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European Heart Journal Advance Access published online on December 12, 2007
European Heart Journal, doi:10.1093/eurheartj/ehm525
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Mild renal dysfunction associated with incident coronary artery disease in young males

David Pereg1, Amir Tirosh2,3, Tzippora Shochat3, David Hasdai for the Metabolic, Lifestyle and Nutrition Assessment in Young adults (MELANY) Investigators4,5,*

1 Department of Internal Medicine A, Meir Medical Center, Kfar Sava, Israel
2 Department of Internal Medicine A, Sheba Medical Center, Tel-Hashomer, Israel
3 Medical Corps Headquarters, Israeli Defense Forces, Tel-Hashomer, Israel
4 Department of Cardiology, Rabin Medical Center, 39 Jabotinsky Street, Petah Tikva 49100, Israel
5 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Received 9 February 2007; revised 22 October 2007; accepted 25 October 2007.

* Corresponding author. Tel: +972 3 9377130, Fax: +972 3 9249850, Email: dhasdai{at}post.tau.ac.il


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Aims: Although impaired renal function is associated with adverse cardiovascular outcomes, it is unknown whether this association exists in young, healthy adults with normal or mildly impaired renal dysfunction.

Methods and results: We calculated the baseline creatinine clearance of young males without antecedent diabetes mellitus, coronary artery disease (CAD), or renal dysfunction, and examined their subsequent diagnosis of CAD, defined as coronary artery diameter stenosis of at least 50% and/or myocardial infarction. The 23 964 males, 32.5 ± 5.9 years old, had a baseline estimated creatinine clearance of 107.9 ± 0.6 mL min–1 per 1.73 m2 (60–150 mL min–1 per 1.73 m2). During a mean follow-up of 3.5 ± 1.9 years, 77 subjects were diagnosed with CAD. After age adjustment, there was a progressive increase in the risk for CAD as the estimated creatinine clearance decreased [hazard ratio (HR) 4.77, 95% confidence interval 3.22–7.06, P < 0.001 for comparison between the fifth and first quintiles]. This association also persisted after further adjustments for conventional and ancillary risk factors for CAD (HR 2.10, 95% confidence interval 1.40–3.14, P < 0.001).

Conclusion: Reduced renal function in the normal to mildly impaired range is independently associated with increased risk for CAD among young, healthy males.

Key Words: Coronary artery disease • Myocardial infarction • Renal failure • Coronary angiography • Creatinine clearance


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Chronic renal failure is a well-established risk factor for cardiovascular morbidity and mortality.1 Most prior studies that examined the relationship between renal function and cardiovascular outcomes relied on serum creatinine, an unreliable proxy of renal function.2 Indeed, a significant proportion of patients with serum creatinine levels slightly above the upper limit of the normal range or even within the normal range have impaired renal function, often even significant renal dysfunction,2 thus compromising the validity of the prior studies.

More recently, renal function has been assessed using equations estimating the glomerular filtration rate.2 Several studies have clearly demonstrated that reduced values of glomerular filtration rate that are even within the mildly impaired or normal range are associated with worse cardiovascular outcomes among a wide spectrum of patients with established cardiovascular conditions, including asymptomatic and symptomatic heart failure,3 acute myocardial infarction,4 and surgical5 or percutaneous6 revascularization. There are also data that a glomerular filtration rate <60 mL min–1 per 1.73 m2 is a risk factor for both new and recurrent cardiovascular disease in the general population and in people at increased risk for cardiovascular disease.7–9 More recent studies demonstrated a correlation between elevated levels of cystatin C, a serum measure of renal function, and an increased risk of cardiovascular events and death among elderly outpatients without acute cardiovascular conditions.10,11 The linear association of cystatin C with the risk of death or cardiovascular disease among elderly subjects with renal function within the normal range (glomerular filtration rate of at least 60 mL min–1 per 1.73 m2) suggests that differences in renal function within the normal range impact on cardiovascular outcomes. However, similar to most other studies, this study included only elderly patients, many of whom had different co-morbidities that may be associated with renal dysfunction, such as diabetes mellitus and heart failure. There are no firm data hitherto regarding a possible correlation between differences in renal function within the normal or mildly impaired range and cardiovascular outcomes among young, healthy adults.

