Atherosclerotic risk factors and renal function in the elderly: the role of hyperfibrinogenaemia and smoking. Results from the Italian Longitudinal Study on Ageing (ILSA)

B. Baggio1, A. Budakovic1, E. Perissinotto2, S. Maggi3, S. Cantaro1, G. Enzi4 and F. Grigoletto2 for the ILSA Working Group

1 Department of Medical and Surgical Sciences, Division of Nephrology, 2 Department of Environmental Medicine and Public Health, 3 CNR, Study Center on Aging and 4 Division of Geriatrics, University of Padua, Italy

Correspondence and offprint requests to: Professor Bruno Baggio, MD, DSc, Dipartimento di Scienze Mediche e Chirurgiche, Policlinico Universitario, Via Giustiniani 2, 35120 Padova, Italy. Email: bruno.baggio{at}unipd.it



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 
Background. We examined associations between cardiovascular diseases and risk factors with pathological levels of and significant changes in serum creatinine (SCr) in a large prevalence phase and longitudinal phase community-based sample of an elderly Italian population (ILSA Study) showing no clinical evidence of renal impairment.

Methods. The prevalence phase was performed on 2981 subjects, aged 65–84 years, who were negative for renal diseases, had available SCr values and had complete clinical information on their cardiovascular risk factors. Of these, 371 were considered ‘healthy’ since they were not affected by cardiovascular diseases or diabetes, whereas 2610 tested positive for cardiovascular diseases and were considered ‘diseased’. The sex-specific 95th percentiles for SCr (cut-off points) were calculated in the healthy reference sample to define the upper limit for normal SCr values. The distribution and prevalence of diseased subjects having values over the cut-off point values were then estimated. Associations between values over the cut-off point levels and pathological or clinical conditions were analysed from the diseased sample. The longitudinal phase was carried out on 1906 subjects who had SCr values and sufficient clinical information for our investigation. The incidence of an increase of >26.5 µmol/l of SCr was evaluated in the longitudinal cohort.

Results. In healthy subjects, the 95th SCr percentiles (cut-off points) were 123.8 µmol/l in men and 97.2 µmol/l in women. In diseased subjects, the prevalence of SCr values over the cut-off point was 4.6% in men and 9.3% in women. In logistic regression analysis, independent variables that correlated with over the cut-off point SCr values were: age >75 years [odds ratio (OR) = 2.2; 95% confidence interval (CI) = 1.5–3.4], atherosclerosis of the lower limbs (OR = 2.0; 95% CI = 1.2–3.3), cerebrovascular disease (OR = 1.9; 95% CI = 1.2–3.3), angiotensin-converting enzyme (ACE) inhibitor medication (OR = 1.8; 95% CI = 1.2–2.8), fibrinogen values >3.5 g/l (OR = 1.2; 95% CI = 1.2–2.7) and diuretic treatment (OR = 1.6; 95% CI = 1.1–2.4). After a mean 3.6 years follow-up, multiple logistic regression analysis showed that risk factors for pathological loss of renal function (rise of SCr >26.5 µmol/l) were: current smokers >20 cigarettes/day (OR = 2.3; 95% CI = 1.0–5.3), fibrinogen values >3.5 g/l (OR = 2.2; 95% CI = 1.6–3.3), diabetes (OR = 1.8; 95% CI = 1.1–2.8), age >75 years (OR = 1.7; 95% CI = 1.2–2.4) and isolated systolic hypertension (OR = 1.6; 95% CI = 1.0–2.6). The loss of renal function examined during the longitudinal phase appeared to be independent of baseline SCr levels.

Conclusion. The present prevalence and longitudinal studies show that age-associated decline in renal function in elderly subjects is associated with co-existing cardiovascular diseases and risk factors. These observations should be incorporated into clinical practice since some of the factors detrimental to kidney function, such as smoking, altered fibrinogen levels and elevated systolic blood pressure, can be prevented and/or modified when appropriate measures are taken.

Keywords: ageing; cardiovascular risk factors; ischaemic nephropathy; peripheral vascular disease; renal function



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 
Several prevalence and longitudinal studies have shown that the well-known age-associated decline in renal function is more pronounced in patients with co-existing cardiovascular risk factors, suggesting that this decline is not a constant and unavoidable phenomenon [1–3]. Clinical researchers have not yet determined which portion of kidney function decline with senescence is due to ageing and which is due to cardiovascular factors, such as hypertension, diabetes mellitus, hyperlipidaemia and smoking. Many cardiovascular risk factors have been associated with renal artery stenosis and changes in the renal microvasculature, which are important for classic renovascular hypertension and for so-called ischaemic nephropathy, two important clinical conditions [4]. The identification of co-morbid conditions associated with renal function impairment in the elderly and the estimation of their relative roles in this impairment are important to establish adequate measures to prevent progressive deterioration of renal function, particularly in subjects with no apparent or only modest clinical and laboratory signs of renal involvement.

