- Email: [email protected]
Smoking and dialysis: A dreadful scenario for the cardiovascular system?
Kidney International, Vol. 63 (2003), pp. 1580–1581
EDITORIAL
Smoking and dialysis: A dreadful scenario for the cardiovascular system? Although the cardiac death rate of dialysis patients has decreased significantly over the past three decades, cardiovascular morbidity still accounts for approximately one half of the deaths among adults undergoing chronic dialysis. Compared to age- and gender-matched cohorts from the general population, cardiac death is up to 20 times more frequent in dialysis patients. Thus, this nonrenal comorbid condition is the major determinant of the fate of patients on renal replacement therapy. Against this background it is amazing that smoking, the most important modifiable cardiovascular risk factor, has been treated like the Cinderella of dialysis research. This may be due to the fact that some earlier reports had found no association between smoking and the risk of developing cardiovascular complications in hemodialysis patients [1]. In this issue of Kidney International, Foley, Herzog, and Collins [2] present data from the United States Renal Data System (USRDS) Wave 2 Study, which address the possible impact of smoking on cardiovascular outcomes in dialysis patients. Wave 2, a substudy of the Dialysis Morbidity and Mortality Study (DMMS) prospectively follows a group of patients who initiated their dialysis therapy during 1996 and 1997. The smoking status of the 4024 patients in the study was obtained at the initial data collection 60 days after the initiation of chronic dialysis (hemodialysis or continuous ambulatory peritoneal dialysis). New-onset cardiovascular events and death after the initiation of dialysis were identified with the help of the USRDS identification numbers from Medicare claims records over a mean follow-up period of about 2 years. The major finding of the study is that active smoking at study inception was associated with increased rates of new-onset congestive heart failure, new-onset peripheral vascular disease, and shorter patient survival. This finding persisted after adjustment for baseline age, demography, comorbidity, and mode of dialysis therapy. In contrast, former smokers had adjusted event risks similar to those who had never smoked. The fact that smoking did not predispose to acute coronary syndromes or stroke in this study may be due to an insufficient follow-up time. Interestingly, an analysis using the same DMMS Wave 2 data set of 4024 patients,
2003 by the International Society of Nephrology
but with the exclusion of all patients ⬍15 years of age (N ⫽ 99) and a shorter follow-up time of 9 to 12 months, revealed that smoking independently increased the likelihood of having coronary artery disease by 22% as compared with nonsmokers [3]. This implicates that smoking would indeed increase the risk of myocardial infarction. In favor of this assumption, smoking was shown to be a risk factor for atherosclerotic cardiovascular accidents during a follow-up of 9 years in a prospective study, including 147 patients with predialysis chronic renal failure [4]. It is noteworthy, however, that in a cross-sectional analysis of 936 hemodialysis patients enrolled in the baseline phase of the hemodialysis study (HEMO), smoking was not significantly associated with coronary artery disease [5]. In contrast, smoking was associated with cerebrovascular disease (odds ratio 1.68; P ⫽ 0.008) and peripheral vascular disease (odds ratio 1.74; P ⫽ 0.003). The latter confirms the finding of Foley, Herzog, and Collins [2] and others [6]. The observation of an increased risk of new-onset congestive heart failure in smokers on dialysis confirms earlier reports. Smoking had previously been shown to be a risk factor for systolic dysfunction [7] and to be one of the most significant independent predictors for lowoutput left ventricular failure in end-stage renal disease (ESRD) [8]. The shorter survival of smokers as compared with nonsmokers observed in the study of Foley, Herzog, and Collins [2] is of particular concern. Others had previously reported the same association. In a prospective study [9], lifelong smoking level was significantly higher in 10 out of 57 hemodialysis patients who died during a followup of nearly 3 years. In another prospective study, including 188 hemodialysis patients, smoking was significantly more frequent in the deceased group after a follow-up of 30 months [10]. Smoking is a risk factor for death during the first 90 days of dialysis [7]. Conversely, longterm ESRD survivors are characterized by a very low prevalence of active smokers [11]. The risk seems to be excessively high for dialysis patients with diabetes mellitus, where cigarette smoking at the start of renal replacement therapy leads to a particularly deleterious outcome (relative risk of mortality 2.28; P ⬍ 0.05) [12]. Lower serum albumin concentrations predict increased mortality in hemodialysis patients. Baseline serum albu-
1580
1581
Editorial
