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Renal function: an emerging risk factor for cardiovascular disease?
ED I TO R I AL
Renal function: an emerging risk factor for cardiovascular disease? Clinical Trial Service Unit, University of Oxford, Oxford, UK
It is now clearly established that vascular disease develops prematurely in association with chronic renal failure. Cardiac mortality in dialysis patients aged under 45 years is about 100 times greater than in the general population.1 An improved understanding of the underlying mechanisms of this accelerated vasculopathy is the focus of much nephrological research. However, there is growing evidence that even mild degrees of renal impairment are associated with an increased risk of vascular disease. Since such impairment is common (8% of men in the Framingham study had serum creatinine '135 lmol/L),2 an understanding of the influence of renal function on vascular disease may be of substantial relevance to public health.
INCREASED RISK OF VASCULAR DISEASE IN MILD RENAL IMPAIRMENT Around a quarter of patients reaching end-stage renal failure and starting dialysis already have a history of atherosclerotic heart disease (e.g. angina pectoris, myocardial infarction or coronary revascularization) whilst about three-quarters have evidence of structural heart disease (e.g. left ventricular hypertrophy, dilatation or dysfunction).3 It is not surprising, therefore, that some form of cardiovascular disease is present in about one-third of nephrology clinic patients with mild chronic renal impairment (serum creatinine 5130 lmol/L).4 These findings suggest that changes in renal function may be associated with accelerated vasculopathy even in those without clinically apparent renal impairment. Studies amongst individuals with prevalent vascular disease at baseline, or who are at a high risk of vascular disease (e.g. diabetic or hypertensive populations), have reported moderate positive associations between serum creatinine concentration and the risk of subsequent vascular events.5 For example, in the Heart Outcomes and Prevention Evaluation (HOPE) study (which excluded individuals with serum creatinine 5200 lmol/L), the relative risk of a major vascular event (cardiovascular death, myocardial infarction or stroke) among those with raised serum creatinine (5124 lmol/L) was 1.4.6 However, this apparent association 32
Evidence-based Cardiovascular Medicine (2001) 5, 32d33 doi:10.1054/ebcm.2001.0360, available online at http://www.idealibrary.com on
might arise if vascular disease, hypertension, or diabetes were to increase both the risk of renal impairment and, independently, the risk of major vascular events.5 In principle, this explanation would be less likely if a positive association was present in studies of similar design where baseline measurements of serum creatinine had been made in apparently healthy individuals. However, such studies have produced inconsistent results, for whilst one such study reported a clear positive association between raised serum creatinine and incident vascular events,7 others have reported only weak and statistically non-significant associations.8,9 Hence, it remains unclear whether elevated serum creatinine is simply a marker of end-organ vascular disease, or renal dysfunction is a primary cause of vascular disease, or both.
THE INFLUENCE OF RENAL FUNCTION ON RISK FACTORS FOR VASCULAR DISEASE The relationship between renal impairment and vascular disease is likely to be complex, and may depend on factors such as the cause and severity of renal impairment, the presence of comorbid illness (e.g. diabetes mellitus) and associated treatments (e.g. steroids and immunosuppressants). However, there is some evidence that renal impairment per se promotes the development of vascular disease through a cluster of physiological and metabolic risk factors including, for example, abnormalities of blood pressure and intravascular hemodynamics, and lipoprotein and homocysteine metabolism.4,5 For instance, there is good evidence that plasma homocysteine concentration is strongly inversely correlated with renal function, not only in patients with established chronic renal failure, but also in those with normal renal function and in diabetics with supra-normal glomerular filtration rates (hyperfiltration).5,10 Hence, small differences in renal function (even within the ‘normal range’) are associated with alterations in homocysteine concentration which might well translate into an increased risk of vascular disease. Similar research is now needed to determine the extent to which renal impairment is a primary cause of perturbations of other risk factors. ^ 2001 Harcourt Publishers Ltd
MEASUREMENT OF RENAL FUNCTION Investigation of the influence of renal function both on levels of vascular risk factors and the incidence of vascular events is hindered by the lack of sufficiently accurate measures of renal function. Serum creatinine concentration is a highly variable measure, influenced by factors such as age, sex and weight, and does not generally rise above the reference range until glomerular filtration rate has fallen by over 50%. Within the reference range a single creatinine-based measurement (e.g. serum creatinine concentration, or creatinine clearance as estimated by the Cockcroft} Gault formula) is too imprecise to allow subtle associations to be assessed reliably. At present, more accurate measurements may only be achieved by venous sampling of intravenously administered tracers such as 51Cr-EDTA or iohexol. These techniques are expensive and time-consuming, and as such are poorly suited to either large-scale epidemiological studies or widespread clinical practice. Widely practicable methods of estimating glomerular filtration rate accurately would be a major advance in this area. THE ROLE OF THE KIDNEY IN VASCULAR EPIDEMIOLOGY There is a clear need for large prospective studies observing the association between renal function and the risk of vascular disease among healthy middle-aged individuals. Concurrently, large-scale randomized controlled trials of preventative treatments are needed among patients with established renal impairment. Such trials will not only establish the clinical benefits and hazards of such treatments (e.g. HMG-CoA reductase inhibitors) in a population that has been systematically excluded from such studies in the past, but will also help clarify the relevance of factors such as dyslipidemia in the vasculopathy associated with renal impairment. Approximately one in ten individuals have biochemical evidence of renal
