QJM Advance Access originally published online on January 11, 2006
QJM 2006 99(2):97-102; doi:10.1093/qjmed/hcl002
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Moderate renal insufficiency at 70 years predicts mortality
From the Department of Rehabilitation and Geriatric Medicine and 1Department of Medicine, Hadassah University Hospital, Jerusalem, Israel
Address correspondence to Dr Y. Maaravi, Department of Rehabilitation and Geriatric Medicine, Hadassah University Hospital, Mount Scopus, PO Box 24035, Jerusalem 91240, Israel. email: maaravi{at}md2.huji.ac.il
Received 9 July 2005 and in revised form 26 November 2005
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Summary |
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Background: Glomerular filtration rate (GFR) diminishes with age. Kidney function in the elderly is often assessed by serum creatinine alone, although it is insensitive in this age group. Formulae for predicting GFR are not widely used.
Aim: To study the effect of low predicted GFR on mortality.
Design: Longitudinal cohort study.
Setting: The community-based Jerusalem Seventy Year Olds Longitudinal Study.
Methods: We studied 445 subjects, all aged 70 years, using questionnaires, a medical examination with history-taking, and standard laboratory tests. Moderate renal insufficiency was defined as a predicted GFR of <60 ml/min, based on the Cockcroft-Gault (CG) and the Modification of Diet in Renal Disease (MDRD) equations.
Results: Predicted GFR was normally distributed, with a mean ± SD of 62.4 ± 15.27 ml/min. Predicted GFR was <60 ml/min in 221 (46%), most of whom had normal serum creatinine. Twelve-year mortality was 38.7% in these 221 vs. 27% in the other 204. The survival advantage was already evident after 3 years. Under Cox proportional hazard analysis using numerous common risk factors as independent variables, lower predicted GFR had a significant mortality risk (hazard ratio 2.108, 95%CI 1.43–3.12, p = 0.0002).
Discussion: In community-dwelling elderly people, moderate renal insufficiency as assessed using the CG equation is a strong and independent predictor of mortality. Most of these at-risk patients have 'normal' serum creatinine.
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Introduction |
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The principal clinical measure of renal function, glomerular filtration rate (GFR), diminishes with age.1,2 Since GFR is estimated by creatinine clearance, which is time-consuming and logistically difficult to obtain, kidney function in the elderly is usually assessed by serum creatinine alone. Because this measure does not accurately reflect renal function in elders, primarily due to the decrease in muscle mass with age, formulae have been developed to predict GFR based on serum creatinine, gender and age.3,4 Unfortunately, these formulae are not widely used, and frequently older patients presenting with a 'normal' serum creatinine concentration are erroneously diagnosed as having normal kidney function.
The majority of studies relate established renal insufficiency to mortality in all age groups through the pathophysiology of end-stage renal disease.5 However, moderate and even minor renal insufficiency, as reflected by lesser elevation in serum creatinine levels, also correlates with poor outcomes.6,7 There are few studies addressing the question of moderate renal insufficiency and mortality in old age. We therefore studied the significance of moderately reduced kidney function as part of the Jerusalem Longitudinal Study.
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Methods |
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Subjects
The Jerusalem Longitudinal Study comprises a representative sample of west Jerusalem residents, all born between June 1920 and May 1921. At the initiation of the study in 1990, 759 of the population of 1859 70-year-olds in Jerusalem were invited to participate: 605 of them agreed. This sample was representative of the whole population stratum in terms of health services use and mortality.8 The study instrument was a two-part questionnaire offering respondents graded multiple-choice answers, and included detailed demography, personal history, life style, health services use, functional and cognitive status. A thorough medical history was taken, and a medical examination and standard clinical laboratory tests were also performed.8,9 All subjects gave informed consent, and the institutional review board approved the study. This study examines the 445 subjects for whom complete data for the prediction of GFR were available. Of these 445, 152 were re-examined in 1998.
Variables
Subjects graded their performance of the activities of daily living (ADL)10 and the instrumental activities of daily living.11 Because of the near universality of function without assistance, independence was defined as performance with ease, as previously described.12 Subjects were asked to define their health status as being healthy or not. Based on subjects’ answers about smoking habits, smoking was quantified in pack-years (one pack of cigarettes smoked daily for a year). Exercise was defined as light activity, such as walking, at least 4 h weekly or sport at least twice weekly. Blood pressure was measured twice with a mercury sphygmomanometer.9 Hypertension was defined as at least one of the following: treatment with blood-pressure-lowering medications; systolic blood pressure 
140 mmHg; diastolic blood pressure 90 mmHg. All subjects had baseline serum creatinine measured as part of the laboratory profile. Serum creatinine was measured using the modified kinetic Jaffe method. GFR was predicted based on the Cockcroft-Gault (CG)3 and Modification of Diet in Renal Disease (MDRD) equations.4 Predicted GFR was dichotomized, and subjects were classified as having moderate chronic kidney disease (CKD) when their GFR was <60 ml/min.