min is significantly lower in active as compared to nonsmokers on hemodialysis [7]. The limitations of the study design of Foley, Herzog, and Collins [2] are obvious and mainly discussed by the authors. The results are weakened by the fact that some confounders were not addressed (e.g., residual renal function, which is protective against mortality even after adjustment for smoking and other cardiovascular risk factors [13]). A major limitation is that the authors did neither analyze possible gender differences in the impact of smoking on the outcome variables investigated, nor did they address a possible interaction between smoking and race. This may be of importance, since there is some evidence that in dialysis patients who smoke, Caucasians have a higher mortality risk compared with non-Caucasians [14]. There is only limited information available about the mechanisms leading to an increased cardiovascular risk in smokers with ESRD, but it is reasonable to assume that several of the pathogenetic mechanisms described in the general population also play a major role in renal patients [7]. It can be hypothesized that smoking has a particularly negative impact in ESRD patients because it adds to an already high-risk profile for the development of atherosclerosis. One important mediator in patients with ESRD may be sympathetic nerve overactivity. This has been described as a possible mediator of atherosclerosis, which is associated with mortality and cardiovascular outcomes in ESRD [15]. The already enhanced sympathetic nerve activity in ESRD may be further exacerbated by smoking-induced sympathetic overactivity (for review see [7]). Regarding the management of patients on renal replacement therapy, it is noteworthy that noncompliance with hemodialysis therapy is significantly more frequent in smokers and is often associated with an adverse outcome. The study by Foley, Herzog, and Collins [2] was not designed to investigate the influence of changing the smoking status. No intervention was done and the smoking status was obtained only at study entry, thus, not accounting for possible changes in the smoking behavior. The conclusion of the authors that their findings suggest that efforts to encourage patients to stop smoking can abrogate the risk of cardiovascular disease is therefore not undermined by their data. Unfortunately, there are no reports of smoking cessation programs for patients with ESRD. Nevertheless, a possible beneficial effect of smoking cessation on cardiovascular disease can be expected from studies in the general population. This,
together with the finding of the current study that the status of former smoker was not related to any negative effect on cardiovascular disease and mortality, leads to the conclusion that there is probably no harm done, when we take a nonevidence-based approach and convince our patients on renal replacement therapy to stop smoking even before controlled data from interventional trials are available to prove a potential benefit of this intervention. Stephan R. Orth and Dominik E. Uehlinger Schwandorf, Germany, and Berne, Switzerland Correspondence to Dr. Stephan R. Orth, Dialysezentrum Schwandorf, Marktplatz 32, D-92421 Schwandorf, Germany. E-mail: [email protected]
REFERENCES 1. Rostand SG, Kirk KA, Rutsky EA: Relationship of coronary risk factors to hemodialysis-associated ischemic heart disease. Kidney Int 22:304–308, 1982 2. Foley RN, Herzog CA, Collins A: Smoking and cardiovascular outcomes in dialysis patients. The United States Renal Data System Wave 2 Study. Kidney Int 63:1462–1467, 2003 3. Stack AG, Bloembergen WE: Prevalence and clinical correlates of coronary artery disease among new dialysis patients in the United States: A cross-sectional study. J Am Soc Nephrol 12:1516–1523, 2001 4. Jungers P, Massy ZA, Nguyen Khoa T, et al: Incidence and risk factors of atherosclerostic cardiovascular accidents in predialysis chronic renal failure patients: A prospective study. Nephrol Dial Transplant 12:2597–2602, 1997 5. Cheung AK, Sarnak MJ, Yan G, et al: Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients. Kidney Int 58:353–362, 2000 ´ hare AM, Hsu C-Y, Bacchetti P, Johansen KL: Peripheral 6. O vascular disease risk factors among patients undergoing hemodialysis. J Am Soc Nephrol 13:497–503, 2002 7. Orth SR, Viedt C, Ritz E: Adverse effects of smoking in the renal patient. Tohoku J Exp Med 194:1–15, 2001 8. Parfrey PS, Harnett JD, Griffiths S, et al: Low-output left ventricular failure in end-stage renal disease. Am J Nephrol 7:184–191, 1987 9. Amar J, Vernier I, Rossignol E, et al: Nocturnal blood pressure and 24-hour pulse pressure are potent indicators of mortality in hemodialysis patients. Kidney Int 57:2485–2491, 2000 10. Tepel M, Van Der Giet M, Park A, Zidek W: Association of calcium channel blockers and mortality in haemodialysis patients. Clin Sci Lond 103:511–515, 2002 11. Owen WF, Madore F, Brenner BM: An observational study of cardiovascular characteristics of long-term end-stage renal disease survivors. Am J Kidney Dis 28:931–936, 1996 12. McMillan MA, Briggs JD, Junor BJ: Outcome of renal replacement treatment in patients with diabetes mellitus. BMJ 301:540– 544, 1990 13. Shemin D, Bostom AG, Laliberty P, Workin LD: Residual renal function and mortality risk in hemodialysis patients. Am J Kidney Dis 38:85–90, 2001 14. Pei YPC, Greenwood CMT, Chery AL, Wu GG: Racial differences in survival of patients on dialysis. Kidney Int 58:1293–1299, 2000 15. Zoccali C, Mallamaci F, Parlongo S, et al: Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation 105:1354–1359, 2002