The aim of the current study was to test the hypothesis that mild renal dysfunction is associated with incident coronary artery disease (CAD) in otherwise healthy, young males enrolled in the Metabolic, Lifestyle and Nutrition Assessment in Young adults (MELANY) study.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The MELANY study
The MELANY study is conducted in the Israel Defense Force Staff Periodic Examination Center, to which all career service personnel above the age of 25 years have been referred every 3 to 5 years since 1992.12 The referral of all military personnel to the periodic examination is obligatory and supervised by the military authorities. A computerized database established in 1992 is the source of data for MELANY, which was designed to study the risk factors for common diseases in young adults. At each visit to the Staff Periodic Examination Center, each examinee completed a detailed questionnaire assessing demographic, nutritional, lifestyle, and medical factors. Thereafter, blood samples were drawn after a 14 h fast and analysed. A trained medical technician measured height and weight, and a physician at the centre performed a complete physical examination. Between scheduled visits to the centre, patients were followed-up at designated military primary care clinics. All medical information from both the Staff Periodic Examination Center and the primary care clinics was recorded in the same central database, thereby facilitating ongoing, tight, and uniform follow-up.

Ethical considerations
The institutional review board of the Israel Defense Forces Medical Corp approved this study on the basis of strict maintenance of participant anonymity during database analyses. Data from subjects were recorded anonymously, and therefore no individual consent was obtained. The authors are solely responsible for the design of the study, analysis and interpretation of the data, and writing of the manuscript, without any form of censorship or limitation by the Israel Defense Forces.

Inclusion and exclusion criteria
Included in the study were males whose serum creatinine levels were measured at their initial Staff Periodic Examination Center visit as of 1999. Patients were excluded from the study if they had confirmed diabetes mellitus (types 1 or 2), an established diagnosis of CAD, or an estimated creatinine clearance of <60 mL min–1 per 1.73 m2 or >150 mL min–1 per 1.73 m2 in their initial examination. Females were not included in the current analysis because their insufficient number precluded meaningful analysis.

Outcome definitions
The outcome definition of the study was the presence of a significant CAD (angiographically proved diameter stenosis >50% in at least one coronary artery) or the occurrence of fatal or non-fatal myocardial infarction. At each serial visit, all military personnel participating in the current analysis underwent a routine treadmill exercise test (Bruce protocol), supervised by a board-certified cardiologist. The test was considered pathological if ST-segment depression (>2 mm in two contiguous leads, measured 80 ms after the J point) occurred. Otherwise, the test was terminated if symptoms of severe angina or exhaustion occurred or if the target heart rate was achieved. Participants with a pathological stress test were referred for coronary angiography. In the presence of borderline results or when participants reported angina without diagnostic electrocardiographic changes, a myocardial perfusion imaging test using thallium-201 was performed. Coronary angiography was performed in those who underwent a pathological myocardial perfusion imaging test. Individuals presenting with symptoms of angina and/or myocardial infarction between the serial visits were also referred for coronary angiography following consultation with a board-certified cardiologist, and results were recorded in the central database.

Family history of CAD was defined as the occurrence of CAD in a male first-degree relative under the age of 55 years or in a female first-degree relative under the age of 65 years. Hypertension was defined as repeated blood pressure measurements > 140/90 mmHg, and impaired fasting glucose as fasting plasma glucose level > 100 mg/dL.