^ 2001 Harcourt Publishers Ltd
dysfunction, and this disorder may contribute appreciably to their risk of vascular disease through mechanisms which are poorly understood. Abnormal renal function is associated with a cluster of metabolic and physiological abnormalities and further research is now needed to determine the extent to which intra-renal mechanisms are directly responsible for these disturbances. Martin J. Landray, MRCP Colin Baigent, BM BCh MSc Literature cited 1. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32(Suppl 3): S112}S119 2. Culleton BF, Larson MG, Evans JC, et al. Prevalence and correlates of elevated serum creatinine levels. Arch Intern Med 1999; 159: 1785}1790 3. Baigent C, Burbury K, Wheeler D. Premature cardiovascular disease in chronic renal failure. Lancet 2000; 356: 147}152 4. Landray MJ, Thambyrajah J, McGlynn FJ, et al. Epidemiological evaluation of known and suspected cardiovascular risk factors in chronic renal impairment. Am J Kidney Dis, in press 5. Kasiske B. The kidney in cardiovascular disease. Ann Intern Med 2001; 134: 707}709 6. Mann JF, Gerstein HC, Pogue J, et al. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 2001; 134: 629}636 7. Wannamethee SG, Shaper AG, Perry IJ. Serum creatinine concentration and risk of cardiovascular disease. A possible marker for increased risk of stroke. Stroke 1997; 28: 557}563 8. Flack J, Neaton J, Daniels B, et al. Ethnicity and renal disease: lessons from the Multiple Risk Factor Intervention Trial and the Treatment of Mild Hypertension Study. Am J Kidney Dis 1993; 21: 31}40 9. Culleton BF, Larson MG, Wilson PWF, et al. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 1999; 56: 2214}2219 10. Wollesen F, BrattstroK m B, Refsum H, et al. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int 1999; 55: 1028}1035
Evidence-based Cardiovascular Medicine (2001) 5, 32d33
33
Renal function: an emerging risk factor for cardiovascular disease? Clinical Trial Service Unit, University of Oxford, Oxford, UK
It is now clearly established that vascular disease develops prematurely in association with chronic renal failure. Cardiac mortality in dialysis patients aged under 45 years is about 100 times greater than in the general population.1 An improved understanding of the underlying mechanisms of this accelerated vasculopathy is the focus of much nephrological research. However, there is growing evidence that even mild degrees of renal impairment are associated with an increased risk of vascular disease. Since such impairment is common (8% of men in the Framingham study had serum creatinine '135 lmol/L),2 an understanding of the influence of renal function on vascular disease may be of substantial relevance to public health.
INCREASED RISK OF VASCULAR DISEASE IN MILD RENAL IMPAIRMENT Around a quarter of patients reaching end-stage renal failure and starting dialysis already have a history of atherosclerotic heart disease (e.g. angina pectoris, myocardial infarction or coronary revascularization) whilst about three-quarters have evidence of structural heart disease (e.g. left ventricular hypertrophy, dilatation or dysfunction).3 It is not surprising, therefore, that some form of cardiovascular disease is present in about one-third of nephrology clinic patients with mild chronic renal impairment (serum creatinine 5130 lmol/L).4 These findings suggest that changes in renal function may be associated with accelerated vasculopathy even in those without clinically apparent renal impairment. Studies amongst individuals with prevalent vascular disease at baseline, or who are at a high risk of vascular disease (e.g. diabetic or hypertensive populations), have reported moderate positive associations between serum creatinine concentration and the risk of subsequent vascular events.5 For example, in the Heart Outcomes and Prevention Evaluation (HOPE) study (which excluded individuals with serum creatinine 5200 lmol/L), the relative risk of a major vascular event (cardiovascular death, myocardial infarction or stroke) among those with raised serum creatinine (5124 lmol/L) was 1.4.6 However, this apparent association 32
Evidence-based Cardiovascular Medicine (2001) 5, 32d33 doi:10.1054/ebcm.2001.0360, available online at http://www.idealibrary.com on
might arise if vascular disease, hypertension, or diabetes were to increase both the risk of renal impairment and, independently, the risk of major vascular events.5 In principle, this explanation would be less likely if a positive association was present in studies of similar design where baseline measurements of serum creatinine had been made in apparently healthy individuals. However, such studies have produced inconsistent results, for whilst one such study reported a clear positive association between raised serum creatinine and incident vascular events,7 others have reported only weak and statistically non-significant associations.8,9 Hence, it remains unclear whether elevated serum creatinine is simply a marker of end-organ vascular disease, or renal dysfunction is a primary cause of vascular disease, or both.