EDITORIAL
Smoking and dialysis: A dreadful scenario for the cardiovascular system? Although the cardiac death rate of dialysis patients has decreased significantly over the past three decades, cardiovascular morbidity still accounts for approximately one half of the deaths among adults undergoing chronic dialysis. Compared to age- and gender-matched cohorts from the general population, cardiac death is up to 20 times more frequent in dialysis patients. Thus, this nonrenal comorbid condition is the major determinant of the fate of patients on renal replacement therapy. Against this background it is amazing that smoking, the most important modifiable cardiovascular risk factor, has been treated like the Cinderella of dialysis research. This may be due to the fact that some earlier reports had found no association between smoking and the risk of developing cardiovascular complications in hemodialysis patients [1]. In this issue of Kidney International, Foley, Herzog, and Collins [2] present data from the United States Renal Data System (USRDS) Wave 2 Study, which address the possible impact of smoking on cardiovascular outcomes in dialysis patients. Wave 2, a substudy of the Dialysis Morbidity and Mortality Study (DMMS) prospectively follows a group of patients who initiated their dialysis therapy during 1996 and 1997. The smoking status of the 4024 patients in the study was obtained at the initial data collection 60 days after the initiation of chronic dialysis (hemodialysis or continuous ambulatory peritoneal dialysis). New-onset cardiovascular events and death after the initiation of dialysis were identified with the help of the USRDS identification numbers from Medicare claims records over a mean follow-up period of about 2 years. The major finding of the study is that active smoking at study inception was associated with increased rates of new-onset congestive heart failure, new-onset peripheral vascular disease, and shorter patient survival. This finding persisted after adjustment for baseline age, demography, comorbidity, and mode of dialysis therapy. In contrast, former smokers had adjusted event risks similar to those who had never smoked. The fact that smoking did not predispose to acute coronary syndromes or stroke in this study may be due to an insufficient follow-up time. Interestingly, an analysis using the same DMMS Wave 2 data set of 4024 patients,
2003 by the International Society of Nephrology
but with the exclusion of all patients ⬍15 years of age (N ⫽ 99) and a shorter follow-up time of 9 to 12 months, revealed that smoking independently increased the likelihood of having coronary artery disease by 22% as compared with nonsmokers [3]. This implicates that smoking would indeed increase the risk of myocardial infarction. In favor of this assumption, smoking was shown to be a risk factor for atherosclerotic cardiovascular accidents during a follow-up of 9 years in a prospective study, including 147 patients with predialysis chronic renal failure [4]. It is noteworthy, however, that in a cross-sectional analysis of 936 hemodialysis patients enrolled in the baseline phase of the hemodialysis study (HEMO), smoking was not significantly associated with coronary artery disease [5]. In contrast, smoking was associated with cerebrovascular disease (odds ratio 1.68; P ⫽ 0.008) and peripheral vascular disease (odds ratio 1.74; P ⫽ 0.003). The latter confirms the finding of Foley, Herzog, and Collins [2] and others [6]. The observation of an increased risk of new-onset congestive heart failure in smokers on dialysis confirms earlier reports. Smoking had previously been shown to be a risk factor for systolic dysfunction [7] and to be one of the most significant independent predictors for lowoutput left ventricular failure in end-stage renal disease (ESRD) [8]. The shorter survival of smokers as compared with nonsmokers observed in the study of Foley, Herzog, and Collins [2] is of particular concern. Others had previously reported the same association. In a prospective study [9], lifelong smoking level was significantly higher in 10 out of 57 hemodialysis patients who died during a followup of nearly 3 years. In another prospective study, including 188 hemodialysis patients, smoking was significantly more frequent in the deceased group after a follow-up of 30 months [10]. Smoking is a risk factor for death during the first 90 days of dialysis [7]. Conversely, longterm ESRD survivors are characterized by a very low prevalence of active smokers [11]. The risk seems to be excessively high for dialysis patients with diabetes mellitus, where cigarette smoking at the start of renal replacement therapy leads to a particularly deleterious outcome (relative risk of mortality 2.28; P ⬍ 0.05) [12]. Lower serum albumin concentrations predict increased mortality in hemodialysis patients. Baseline serum albu-
1580
1581
Editorial