Laboratory methods
The biochemical analyses of blood samples, including the measurement of serum creatinine, glucose, and lipids, were performed on fresh samples in a core laboratory facility that handles 1.2 million samples per year. The laboratory is authorized to perform tests according to the international quality standard ISO-9002. Periodic assessment of quality control (National External Quality Assessment Service, UK) is performed regularly. All measured biochemical markers were identified with the use of a BM/Hitachi917 automated analyzer (Boehringer Mannheim).

Medical technicians with the use of mercury sphygmomanometers performed blood pressure measurements after 5 min rest and in the sitting position. Urine collections for protein or albumin were not routinely performed during the study period.

Renal function assessment
Creatinine clearance was calculated using the Cockcroft–Gault equation, where CrCl = {(140–age) x weight (kg)}/72 x Scr.13 This equation was chosen because it is preferred over the alternative equation, the Modification of Diet in Renal Disease equation, in healthy patients under the age of 65 without known chronic kidney disease.14,15

Statistical analysis
General linear models were used to obtain the age-adjusted means of the various populations’ characteristics listed in Table 1 across quintiles of creatinine clearance. For the categorical values presented, we used it with specification of the link function and response distribution. The proportions in these variables were corresponding to the mean of values 1 (yes) and 0 (no) distribution. We conducted a Cox proportional hazards analysis to estimate the hazard ratios (HRs) and 95% confidence intervals for the development of CAD, using the estimated creatinine clearance as the independent variable either divided into quintiles or as a continuous variable. For the latter, we used log-transformed creatinine clearance. We conducted a further analysis using the estimated creatinine clearance in the range of 60–150 mL min–1 per 1.73 m2 divided into nine groups of equal intervals of 10 mL min–1 per 1.73 m2. In our analyses, we also added the values of the known independent risk factors for CAD (blood pressure, low-density and high-density cholesterol, smoking status, and family history of CAD) separately to the age-adjusted model to evaluate the potential role of each as a confounder of the tested association between the estimated creatinine clearance and CAD. We further conducted a multivariable model in which the adjustment for the co-variates was as follows: adjustment for age, levels of fasting plasma high- and low-density lipoprotein, triglycerides and glucose, mean arterial blood pressure, and body mass index was performed as continuous variables. All variables were assessed for co-linearity to avoid adjustment of variables with correlation ≥0.8. Family history of CAD (positive, negative, or missing information), physical activity (non-active, active, or missing information), smoking status (current smoker, past smoker, never smoked, or missing information), and state of impaired fasting glucose (impaired, normoglycaemics, missing information) were added to the model as categorical variables. All statistical analyses were performed with the use of SAS statistical software, version 9.1.


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  		Table 1 Age-adjusted baseline characteristics of 23 964 men according to quintiles of estimated creatinine clearance

 

   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Of the 24 038 subjects that were included in the study, 74 were excluded: 16 due to estimated creatinine clearance values <60 mL min–1 per 1.73 m2, 25 due to values >150 mL min–1 per 1.73 m2, 27 due to an antecedent diagnosis of diabetes mellitus, and six due to an established diagnosis of CAD at the time of enrolment. Thus, the cohort of our current analysis consists of 23 964 male subjects with a mean age of 32.5 ± 5.9 years. A minority of the population had independent risk factors for CAD, such as cigarette smoking, dyslipidaemia, hypertension, and a family history of premature CAD (Table  1). Other features associated with CAD such as obesity, impaired glucose tolerance, and physical inactivity were also reported in a minority of subjects (Table  1). The mean estimated creatinine clearance was 107.9 ± 0.6 mL min–1 per 1.73 m2, with a range of 60–150 mL min–1 per 1.73 m2, in accordance with the inclusion criteria.

When we divided the cohort into quintiles on the basis of the estimated creatinine clearance values, we noticed that as the creatinine clearance was lower, the patients were older and with a higher proportion of smokers. In addition, even following age adjustment, individuals with the lower creatinine clearance had higher cholesterol levels, blood pressure values, and body mass index, more commonly had impaired fasting glucose and less commonly engaged in physical activity (Table  1).