THE INFLUENCE OF RENAL FUNCTION ON RISK FACTORS FOR VASCULAR DISEASE The relationship between renal impairment and vascular disease is likely to be complex, and may depend on factors such as the cause and severity of renal impairment, the presence of comorbid illness (e.g. diabetes mellitus) and associated treatments (e.g. steroids and immunosuppressants). However, there is some evidence that renal impairment per se promotes the development of vascular disease through a cluster of physiological and metabolic risk factors including, for example, abnormalities of blood pressure and intravascular hemodynamics, and lipoprotein and homocysteine metabolism.4,5 For instance, there is good evidence that plasma homocysteine concentration is strongly inversely correlated with renal function, not only in patients with established chronic renal failure, but also in those with normal renal function and in diabetics with supra-normal glomerular filtration rates (hyperfiltration).5,10 Hence, small differences in renal function (even within the ‘normal range’) are associated with alterations in homocysteine concentration which might well translate into an increased risk of vascular disease. Similar research is now needed to determine the extent to which renal impairment is a primary cause of perturbations of other risk factors. ^ 2001 Harcourt Publishers Ltd
MEASUREMENT OF RENAL FUNCTION Investigation of the influence of renal function both on levels of vascular risk factors and the incidence of vascular events is hindered by the lack of sufficiently accurate measures of renal function. Serum creatinine concentration is a highly variable measure, influenced by factors such as age, sex and weight, and does not generally rise above the reference range until glomerular filtration rate has fallen by over 50%. Within the reference range a single creatinine-based measurement (e.g. serum creatinine concentration, or creatinine clearance as estimated by the Cockcroft} Gault formula) is too imprecise to allow subtle associations to be assessed reliably. At present, more accurate measurements may only be achieved by venous sampling of intravenously administered tracers such as 51Cr-EDTA or iohexol. These techniques are expensive and time-consuming, and as such are poorly suited to either large-scale epidemiological studies or widespread clinical practice. Widely practicable methods of estimating glomerular filtration rate accurately would be a major advance in this area. THE ROLE OF THE KIDNEY IN VASCULAR EPIDEMIOLOGY There is a clear need for large prospective studies observing the association between renal function and the risk of vascular disease among healthy middle-aged individuals. Concurrently, large-scale randomized controlled trials of preventative treatments are needed among patients with established renal impairment. Such trials will not only establish the clinical benefits and hazards of such treatments (e.g. HMG-CoA reductase inhibitors) in a population that has been systematically excluded from such studies in the past, but will also help clarify the relevance of factors such as dyslipidemia in the vasculopathy associated with renal impairment. Approximately one in ten individuals have biochemical evidence of renal
^ 2001 Harcourt Publishers Ltd
dysfunction, and this disorder may contribute appreciably to their risk of vascular disease through mechanisms which are poorly understood. Abnormal renal function is associated with a cluster of metabolic and physiological abnormalities and further research is now needed to determine the extent to which intra-renal mechanisms are directly responsible for these disturbances. Martin J. Landray, MRCP Colin Baigent, BM BCh MSc Literature cited 1. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32(Suppl 3): S112}S119 2. Culleton BF, Larson MG, Evans JC, et al. Prevalence and correlates of elevated serum creatinine levels. Arch Intern Med 1999; 159: 1785}1790 3. Baigent C, Burbury K, Wheeler D. Premature cardiovascular disease in chronic renal failure. Lancet 2000; 356: 147}152 4. Landray MJ, Thambyrajah J, McGlynn FJ, et al. Epidemiological evaluation of known and suspected cardiovascular risk factors in chronic renal impairment. Am J Kidney Dis, in press 5. Kasiske B. The kidney in cardiovascular disease. Ann Intern Med 2001; 134: 707}709 6. Mann JF, Gerstein HC, Pogue J, et al. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 2001; 134: 629}636 7. Wannamethee SG, Shaper AG, Perry IJ. Serum creatinine concentration and risk of cardiovascular disease. A possible marker for increased risk of stroke. Stroke 1997; 28: 557}563 8. Flack J, Neaton J, Daniels B, et al. Ethnicity and renal disease: lessons from the Multiple Risk Factor Intervention Trial and the Treatment of Mild Hypertension Study. Am J Kidney Dis 1993; 21: 31}40 9. Culleton BF, Larson MG, Wilson PWF, et al. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 1999; 56: 2214}2219 10. Wollesen F, BrattstroK m B, Refsum H, et al. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int 1999; 55: 1028}1035
Evidence-based Cardiovascular Medicine (2001) 5, 32d33
33