Elevated serum creatinine was defined as >1.2 mg/dl (106 µmol/l), the upper limit of the normal laboratory value at our institution.
Survival was determined annually for 12 years following the initial examination at age 70, from the national Interior Ministry registry of death certificates.
Statistical analysis
Data was entered into a PC using SAS software version 8.1. The dependent variable of the study was survival during 12-year follow-up. Baseline characteristics at age 70 were compared using the 
2 test, t test or Wilcoxon rank sum test, as appropriate. Differences in survival between subjects stratified by creatinine clearance were assessed using Kaplan-Meier curves, and statistical significance was evaluated using the log rank test. Multivariate survival analysis using a Cox proportional hazard model was used to determine the impact of moderate CKD at age 70 on mortality over 12 years. To account for confounding factors, demographic, functional, medical and other laboratory variables at age 70 were introduced into the regression as independent variables.
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Results |
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All the following results are based on the CG equation for GFR prediction, except where stated as being based on the MDRD equation.
Distribution of the predicted GFR of the study population at age 70 (Figure 1) was normal, with mean 62.4 ± 15.3 ml/min. GFR was <60 ml/min in 46%, and <30 ml/min in 1%, but none had a GFR <15 ml/min. Baseline characteristics of the study population stratified by predicted GFR are shown in Table 1. Nearly all participants were independent in ADL, and more than half engaged in regular physical activity. One in six had diabetes mellitus, and one in four, ischaemic heart disease. The prevalence of these conditions did not differ between groups. Body mass index (BMI) was significantly lower in participants with moderate CKD (25.4 vs. 28.6 kg/m2, p < 0.0001) and serum cholesterol level was significantly higher (6.1 vs. 5.8 mmol/l, p < 0.01). Figure 2 shows the distribution of baseline serum creatinine at age 70, stratified by predicted GFR. The majority of subjects with reduced GFR had serum creatinine within normal limits.
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Renal function of the 152 subjects re-examined in 1998 showed mean serum creatinine 1.08 ± 0.22 mg/dl and mean predicted GFR 53.12 ± 13.04 ml/min. Twelve-year mortality was 27% in the higher, and 38.7% in the reduced predicted GFR group. Survival was significantly better for those whose GFR was higher (Figure 3) (p = 0.008). The survival advantage was already evident after 3 years.
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60 and >60 ml/min, respectively, at age 70 years.Cox proportional hazard analysis used the following independent variables at age 70: gender, smoking, hypertension, diabetes mellitus, serum cholesterol level, ischaemic heart disease, cerebrovascular and malignant diseases, anaemia, body mass index, physical activity, independence in ADL, self reported health and predicted GFR. Subjects with moderate CKD had a significantly greater risk of mortality (hazard ratio 2.108, 95%CI 1.43–3.12, p = 0.0002). When using reduced GFR based on the MDRD equation, correlation with mortality was not significant (hazard ratio 1.103, 95%CI 0.763–1.595, p = 0.602). Correlation with mortality was also not significant when using elevated serum creatinine in the same analysis (hazard ratio 1.139, 95%CI 0.784–1.654, p = 0.494).
No significant difference in 12-year mortality was found between subjects with CKD and elevated serum creatinine compared to those with normal serum creatinine (30.16% vs. 42.55%, p = 0.09). Twelve-year mortality was also not significantly different between subjects without CKD but with elevated serum creatinine, compared to those with normal serum creatinine (23.72% vs. 32.94%, p = 0.12).
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Discussion |
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Our results show that in community-dwelling elderly people, moderate renal insufficiency (as identified by the CG equation) is a strong and independent predictor of mortality. The significant correlation between predicted GFR and mortality persisted after adjustment for the effects of numerous common risk factors, including gender, smoking, hypertension, diabetes, serum cholesterol level, ischaemic heart and cerebrovascular disease, BMI and physical activity. Dichotomization of predicted GFR to moderate renal insufficiency (<60 ml/min) or 'normal' renal function (
60 ml/min) is based on the National Kidney Foundation Practice Guidelines for Chronic Kidney Disease.13 Although a GFR cut-off of 60 ml/min was used as recommended, some subjects classified as 'normal' renal function could be classified as mild renal insufficiency (GFR 60–89 ml/min). However, most data to date indicate that mortality risk increases below GFR 60 ml/min. Serum creatinine levels were within the normal range for most of the subjects identified with reduced GFR. Thus without prediction of GFR in our elderly subjects, this increased risk would have gone undetected.