During a mean follow-up of 3.5 ± 1.9 years, 77 subjects were diagnosed with CAD. Of them, 69 were diagnosed angiographically with sub-clinical disease following a pathological stress test, five were diagnosed angiographically owing to symptoms between the serial visits, and three were diagnosed clinically with acute, non-fatal myocardial infarction (with angiographically proved CAD). There were no cases of fatal myocardial infarction during the follow-up period. Of note, 31 subjects with CAD were in the fifth quintile (Table  2). When an age adjustment analysis was performed, we observed a significant and progressive increase in the risk for CAD as the estimated creatinine clearance decreased, and the risk for CAD was found to be significantly higher in the fifth compared with the first quintile (HR = 4.77, 95% confidence interval 3.22–7.06, P < 0.001) (Table  2). In a multivariable model, adjusted for family history of CAD, blood pressure, cholesterol values, and smoking status, the inverse association between estimated creatinine clearance and the risk for CAD remained, and the increased risk for CAD in the fifth compared with the first quintile persisted (HR = 2.69, 95% confidence interval 1.19–5.72, P < 0.001) (Table  2). This association also persisted after further adjustments for body mass index, triglyceride levels, impaired fasting glucose, and physical activity (HR = 2.10, 95% confidence interval 1.40–3.14, P < 0.001) (Table  2).


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  		Table 2 Hazard ratios for coronary artery disease according to quintiles of estimated creatinine clearance

 
When we calculated the risk for CAD using the estimated creatinine clearance as a continuous variable (log-transformed), adjusting for the conventional risk factors for CAD and ancillary risks listed in Table  2, the hazard for CAD increased as the estimated creatinine clearance decreased (HR = 2.03, 95% confidence interval 1.62–2.54, P < 0.001).

Because some of the recent studies used the Modified Diet in Renal Disease formula to assess the impact of renal function on cardiovascular outcomes, we repeated our analysis using this equation, which is a more appropriate formula for patients with renal dysfunction. We found that the number of cases with CAD and their distribution in the different quintiles did not differ significantly from the analysis we performed using the Cockcroft–Gault equation (data not shown).

In order to depict our results graphically, and given the non-linear association between the creatinine clearance and the risk for CAD, we further divided the study population into nine groups of equal intervals of 10 mL min–1 per 1.73 m2, in the range of 60–150 mL min–1 per 1.73 m2. For each group, we calculated the HRs and 95% confidence interval for the development of CAD and created a graph demonstrating an association between reduced values of estimated creatinine clearance and increased risk for developing CAD within the range of 60–150 mL min–1 per 1.73 m2. This association seemed to become apparent when the estimated creatinine clearance values dropped below the level of ~100 mL min–1 per 1.73 m2 (Figure 1).


Figure 1
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  		Figure 1 Age-adjusted hazard ratios and 95% confidence intervals for the development of coronary artery disease on the basis of the estimated creatinine clearance.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Main findings
The main finding of the current study was an inverse association between the estimated creatinine clearance values and the risk for developing CAD in a population-based cohort of ambulatory, young, and healthy males with normal or mildly reduced renal function (estimated creatinine clearance 60–150 mL min–1 per 1.73 m2). The association between the estimated creatinine clearance and the risk of CAD, however, was not linear and seemed to become apparent when the estimated creatinine clearance values dropped below the level of ~100 mL min–1 per 1.73 m2.