The aim of this work was to examine associations between cardiovascular risk factors and diseases with over the cut-off point serum creatinine (SCr) levels and significant changes in SCr in a large prevalence phase and longitudinal phase community-based sample of an elderly Italian population showing no clinical evidence of renal impairment.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 
Study sample
Our sample population was drawn from the Italian Longitudinal Study on Ageing (ILSA) cohort. The ILSA study is a population-based multicentric, longitudinal study of the health status of Italians aged 65–84 years. The main objective of ILSA was to determine the prevalence and incidence rates of common chronic conditions in an elderly population and to identify their risk and protective factors. A random sample of 5632 individuals, stratified by age and gender using the equal allocation strategy, was identified using the demographic list of the registry office of eight Italian municipalities. A complete design of the ILSA study has been published previously. In brief, the study included a prevalence component that consisted of a two-phase examination: a screening phase for all participants which included a personal interview, a physical examination, and laboratory and diagnostic tests; and a second phase (medical confirmation) for those who tested positive for one or more diseases; these patients underwent clinical assessment by board-certified physicians (geriatrician or neurologist) and a review of medical records. A complete personal interview and physical examination, together with all diagnostic tests administered during the prevalence survey at baseline and clinical assessment, were re-administered at the follow-up ~4 years later. This report is based on data from the baseline examination carried out between March 1992 and June 1993, and from the first follow-up study beginning in September 1995.

Participants
At baseline, 5462 of the 5632 original participants were eligible for the study and 4521 were screened. Of these, 427 refused to undergo clinical assessment at baseline while 4094 possessed sufficient information to be included in our investigation (Figure 1). Among these, 998 subjects who did not have creatinine data and 115 subjects suspected to be positive for renal diseases were not included. The remaining 2981 participants (73%) with available SCr measurements at baseline were included in the prevalence analysis. The criteria for defining possible renal disease were a self-reported generic history of the disease (confirmed by hospital admission records and/or by medication the patients indicated they were using), and/or SCr ≥176.8 µmol/l for males and ≥159.1 µmol/l for females at baseline and at follow-up visits. At follow-up, 1051 (35%) were not available and 24 were suspected to be positive for renal diseases. The 1906 (64%) subjects that underwent evaluation of SCr both at baseline and follow-up visits were included in the longitudinal analysis.



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Fig. 1. Italian Longitudinal Study on Ageing (ILSA) profile.

 
Study variables and definitions
Measurements and methods have been described in detail elsewhere [5]. Briefly, participants were asked to fast for 12 h before the nurse's morning visit, during which sitting blood pressure and pulse rate measurements were taken and blood samples drawn. The following demographic and clinical parameters were also recorded: age, gender, weight, body mass index (BMI), systolic and diastolic blood pressure, SCr, serum glycaemia, plasma fibrinogen, serum triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and total serum cholesterol levels. Moreover, antihypertensive medications [diuretics, ß-blockers, angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists] and cardiac drugs (diuretics, nitrates, antiarrhythmic drugs and cardiac glycosides) were recorded. Systolic and diastolic blood pressure values were obtained on three different occasions from seated subjects after a 5 min rest, using an appropriately sized cuff and a random zero mercury column sphygmomanometer. During the interview and the subsequent physical examination, measurements were made by each examiner (nurse or physician) on the left arm, and the mean of the second and third of three readings was used for each blood pressure measurement. Blood pressure was also taken twice on both arms by a specialist during the clinical examination and all four values were recorded. In the present study, prevalent cardiovascular disease was defined as a confirmed history of hypertension, coronary heart disease, intermittent claudication, stroke or congestive heart failure at baseline. The diagnosis of hypertension was based on the criteria of the 1988 Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [6]. Coronary heart disease included myocardial infarction, angina pectoris and cardiac arrhythmia. The criteria for diagnosis of myocardial infarction were adopted from the ARIC Study [7], while those for angina pectoris, arrhythmia, congestive heart failure and intermittent claudication were taken from the Cardiovascular Health Study Guidelines [8]. The diagnostic criteria for cerebrovascular diseases (transient ischaemic attack, cerebral infarction, intracerebral haemorrhage or subarachnoid haemorrhage) were in accordance with WHO guidelines [9] and pathological subtype classifications were those of the Oxfordshire Community Stroke Project [10]. Diabetes was defined on the basis of the WHO Expert Committee on Diabetes criteria [11]. Smoking history was obtained from the home and from clinical interviews conducted at baseline and at follow-up. The average number of cigarettes smoked per day was calculated. Smokers were considered as those who smoked >5 cigarettes/day, independent of effective cigarette dose or current or former status. Moreover, subjects were considered ‘former smokers’ if they had quit smoking at least 5 years before the baseline examination. Finally, current and former smokers were subdivided into mild (>5–10 cigarettes/day), moderate (>10–20 cigarettes) and heavy smokers (>20 cigarettes/day). The eating habits of subjects were assessed at baseline by a comprehensive questionnaire administered at home, and concerned the kind and weekly frequency of food consumption. Alimentary habits were then classified into 12 food consumption categories: complex carbohydrates (pasta, bread and cereals), potatoes, legumes, vegetables, meat, fish, eggs, cheese, milk, fatty seasoning, sugar and sweetmeats (cakes and biscuits). To estimate a cut-off for ‘normal’ SCr values in the elderly, we considered a subsample reference of healthy people. Among the 2981 individuals with negative findings at baseline for renal disease and for whom SCr values were collected, 371 individuals (211 males and 160 females) did not present hypertension, diabetes, cardiovascular diseases or related pharmacological treatment and were considered ‘healthy’. The remaining 2610 individuals (1345 males and 1265 females) positive for at least one of the chosen criteria for risk factors and cardiovascular diseases were considered ‘diseased’, and the prevalence analysis was carried out from this sample. Correlations between cardiovascular risk factors/diseases and significant changes in SCr levels were also studied over a period of time (longitudinal phase). Analysis was performed on a broad sample of 1906 individuals (1016 male and 890 female). Of these, 235 were healthy (~63% of the healthy sample) and 1671 diseased (~64% of the diseased sample) at the prevalence phase and all had available SCr values at follow-up. The average length of time between the ILSA baseline examination and the first follow-up was 3.6 years. Information on death was obtained from relatives and general practitioners. Death certificates were obtained from the national registry. Of the 1051 subjects missing at the longitudinal phase, ~39% (421) were dead, 46% (484) had refused to complete the study and it was not possible to contact the remaining 14% (146).