Previous studies
Several studies found that elevated serum creatinine predicts mortality in patients with acute myocardial infarction,14,15 undergoing coronary angioplasty,16 after stroke17 and after cardiac18 and general surgery.19 However, these studies analysed frankly elevated serum creatinine levels, and not subclinical impairment. In the Digitalis Investigation Group (DIG), Mahon et al. found estimated creatinine clearance predicted mortality in patients with congestive heart failure.19,20 In the Hypertension Optimal Treatment (HOT) study, Ruilope et al. reported that both serum creatinine and estimated creatinine clearance predict mortality in hypertensive patients.21 In the Studies of Left Ventricular Dysfunction (SOLVD) Prevention and Treatment Trials, Dries et al. found reduced estimated creatinine clearance to be associated with all-cause mortality.22 All these studies, however, focused on specific diseases and their findings may not pertain to the general, healthy, community-dwelling elderly population. Recent studies from the Cardiovascular Health Study report elevated serum creatinine and cystatin C levels to be associated with increased risk of mortality in community dwelling older adults.23,24 The last and most recent report bears some similarity to the present study by addressing the prognostic importance of renal function in a population-based study of elderly people with a long follow-up, yet cystatin C used as an index of GFR has been previously reported to have no advantage over creatinine-based GFR estimates,25 and is less widely available worldwide.
There is currently no single recommended measure of kidney function in the elderly, and limitations have been reported in this age group for every measure available, including the two most popular GFR prediction equations, the CG and the MDRD. Both these formulas were developed in young populations with chronic kidney diseases. No study has yet compared these formulae with measured GFR in the elderly. Indeed the National Kidney Foundation Practice Guidelines for Chronic Kidney Disease recommend both these formulae for diagnosing and staging chronic kidney disease.
Present study
The present study is unique in examining the relation of moderate renal insufficiency, detected by predicted GFR, and long-term mortality in a population of community-dwelling elderly people. The association remained after adjustment for numerous widely accepted independent predictors of mortality. Our subjects with predicted GFR <60 ml/min were accurately classified with moderate renal insufficiency, since there were no subjects with severe renal insufficiency (GFR <15 ml/min).
The distribution of some variables in Table 1 is not as expected. The lack of difference in the rates of hypertension and diabetes between the two groups are particularly surprising. It is possible that in this age group, a survival bias is already evident, and the survivors with CKD are healthier. No difference in the rate of diabetes was also evident in the Cardiovascular Health Study.24 The term ‘predicted GFR' is used here to describe results of the MDRD as well as the CG equation. This last equation was developed for estimating creatinine clearance, but has been tested widely in its prediction of GFR.26
The increased mortality risk of reduced predicted GFR was evident only with the CG equation and not with the MDRD. As mentioned above there are reported limitations for each of these formulae, and there is currently no single recommended measure of kidney function in the elderly. Both formulae are recommended for diagnosing and staging CKD. In the recent report from the Cardiovascular Health Study, predicted GFR based on the MDRD equation was only a slightly better predictor of mortality than the serum creatinine level. Our study population is smaller, and the correlation based on the MDRD is therefore possibly weaker.
The correlation demonstrated here between moderate renal insufficiency and mortality suggests that earlier recognition of CKD and successful intervention may improve mortality risk and cardiovascular disease outcomes. The mechanism of increased mortality and cardiovascular risk in CKD is currently uncertain, and there is no evidence yet for improved outcomes (cardiovascular and general) from interventions to delay CKD progression. Possible links between CKD and cardiovascular disease include inflammation, as well as the metabolic and hormonal abnormalities associated with CKD.27
Study limitations
A limitation of our study is the prediction of GFR rather than its direct measure. However, 24-h creatinine clearances are unreliable,28 and measuring GFR is cumbersome for use in clinical practice. The CG equation is based on widely available parameters, and is eminently practicable. Food and Drug Administration guidelines already suggest its use in dosing nephrotoxic drugs29 and as mentioned, the National Kidney Foundation Practice Guidelines for Chronic Kidney Disease recommend it (along with the MDRD) for prediction of GFR in adults.13
As all participants were 70 years old, age was not a factor in the present study, so the CG equation mathematically presents body weight/creatinine. This explains the difference in BMI between the two predicted GFR groups in Table 1.
Furthermore the prognostic significance of low predicted GFR may be different in older subjects. Another limitation of our study is the lack of data on causes of mortality. Cause of death as recorded in death certificates may be inaccurate, and were therefore not collected. The strength of our study is the representative nature of the sample its age homogeneity, and the long period of follow-up.
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Conclusions |
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In the present study, moderate renal dysfunction in the elderly was strongly and independently associated with mortality. Some 46% of our subjects had reduced predicted GFR as calculated by the CG equation, but most had serum creatinine within the normal range, implying that they would not have been diagnosed as having renal dysfunction without use of the CG equation. Predicted GFR identifies a large proportion of our cohort at significant risk of mortality. Furthermore, these subjects at risk are not identified through other common risk factors for cardiovascular disease. Routine use of GFR prediction formulae merits a place in every geriatric assessment.
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Acknowledgments |
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The authors have had no financial or other relationship that might lead to a conflict of interest. This study was partially supported by the Israeli Ministry of Labor.
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References |
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