Prior studies
Recently, several studies have been published dealing with the association between renal dysfunction and cardiovascular risk in ambulatory patients with different co-morbidities, including ischaemic heart disease, congestive heart failure, and diabetes mellitus.8,9,16 These studies have demonstrated that the increased risk for cardiovascular morbidity and mortality seemed to become apparent when the estimated glomerular filtration rates values dropped <60 mL min–1 per 1.73 m2. The relative small number of incident cases in our study precluded the determination of an exact threshold. Nonetheless, our findings support the hypothesis that mild reductions in renal function, even within the normal or mildly impaired range, capture a pre-clinical state of chronic kidney disease that predates the development of clinical disease, especially cardiovascular disease.11

Possible mechanisms
Several factors associated with impaired renal function are believed to contribute to the increased risk for CAD, including insulin resistance,17 increased oxidative stress,18 a pro-inflammatory state,19 and increased plasma fibrinogen and homocysteine.20 However, because chronic kidney disease is casually or associatively linked to traditional risk factors for cardiovascular disease, it is difficult to assess the relative weight of these non-traditional risk factors. Indeed, in our cohort, the patients with the lower levels of estimated creatinine clearance were more likely to be cigarette smokers and had higher levels of cholesterol and blood pressure. However, their predisposition to CAD persisted even after statistical adjustment for these standard risk factors. Overall, it seems that renal dysfunction, even very mild, may simply serve as a readily available, easy to measure, proxy of systemic vascular disease and an index of overall vascular health. Indeed, even mild renal dysfunction has been associated with impaired vascular function,20,21 including impaired coronary artery vasomotion,21 considered the forme fruste of CAD.

Limitations
Several limitations of this study warrant consideration. Our analysis pertains only to males. Because atherosclerosis may be differentially affected based on sex, our results should be extrapolated to young, healthy females with caution. The mean follow-up of the study population was relatively short (3.5 ± 1.9 years), and therefore there was a relatively low incidence of CAD (a total of 77 cases), and most cases were diagnosed in a sub-clinical phase. Further analysis is warranted in order to prove the association between normal-to-mildly impaired renal function and long-term CAD morbidity and mortality.

Our cohort did not undergo urine collection for protein or albumin. Microalbuminuria, even very mild, has clearly been shown to be a risk factor for both cardiovascular morbidity and mortality,22,23 particularly among patients with diabetes mellitus, but also among non-diabetics. Although microalbuminuria screening in apparently healthy, non-diabetic individuals is not considered cost-effective, and its prevalence in our cohort is expected to be very low,24 it still may be a significant confounder for the development of CAD, and the lack of data regarding its prevalence in our population is an important limitation. Further investigation is needed in order to evaluate the correlation between urinary protein secretion and the incidence of CAD in non-diabetic, young individuals.

All the equations that are used to estimate the glomerular filtration rate, including the Cockcroft–Gault equation, are based on serum creatinine. Because of the tubular secretion of creatinine, these equations mildly overestimate the measured glomerular filtration rate. However, they are still considered relatively accurate and easy to use and are still, by far, the most commonly used mode for renal function assessment in clinical studies and current clinical practice. As mentioned earlier, cystatin C is an alternative serum measure of kidney function that approximates direct measures of glomerular filtration rate and is less influenced by age, sex, or muscle mass.2 Moreover, a recent study has suggested that it may be a more accurate predictor of cardiovascular outcomes than the estimated creatinine clearance among elderly individuals without chronic kidney disease.11 Thus, the association between renal function and cardiovascular outcomes in our cohort of young males may be more accurately assessed using cystatin C measurements rather than the estimated creatinine clearance. However, cystatin C was not measured in our cohort, and serum samples were not routinely stored.

Finally, differences in laboratory calibration may make the comparison of our results with other studies quite difficult. However, even if the absolute creatinine clearance values may differ in comparison with other reports, the relative risks of the different quintiles should still be the same.

Conclusions
The current study supports the hypothesis that mild reductions in renal function, even within the normal or mildly impaired range, predate the development of cardiovascular disease. It suggests that renal function assessment in young and healthy males may provide incremental information on cardiovascular risk than a single measure of traditional risk factors. It remains to be determined whether risk factor modification in this early stage affects the progression of renal dysfunction, or conversely, and perhaps more intriguing, whether measures to attenuate the progression of renal dysfunction attenuate the risk for CAD.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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