Statistical analysis
Statistical analysis was performed with SAS statistical software version 8.2 (SAS Institute, Cary, NC). Data were expressed as means±SD or percentage values. By using the limit of SCr as an adequate marker of renal function in the elderly, its distribution was utilized to determine pathological values and loss of renal function over time [12]. In the healthy reference sample, the sex-specific 95th percentiles for SCr (the cut-off point) were determined [13] and this defined the upper limit for normal values. The distribution and prevalence of subjects over the cut-off were assessed by gender and separately in four age categories (65–69, 70–74, 75–79 and 80–84 years) for the diseased sample. The outcome examined in the longitudinal analysis was measured as the incidence of loss in renal function, defined as an increase in follow-up SCr of at least 26.5 µmol/l compared with baseline. A change in creatinine levels >26.5 µmol/l during the approximate 4 year follow-up period was chosen as the cut-off because it represents a true decline in renal function, and not the result of methodological or within-person variability in daily SCr values [14]. Moreover, in our sample, this value roughly corresponded to a 95th percentile rise in SCr levels from baseline to follow-up. Analyses among groups at baseline and at follow-up were performed using {chi}2 tests for categorical variables, and one-way ANOVA, ANCOVA and t-tests for continuous variables. A forward stepwise multiple logistic regression analysis was carried out to identify variables independently associated with SCr values greater than the cut-off points in the diseased sample, and with a pathological rise of 26.5 µmol/l in SCr in the whole sample. Variables associated with pathological plasma fibrinogen values (>3.5 g/l) at baseline, and those independently associated with death were also tested by logistic regression. The probability level for entry variables was 0.10. For all the estimated relationships, the best-fit models are shown in the tables. Variables at baseline used as dichotomic independent variables in the logistic regression analyses were: age (>75 years), BMI (>27 kg/m2 corresponding to overweight condition), total cholesterol level (≥6.22 mmol/l), cholesterol LDL level (≥4.10 mmol/l), cholesterol HDL level (<0.90 mmol/l), serum triglyceride level (≥2.26 mmol/l), fasting serum glycaemia (≥7.7 mmol/l), plasma fibrinogen (>3.5 g/l), and SBP (≥140 or ≥160 mmHg) and DBP (≥90 mmHg) values obtained from the blood pressure recording. Moreover, the baseline condition of presence (yes) or absence (no) of a factor was considered for the following variables: diagnosis of hypertension by a specialist (SBP ≥140 mmHg and DBP ≥90 mmHg by mean values); isolated systolic hypertension (SBP ≥160 mmHg and DBP <90 mmHg by mean values); treatment for hypertension; use of diuretics, ACE inhibitors, calcium antagonists or ß-blockers as antihypertensive medications; diabetes; coronary heart diseases; cerebrovascular disease; intermittent claudication or congestive heart failure; and use of cardiac medications. Other dummy variables were created for smoking conditions (current smokers, former smokers, heavy current smokers and heavy former smokers) at baseline and over the follow-up period. Finally, food category weekly frequency consumption was dichotomized to 75th percentile values. For the stepwise models, the goodness-of-fit statistics were generated, and the odds ratios (ORs) as well as the 95% confidence intervals (95% CIs) were determined for each independent variable entered in the final best-fit models. A two-sided P-value <0.05 was the criterion for statistical significance.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 
Prevalence phase
In the healthy reference population, mean SCr values were 88.4±17.7 µmol/l in men and 74.3±14.1 µmol/l in women (P<0.001), and there were no differences between the two groups in age (73.5±6.0 vs 72.8± 5.8 years; P = 0.13) or BMI (25.5±3.7 vs 26.2±4.6; P = 0.12). The estimated sex-specific 95th percentile cut-off points for SCr were 123.8 µmol/l in men and 97.2 µmol/l in women. In the diseased population, the mean SCr values were 94.6±18.8 µmol/l in 1345 men and 78.1±16.7 µmol/l in 1265 women. The mean SCr levels were significantly different according to age within each gender (P<0.001 in men; P<0.001 in women) and were higher in men than in women in all the age groups (P<0.001) (Figure 2).



