosclerotic CAD and pulse pressure.
We excluded the patients with left ventricular ejection fraction less than 40%, which ruled out the possibility that combined heart failure aggravated CRD progression. Generally, ejection fraction less than 40% is considered as significant heart failure.
In conclusion, atherosclerotic coronary artery disease and pulse pressure were associated with renal disease progression.
Acknowledgment
This study was supported by Baxter Korea.
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