min is significantly lower in active as compared to nonsmokers on hemodialysis [7]. The limitations of the study design of Foley, Herzog, and Collins [2] are obvious and mainly discussed by the authors. The results are weakened by the fact that some confounders were not addressed (e.g., residual renal function, which is protective against mortality even after adjustment for smoking and other cardiovascular risk factors [13]). A major limitation is that the authors did neither analyze possible gender differences in the impact of smoking on the outcome variables investigated, nor did they address a possible interaction between smoking and race. This may be of importance, since there is some evidence that in dialysis patients who smoke, Caucasians have a higher mortality risk compared with non-Caucasians [14]. There is only limited information available about the mechanisms leading to an increased cardiovascular risk in smokers with ESRD, but it is reasonable to assume that several of the pathogenetic mechanisms described in the general population also play a major role in renal patients [7]. It can be hypothesized that smoking has a particularly negative impact in ESRD patients because it adds to an already high-risk profile for the development of atherosclerosis. One important mediator in patients with ESRD may be sympathetic nerve overactivity. This has been described as a possible mediator of atherosclerosis, which is associated with mortality and cardiovascular outcomes in ESRD [15]. The already enhanced sympathetic nerve activity in ESRD may be further exacerbated by smoking-induced sympathetic overactivity (for review see [7]). Regarding the management of patients on renal replacement therapy, it is noteworthy that noncompliance with hemodialysis therapy is significantly more frequent in smokers and is often associated with an adverse outcome. The study by Foley, Herzog, and Collins [2] was not designed to investigate the influence of changing the smoking status. No intervention was done and the smoking status was obtained only at study entry, thus, not accounting for possible changes in the smoking behavior. The conclusion of the authors that their findings suggest that efforts to encourage patients to stop smoking can abrogate the risk of cardiovascular disease is therefore not undermined by their data. Unfortunately, there are no reports of smoking cessation programs for patients with ESRD. Nevertheless, a possible beneficial effect of smoking cessation on cardiovascular disease can be expected from studies in the general population. This,
together with the finding of the current study that the status of former smoker was not related to any negative effect on cardiovascular disease and mortality, leads to the conclusion that there is probably no harm done, when we take a nonevidence-based approach and convince our patients on renal replacement therapy to stop smoking even before controlled data from interventional trials are available to prove a potential benefit of this intervention. Stephan R. Orth and Dominik E. Uehlinger Schwandorf, Germany, and Berne, Switzerland Correspondence to Dr. Stephan R. Orth, Dialysezentrum Schwandorf, Marktplatz 32, D-92421 Schwandorf, Germany. E-mail: [email protected]
REFERENCES 1. Rostand SG, Kirk KA, Rutsky EA: Relationship of coronary risk factors to hemodialysis-associated ischemic heart disease. Kidney Int 22:304–308, 1982 2. Foley RN, Herzog CA, Collins A: Smoking and cardiovascular outcomes in dialysis patients. The United States Renal Data System Wave 2 Study. Kidney Int 63:1462–1467, 2003 3. Stack AG, Bloembergen WE: Prevalence and clinical correlates of coronary artery disease among new dialysis patients in the United States: A cross-sectional study. J Am Soc Nephrol 12:1516–1523, 2001 4. Jungers P, Massy ZA, Nguyen Khoa T, et al: Incidence and risk factors of atherosclerostic cardiovascular accidents in predialysis chronic renal failure patients: A prospective study. Nephrol Dial Transplant 12:2597–2602, 1997 5. Cheung AK, Sarnak MJ, Yan G, et al: Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients. Kidney Int 58:353–362, 2000 ´ hare AM, Hsu C-Y, Bacchetti P, Johansen KL: Peripheral 6. O vascular disease risk factors among patients undergoing hemodialysis. J Am Soc Nephrol 13:497–503, 2002 7. Orth SR, Viedt C, Ritz E: Adverse effects of smoking in the renal patient. Tohoku J Exp Med 194:1–15, 2001 8. Parfrey PS, Harnett JD, Griffiths S, et al: Low-output left ventricular failure in end-stage renal disease. Am J Nephrol 7:184–191, 1987 9. Amar J, Vernier I, Rossignol E, et al: Nocturnal blood pressure and 24-hour pulse pressure are potent indicators of mortality in hemodialysis patients. Kidney Int 57:2485–2491, 2000 10. Tepel M, Van Der Giet M, Park A, Zidek W: Association of calcium channel blockers and mortality in haemodialysis patients. Clin Sci Lond 103:511–515, 2002 11. Owen WF, Madore F, Brenner BM: An observational study of cardiovascular characteristics of long-term end-stage renal disease survivors. Am J Kidney Dis 28:931–936, 1996 12. McMillan MA, Briggs JD, Junor BJ: Outcome of renal replacement treatment in patients with diabetes mellitus. BMJ 301:540– 544, 1990 13. Shemin D, Bostom AG, Laliberty P, Workin LD: Residual renal function and mortality risk in hemodialysis patients. Am J Kidney Dis 38:85–90, 2001 14. Pei YPC, Greenwood CMT, Chery AL, Wu GG: Racial differences in survival of patients on dialysis. Kidney Int 58:1293–1299, 2000 15. Zoccali C, Mallamaci F, Parlongo S, et al: Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation 105:1354–1359, 2002