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Fig. 2. Mean values of serum creatinine related to age categories in diseased subjects. Men {blacksquare}; women {square}. *P<0.05 vs other groups; §P<0.001 vs women.

 
The clinical characteristics of men and women under or over the SCr cut-off points in the diseased sample are summarized in Table 1. Among the men, 1283 subjects had SCr values under the cut-off point, with a mean of 92.3±16.0 µmol/l and 62 showed SCr values over the cut-off point, with a mean of 141.3±12.2 µmol/l. Among the women, 1147 subjects had under the cut-off point SCr values, with a mean 74.6±12.9 µmol/l, while 118 had over the cut-off point SCr values, with a mean of 111.6±11.3 µmol/l. The prevalence of individuals with over the cut-off point SCr values increased with age from 3.6 to 7.4% for men and from 4.8 to 14.2% for women (linear trend P<0.01), and was lower in men than in women in each age subgroup as well as in the overall sample (62 out of 1345, 4.6% vs 118 out of 1265, 9.3%; P<0.001) (Figure 3).


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Table 1. Clinical and laboratory characteristics of subjects both under and over the SCr cut-off points by gender at baseline; ILSA (Italian Study on Ageing) results

 


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Fig. 3. Prevalence (%) of subjects with serum creatinine values greater than the sex-specific 95th percentile cut-off point in the overall diseased sample grouped by gender and by different age categories. Men {blacksquare}; women {square}. *P<0.01 vs other groups.

 
The mean triglyceride value (P<0.05), the prevalence of intermittent claudication (P<0.001) and the use of cardiac glycosides (P<0.05) were higher in men with over the cut-off point SCr levels than in those with normal values. In both sexes, mean age and white blood cell count and the prevalence of cerebrovascular diseases were higher (P<0.01) in subjects with over the cut-off point SCr values compared with individuals with normal levels. Moreover, mean plasma fibrinogen concentration and the prevalence of fibrinogen levels >3.5 g/l were higher in all subjects with over the cut-off point SCr levels, with a significantly higher prevalence of fibrinogen levels >3.5 g/l in women with respect to men in the overall sample. A significantly higher prevalence remained in women when the subjects were subdivided by age groups (Figure 4).



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Fig. 4. Prevalence (%) of subjects with hyperfibrinogenaemia (plasma fibrinogen values >3.5 g/l) in the overall diseased sample grouped by gender and by different age categories. Men {blacksquare}; women {square}. *P<0.01 vs other groups.

 
The prior diagnoses of hypertension were 79.2% in the overall diseased sample, with a significantly higher level in women than in men (83.3 vs 75.0%, P<0.001). Moreover, with respect to men, women showed a higher prevalence of elevated blood pressure values (78.6 vs 74.8%; P = 0.020) and used more antihypertensive medications (68.3 vs 57.3%; P<0.001), in particular diuretics and ACE inhibitors (41.4 vs 37.8%, P<0.001 for diuretics; 28.9 vs 23.3%, P<0.01 for ACE inhibitors). Although there was no difference in the prevalence of prior diagnosis of hypertension and blood pressure mean values between subjects with normal and pathological SCr values in the two sexes, women with pathological SCr levels showed a significantly higher prevalence of antihypertensive (P<0.01) and cardiac (P<0.05) medication, as well as a greater use of diuretics and ACE inhibitors (P<0.01) (Table 1). Finally, there were no difference between the sexes in the diseased subgroups with respect to the 12 food consumption categories (data not shown).

Table 2 shows the best-fit model obtained by multivariate logistic regression for the prevalence phase stratified by gender. Because sex-specific evaluation of the variables produced similar relationships, the analysis was also performed on the whole sample. At baseline, over the cut-off point SCr levels were associated, in decreasing order, with age, intermittent claudication, cerebrovascular diseases, ACE inhibitor medication, fibrinogen values and diuretic medication. On the contrary, the following factors were not associated with over the cut-off point SCr levels: gender, BMI >27 kg/m2, smoking, dislipidaemia, diabetes, coronary disease, prior diagnosis of hypertension, high blood pressure conditions (hypertension, SBP ≥140 mmHg and/or DBP ≥90 mmHg; isolated systolic hypertension, SBP ≥160 mmHg and DBP <90 mmHg), cardiovascular therapy with a calcium antagonist or ß-blockers, or eating habits. Moreover, when fibrinogen was considered as the dependent variable, logistic regression analysis showed that values >3.5 g/l were negatively related to male gender and fish consumption and positively to cigarette smoking (Table 2).


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Table 2. Results of stepwise logistic regression including variables significantly associated with pathological serum creatinine levels (sex-specific and overall regressions) and hyperfibrinogenaemia (overall regression) at baseline

 
Longitudinal phase
Mortality and subject loss during follow-up. At follow-up, vital status data were available for ~92% (2737 out of 2981) of the overall cohort (healthy and diseased people). During the longitudinal study, the cumulative mortality rate was ~15.4%, and was significantly higher for men (17.4%) than for women (13.10%) (P<0.002). Mortality was significantly higher in subjects with over the cut-off point SCr baseline levels, ranging from 12.1 to 23.9% (P<0.001) in women, and from 16.8 to 33.3% (P<0.001) in men. The men and women who died showed a significantly higher prevalence of congestive heart failure, cerebrovascular disease and intermittent claudication at baseline than did the survivors. They also showed significantly higher mean values for age, SCr and fibrinogen levels, and lower mean values for BMI, total cholesterol and LDL. The study also lost 630 persons to follow-up, principally because of their refusal to participate (~77%). The prevalence of over the cut-off point SCr values in this group was 10.8% for women and 4.9% for men. These figures were comparable with the prevalence in the sample population. The clinical conditions at baseline of the subjects lost to follow-up were roughly similar to those of the participants. There were significant differences only for higher prevalence of intermittent claudication among missing women (9.1 vs 5.4%; P<0.02) and missing men (13.5 vs 9.0%; P<0.02), and for higher prevalence of diabetes (18.5 vs 14.0%; P<0.03) and antihypertensive therapy (70.3 vs 63.5%; P<0.03) among missing women.

Serum creatinine change
The distributions of changes in SCr by gender, expressed as the difference between follow-up and baseline concentrations, are shown in Figure 5. The estimated pathological rise in SCr, chosen as an outcome and corresponding to the 95th percentile of the broad sample, was >26.5 µmol/l for both genders. The mean SCr change (–0.4 µmol/l) did not differ significantly from 0 (P = 0.37). During follow-up, 7.1% (136 out of 1906) of the participants experienced a pathological rise in SCr, yielding an overall incidence rate of 20 per 1000 person-years. There were no significant differences between the rates of high increases in SCr in men (7.4%) and women (6.9%) nor between healthy (6.0%) and diseased subjects (7.6%). With respect to subjects showing a rise <26.5 µmol/l, subjects with an SCr rise >26.5 µmol/l had higher mean values of age (74.5±5.5 vs 72.8± 5.6 years, P<0.001), serum glycaemia (6.3±2.3 vs 5.7±1.5 mmol/l, P<0.0001) and plasma fibrinogen (4.0±1.2 vs 3.4±0.9 g/l, P<0.0001), as well as a higher prevalence of plasma fibrinogen level >3.5 g/l (61.2 vs 40.0%; P = 0.001), diabetes (20.6 vs 11.2%, P = 0.001) and isolated systolic hypertension (11.9 vs 6.5%; P = 0.003). Moreover, they presented with lower mean SCr values (78.7±17.7 vs 85.0± 18.0 µmol/l; P<0.001) and this difference persisted when the analysis was adjusted for gender, BMI and age (P<0.001). There were no significant differences in BMI, SBP or DBP mean values or other cardiovascular risk factors, diseases and medication at baseline between the groups with or without a pathological SCr rise.



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Fig. 5. Gender distributions of serum creatinine changes between follow-up and baseline. The figure shows the cut-off point for pathological increases in serum creatinine (26.5 µmol/l). Men {blacksquare}; women {square}.

 
Table 3 shows findings from multivariate logistic regression using pathological SCr rise as a dependent variable. The significant risk factors in the logistic model were: heavy current smokers, baseline fibrinogen levels, diabetes mellitus, age and isolated systolic hypertension. Other smoking habits, including heavy former smokers, and other cardiovascular risk factors and diseases, BMI, medications, gender and baseline over the cut-off point SCr values were not significantly associated with pathological change in SCr.


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Table 3. Risk factors associated with pathological renal decline obtained by stepwise logistic regression that excluded non-significant variables (best fit model)

 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 
The present investigation aimed to evaluate the relationship between cardiovascular disease risk factors and age-dependent declines in renal function in an older Italian population that had no previous evidence of renal impairment. This would allow a pinpoint analysis of the roles that these factors play in the development of chronic renal failure. We are aware of the difficulty in determining creatinine clearance in geriatric patients, which is due to unreliability of urine collections and predictive formulae. SCr levels were thus determined in accordance with Culleton et al. [15], who measured SCr in an adult community-based sample, and used cut-off points corresponding to sex-specific 95th percentiles for SCr as the upper limit of normal values in the healthy reference group. Unlike Culleton et al. [15], our investigation utilized different age brackets and we did not apply a forward stepwise multiple logistic regression to identify variables associated with over the cut-off point SCr values to the broad sample, but restricted it to the diseased group. The prevalence of those considered healthy was low (~10%) since the criteria utilized were restrictive. In fact, subjects were considered healthy only if they had none of the conditions (hypertension, diabetes, cardiovascular diseases or related pharmacological treatment) which have a high prevalence in the general elderly population.

According to our findings, mean SCr levels in healthy subjects, matched for BMI, were significantly lower in women. The mean SCr values increased with age in diseased subjects, and the prevalence of over the cut-off point SCr levels increased with age and was higher in women. This is in accordance with Culleton et al. [15], who demonstrated a reversal of the prevalence of over the cut-off point SCr values in both genders in their broad sample with advancing age, with an abrupt increase in women older than 60 years. Moreover, among the subjects with over the cut-off point SCr values, both men and women showed an increased prevalence of cerebrovascular diseases, higher mean plasma fibrinogen levels and a higher prevalence of fibrinogen values >3.5 g/l (fibrinogen pathological values). Nonetheless, men had a higher prevalence of intermittent claudication, while women showed an increased prevalence in the use of antihypertensive and cardiac medications, such as diuretics and ACE inhibitors.

The logistic regression analysis of diseased subject data showed that over the cut-off point SCr levels were associated with older age and, in decreasing order, with cardiovascular diseases, such as intermittent claudication and cerebrovascular disease, pathological fibrinogen values and ACE inhibitor and diuretic treatments. The same analysis performed on the total sample (healthy and diseased subjects) led to similar results (data not shown), since healthy subjects represented only a small fraction of the sample. Moreover, pathological fibrinogen levels were best explained by male gender and by dietary fish consumption, both showing a protective effect, whereas smoking exerted a worsening effect.

The pathological increase of 26.5 µmol/l in SCr values in the longitudinal study was best explained, in decreasing order, by heavy current smoking, pathological fibrinogen levels, diabetes, older age and isolated systolic hypertension. Age and diabetes are well-known classic risk factors for renal function decline. As has been noted by others [16–18], isolated systolic hypertension was found to be a better predictor of renal function deterioration than diastolic blood pressure or mean arterial pressure.

The most relevant findings of the present prevalence and longitudinal studies were the role of smoking and fibrinogen levels in determining increases in SCr values, and therefore renal function decline in an older population. While numerous previous investigations examined the role of other cardiovascular diseases and risk factors, there is little information about how smoking and fibrinogen levels affect renal function in the elderly. It has been shown that acute and chronic smoking is associated with renal functional impairment, probably as a result of smoking-induced changes in vasoactive hormones. They also have adverse effects on renal outcome in essential hypertension, in primary and secondary nephropathies, and on graft and patient survival in renal transplant recipients [2,19,20]. We recently found in type 2 diabetic patients that smoking increases glomerular basement membrane size, glomerular filtration rate (GFR) and urinary albumin excretion [21]. This finding was confirmed in a retrospective case–control study by Bleyer et al. [16], who reported an association between SCr increase and the number of cigarettes smoked per day in an older non-diabetic population. Smoking induces morphological and functional changes in blood vessels, including the induction of proliferation of intimal smooth muscle cells, decreases in endothelial prostacyclin synthesis and endothelial-derived vascular tone regulators, which induce an imbalance between vasodilator and vasoconstrictor vasoactive mediators. Interference with the vascular responses to acetylcholine, nitric oxide and endothelin-1 has also been reported in healthy smoking subjects [4]. The endothelium appears to play a central role in the development of atherosclerosis, and circulating concentrations of endothelial dysfunction markers were increased in patients with moderate renal impairment and chronic kidney disease [22–24].

Interestingly, the present study showed for the first time a close relationship between plasma fibrinogen levels and renal function. In fact, the prevalence demonstrated showed that higher fibrinogen levels were strongly associated with over the cut-off point SCr values independent of age, heavy atherosclerosis damage at different extrarenal sites or antihypertensive treatment. This link was also confirmed by the longitudinal study, which showed that baseline pathological fibrinogen values, as well as heavy current smoking, diabetes, age and uncontrolled isolated systolic hypertension, were strong independent predictors of early decline in renal function among the elderly. Likewise, pathological fibrinogen levels (at baseline) were positively correlated with smoking, and negatively with male gender as well as consumption of fish more than twice weekly.

Fibrinogen has been identified as a major independent risk factor for cardiovascular disease and atherosclerosis in the general population [25]. Increased fibrinogen levels cluster with other cardiovascular risk factors such as smoking and age, and vary according to sex and menopausal status, creating lower levels in pre-menopausal women than in men of the same age, but with increased levels thereafter [26,27]. Elevated fibrinogen levels have been found to be associated with the presence of atherosclerotic disease independent of renal function and other risk factors in patients with arteriolar nephrosclerosis [27]. Moreover, recent cross-sectional analyses demonstrated that chronic kidney disease is associated with the prevalence of non-traditional cardiovascular risk factors, such as inflammatory markers (elevated circulating levels of fibrinogen and C-reactive protein, and reduced serum albumin concentration), even among patients with moderate renal impairment [22–24]. It is interesting that variations in diet composition, in particular a balanced ratio of n-6/n-3 essential fatty acids, modulate plasma fibrinogen levels [28], and the present findings seem to confirm this. In addition, there is growing evidence supporting the hypothesis that fish oil helps to prevent endothelial dysfunction, which is considered to be an early marker of atherosclerosis and related to fibrinogen levels [29,30]. Current dietary guidelines, in fact, recommend consumption of fish twice weekly for the prevention of coronary artery disease [30].

In the light of previous studies demonstrating that patients with chronic kidney disease develop both inflammation and endothelial dysfunction before end-stage renal disease [23], our results suggest that low-grade inflammatory conditions and endothelial function abnormalities may be responsible for pathological SCr levels and renal function decline with age. Moreover, it is likely that subjects with atherosclerotic nephropathy were those with over the cut-off point SCr levels, which is an indicator of renal failure (defined by [31] an inulin clearance <80 ml/min/1.73 m2), and those with a higher loss of renal function. Surprisingly, the loss of renal function observed in the longitudinal study was independent of baseline SCr values. Instead, renal decline appeared to be more marked in subjects with lower baseline SCr levels, an effect that was independent of age and BMI. This observation may indicate that creatinine is not a good index of renal function nor a valid predictor of renal decline in older subjects. However, the lower baseline SCr values in patients showing accelerated renal function loss may reflect an alteration in renal haemodymanics, such as an increases in intraglomerular capillary pressure or flow, creating a glomerular hyperfiltration condition that could accelerate the progression of renal function decline. This hypothesis appears to be supported by previous observations in older smoking subjects, showing a normal GFR but a reduced renal plasma flow [19], and in smoking diabetic patients who had increased GFR with lower SCr levels [21]. These findings suggest that the haemodynamic renal profile in smokers is similar to that in hypertensive arteriolar nephrosclerosis, in which the earliest sign of overall renal function impairment is a reduction in renal plasma flow [4].

In the broad perspective, the associations revealed by logistic analysis in the present study appear to be robust because of the large sample size, the completeness of the survey protocol and the similarity to previous studies. Our findings may have been biased by the large number of subjects lost during follow-up, particularly if the loss patterns were non-random and linked to the study outcome. However, our non-death-related attrition (~21%, 630 out of 2981) was comparable with or even lower than that of other European longitudinal studies on ageing. Moreover, a possible bias in subject loss was unlikely since the characteristics of lost patients at baseline were comparable with those of the studied cohort. Nevertheless, the higher prevalence of diabetes among the subjects lost to follow-up and the increased fibrinogen levels in the deceased subjects may have led to underestimating the role of these two factors in the longitudinal impairment of renal function.

In conclusion, the current prevalence and longitudinal studies showed that moderately over the cut-off point SCr levels and reductions in renal function were strongly associated with cardiovascular diseases and risk factors in the elderly. These associations suggest that age-associated loss of renal function is more pronounced in older patients in whom these diseases and risk factors co-exist. Among these, smoking and elevated plasma fibrinogen levels appear to exert greater detrimental effects on renal function. The present observations should be incorporated into clinical practice, since some of these nephropathic factors, such as smoking, altered fibrinogen levels and elevated systolic blood pressure, represent conditions that are potentially preventable and/or modifiable.



   Appendix
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 
The ILSA Working Group: M. Baldereschi MD, A. Di Carlo MD, S. Maggi MD (CNR, Italian National Research Council, Padova, Italy), G. Scarlato MD, L. Candelise MD, E. Scarpini MD (University of Milano, Italy), F. Grigoletto ScD, E. Perissinotto ScD, L. Battistin MD, Bressan MD, G. Enzi MD, B. Baggio MD, A. Budakovic MD, S. Cantaro MD, G. Bortolan ScD (University of Padova, Italy), C. Loeb MD (CNR, Italian National Research Council, Genova, Italy), C. Gandolfo MD (University of Genova, Italy), N. Canal MD, M. Franceschi MD (San Raffaele Institute, Milano, Italy), A. Ghetti MD, R. Vergassola MD (ULSS 10, Firenze, Italy), D. Inzitari MD (University of Firenze, Italy), S. Bonaiuto MD, F. Fini MD, A. Vesprini MD, G. Cruciani MD (INRCA Fermo, Italy), A. Capurso MD, P. Livrea MD, V. Lepore MD (University of Bari, Italy), L. Motta MD, G. Carnazzo MD (University of Catania, Italy), F. Rengo MD (University of Napoli, Italy).



   Acknowledgments
 
We are indebted to Mrs Linda Inverso Moretti for help in preparing this manuscript. This study was supported by a grant from the National Research Committee (CNR), Rome, PF INV, 94-XXX-Centro per lo studio dell’ Invecchiamento, Padova, Italy (to B.B.). Preliminary data from this study were published in abstract form in JASN 12: 189A (2001).

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix
 References
 

  1. Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985; 33: 278–285[ISI][Medline]
  2. Iseki K, Ikemiya Y, Fukiyama K. Risk factors of end-stage renal disease and serum creatinine in a community-based mass screening. Kidney Int 1997; 51: 850–854[ISI][Medline]
  3. Baggio B, Budakovic A, Gambaro G. Cardiovascular risk factors, smoking and kidney function. Nephrol Dial Transplant 1998; 13 [Suppl 7]: 2–5[Medline]
  4. Baggio B. Ischemic renal disease: impact of cardiovascular risk factors and smoking. Contrib Nephrol 2000; 130: 68–74[ISI][Medline]
  5. Maggi S, Zucchetto M, Grigoletto F et al. The Italian Longitudinal Study on Aging (ILSA): design and methods. Aging Clin Exp Res 1994; 6: 464–473[ISI]
  6. 1988 Report of the Joint National Commitee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1988; 148: 1023–1029[Abstract]
  7. ARIC Investigators. The Atherosclerosis Risk in Communities (ARIC) study: design and objective. Am J Epidemiol 1989; 129: 687–702[Abstract]
  8. Fried L, Borhani NO, Enright P, for the CHS Research Group. The Cardiovascular Health Study: design and rationale. Ann Epidemiol 1991; 1: 263–276[Medline]
  9. Hatano S. Experience from a multicenter stroke register: a preliminary report. Bull WHO 1976; 54: 541–553[ISI][Medline]
  10. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. A prognostic study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project 1981–86. J Neurol Neurosci Psychiatry 1990; 53: 16–22
  11. WHO Expert Commitee on Diabetes. Diabetes 1979; 28: 1039–1057[ISI][Medline]
  12. Perrone RD, Madias NE, Levey AS. SCr as an index of renal function: new insights into old concepts. Clin Chem 1992; 38: 1933–1953[Abstract/Free Full Text]
  13. Jones CA, McQuillan GM, Kusek JW et al. Serum creatinine levels in the US population: third national health and nutrition examination survey. Am J Kidney Dis 1998; 2: 992–999
  14. James GD, Sealey JE, Alderman M et al. A longitudinal study of urinary creatinine and creatinine clearance in normal subjects: race, sex, and age differences. Am J Hypertension 1988; 1: 124–131[ISI][Medline]
  15. Culleton BF, Larson MG, Evans JC et al. Prevalence and correlates of elevated serum creatinine levels. The Framingham heart study. Arch Intern Med 1999; 159: 1785–1790[Abstract/Free Full Text]
  16. Bleyer AJ, Shemanski LR, Burke GL, Hansen KJ, Appel RG. Tobacco, hypertension, and vascular disease: risk factors for renal function decline in an older population. Kidney Int 2000; 7: 2072–2079[CrossRef]
  17. Young HJ, Klag MJ, Muntner P, Whyte JL, Pahor M, Coresh J. Blood pressure and decline in kidney function: findings from the Systolic Hypertension in the Elderly Program (SHEP). J Am Soc Nephrol 2002; 3: 2776–2782[CrossRef]
  18. De Leeuw PW, Thijs L, Birkenhager WH et al. Prognostic significance of renal function in elderly patients with isolated systolic hypertension: results from the Syst-Eur Trial. J Am Soc Nephrol 2002; 3: 2213–2222[CrossRef]
  19. Gambaro G, Verlato F, Baggio B et al. Renal impairment in chronic cigarette smokers. J Am Soc Nephrol 1998; 9: 562–567[Abstract]
  20. Orth SR. Effects of smoking on systemic and intrarenal hemodynamics: influence on renal function. J Am Soc Nephrol 2004; S15: S58–S63[CrossRef]
  21. Baggio B, Budakovic A, Dalla Vestra M, Saller A, Bruseghin M, Fioretto P. Effects of cigarette smoking on glomerular structure and function in type 2 diabetic patients. J Am Soc Nephrol 2002; 3: 2730–2736[CrossRef]
  22. Landray MJ, Wheeler DC, Lip GYH et al. Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: the chronic renal impairment in Birmingham (CBIB) study. Am J Kidney Dis 2004; 43: 244–253[CrossRef][ISI][Medline]
  23. Stam F, Van Guldener C, Schalkwijk CG et al. Impaired renal function is associated with markers of endothelial dysfunction and increased inflammatory activity. Nephrol Dial Transplant 2003; 18 : 892–898[Abstract/Free Full Text]
  24. Muntner P, Hamm L, Kusek JW et al. The prevalence of non-traditional risk factors for coronary heart disease in patients with chronic kidney disease. Ann Intern Med 2004; 140: 9–17[Abstract/Free Full Text]
  25. Thompson SG, Kienast J, Pyke SDM, Haverkate F, Van de Loo JCW. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 32: 635–645[CrossRef]
  26. Krobot K, Hense HW, Cremer P, Eberle E, Keil U. Determinants of plasma fibrinogen: relation to body weight, waist-to-hip ratio, smoking, alcohol, age, and sex. Results from the second MONICA Augsburg survey, 1989–1990. Arterioscler Thromb 1992; 2: 780–788
  27. Sechi LA, Zingaro L, Catena C, De Marchi S. Increased fibrinogen levels and hemostatic abnormalities in patients with arteriolar nephrosclerosis: association with cardiovascular events. Thromb Haemost 2000; 84: 565–570[ISI][Medline]
  28. Singh RB, Dubnov G, Niaz MA et al. Effect of an Indo-Mediterranean diet on progression of coronary artery disease in high risk patients (Indo-Mediterranean Diet Heart Study): a randomised single-blind trial. Lancet 2002; 60: 1455–1461[CrossRef]
  29. Goodfellow J, Bellamy MF, Ramsey MW, Jones CJ, Lewis MJ. Dietary supplementation with marine omega-3-fatty acids improves systemic large artery endothelial function in subjects with hypercholesterolemia. J Am Coll Cardiol 2000; 5: 265–270[CrossRef]
  30. Krauss RM, Eckel RH, Howard B et al. AHA Dietary Guidelines revision 2000: a statement for health care professionals from the Nutrition Committee of the American Heart Association. Circulation 2000; 102: 2284–2299[Free Full Text]
  31. Couchoud C, Pozet N, Labeeuw M, Pouteil-Noble C. Screening early renal failure: cut-off values for serum creatinine as an indicator of renal impairment. Kidney Int 1999; 5: 1878–1884[CrossRef]
Received for publication: 30. 3.04
Accepted in revised form: 19. 7.04





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