Abstract
Abstract. Cigarette smoking increases the risk for cancer and cardiovascular disease in the general population, but the effects of smoking in renal transplant recipients are unknown. The effects of smoking were investigated among patients transplanted at Hennepin County Medical Center between 1963 and 1997. Information on smoking was available in 1334 patients. The 24.7% prevalence of smoking at the time of transplantation was similar to that in the general population. After adjusting for multiple predictors of graft failure, smoking more than 25 pack-years at transplantation (compared to smoking less than 25 pack-years or never having smoked) was associated with a 30% higher risk of graft failure (relative risk 1.30; 95% confidence interval [CI], 1.04 to 1.63; P = 0.021). Having quit smoking more than 5 yr before transplantation reduced the relative risk of graft failure by 34% (relative risk 0.66; 95% CI, 0.52 to 0.85; P < 0.001). The increase in graft failure was due to an increase in deaths (adjusted relative risk 1.42; 95% CI, 1.08 to 1.87; P = 0.012). The relative risk for major cardiovascular disease events with smoking 11 to 25 pack-years at transplant was 1.56 (95% CI, 1.06 to 2.31; P = 0.024), whereas that of smoking more than 25 pack-years was 2.14 (95% CI, 1.49 to 3.08; P < 0.001). The relative risk of invasive malignancies was 1.91 (95% CI, 1.05 to 3.48; P = 0.032). Smoking had no discernible effect on the rate of return to dialysis or on serum creatinine during the first year after transplantation. Thus, cigarette smoking is associated with an increased risk of death after renal transplantation. The effects of smoking appear to dissipate 5 yr after quitting. These results indirectly suggest that greater efforts to encourage patients to quit smoking before transplantation may decrease morbidity and mortality.
Cigarette smoking increases the risk for cancer and cardiovascular disease in the general population (1,2). Smoking also may have adverse effects on renal function (3). Therefore, it is likely that cigarette smoking may be particularly deleterious in renal transplant recipients who are already at high risk for cancer, cardiovascular disease, and renal allograft dysfunction. However, surprisingly few studies have examined cigarette smoking and its consequences after renal transplantation. Therefore, we examined the prevalence and clinical correlates of cigarette smoking in a large cohort of renal transplant recipients.
Materials and Methods
Patient Population
We reviewed the clinical records of all 1500 transplants performed between February 13, 1963, and July 22, 1997, at Hennepin County Medical Center. All patients were eligible for at least 12 mo of follow-up.
Smoking History
We determined whether patients had a history of smoking at the time of transplant (“current” smoking history), whether they had smoked within 5 yr of transplant, but not at the time of transplant (“recent” smoking history), or whether they had smoked previously, but not for at least 5 yr before transplantation (“remote” smoking history). We also estimated the total number of packs (20 cigarettes per package) smoked per day for each year before the time of transplantation (“pack-years” at transplant). At least some information concerning smoking history was available in 1334 patients. In 1233 cases there were adequate records to estimate the total number of pack-years smoked at the time of transplantation.
Other Variables
Variables that we examined included: recipient age, gender, race/ethnicity (Caucasian, African-American, Native American, Asian, Hispanic, and other), body weight, height, body mass index (weight in kilograms divided by height in meters-squared), body surface area, cause of renal failure (type 1 or 2 diabetes, primary glomerulonephritis, nephrosclerosis including hypertension and renovascular disease, polycystic kidney disease, systemic lupus erythematosus, and other), total duration of end-stage renal disease before transplant, and previous transplants. Comorbid indicators from the time of transplant included: history of ischemic heart disease (myocardial infarction and/or revascularization procedures), history of cerebral vascular disease (transient ischemic attacks and strokes), history of peripheral vascular disease (revascularization procedures and amputations), and history of invasive malignancy.
Donor factors included source (cadaveric, living-related, and emotionally related), age, gender, and race. In addition, we included the number of previous transplants, major histocompatibility mismatches (A, B, and DR), the percent panel-reactive antibody status at peak and at transplant, whether splenectomy and/or bilateral nephrectomy had been performed before transplant, and the number of blood transfusions before transplant. We also tabulated the type of initial prophylactic immunosuppression that was used: Minnesota antilymphocyte globulin (MALG; University of Minnesota, Minneapolis, MN), antithymocyte globulin (ATG, or ATGAM; Upjohn, Kalamazoo MI), cyclosporin A (CsA, Sandimmune or Neoral; Novartis, Basel, Switzerland), mycophenolate mofetil (Cellcept; Roche, Nutley, NJ), azathioprine (Imuran; Upjohn, Kalamazoo, MI), and/or corticosteroids.
We also tabulated the presence or absence of delayed graft function requiring dialysis within the first posttransplant week and the number of dialysis treatments that were needed. Outcomes we examined included: graft failure (death or return to dialysis), death, development of life-threatening cancer (exclusive of in situ malignancies, e.g., noninvasive squamous cell skin cancer or cervical carcinoma), major ischemic heart disease events (myocardial infarction, revascularization procedures, or death due to ischemic heart disease), cerebral vascular disease (transient ischemic attacks or strokes), and peripheral vascular disease (amputations or revascularization procedures). In a subset of patients surviving with a functioning graft for at least 1 yr, we also collected data on posttransplant total cholesterol and systolic BP. For cholesterol and BP, we used the average of values from 3, 6, and 12 mo posttransplant.
To adjust for time trends, we used indicator variables defining immunosuppression eras during which patients underwent transplantation. These included: (1) the pre-MALG era (before January 1969); (2) the pre-CsA era (January 1969 through December 1985); (3) the CsA era (from January 1986 through August 1992); and (4) the post-MALG era (after August 1992) when MALG was withdrawn. The MALG used for induction was initially replaced with ATG, and then replaced with a CsA-induction protocol. During this latter era, mycophenolate mofetil replaced azathioprine.
Statistical Analyses
We examined differences between group means using ANOVA or t test for continuous variables, and a χ2 test for differences in categorical data. We examined the effects of smoking on survival using Kaplan—Meier plots and the log-rank test for differences. We also carried out multivariate Cox proportional hazards analysis to examine the independent effects of smoking on outcomes. In the multivariate analysis, we included interaction terms to examine possible interactions between the cumulative number of pack-years smoked and having nevertheless quit smoking more than 5 yr before transplantation. To include all events that occurred posttransplant in the multivariate survival analysis, we used only variables known at the time of transplantation or, in the case of delayed graft function, discovered immediately posttransplant. Differences were considered significant at P < 0.05. Results are displayed as means and 95% confidence intervals [CI].
Results
Prevalence of Cigarette Smoking
Of the 1334 patients for whom there was adequate information, 24.7% smoked at the time of transplant, 18.4% quit more than 5 yr before transplant, 10.9% quit within 5 yr of transplantation, and 46.0% had never smoked. Of the 612 who gave a history of smoking, the number of pack-years was 23.5 (95% CI, 21.8 to 25.3). The number of pack-years was 22.7 (95% CI, 19.5 to 25.9) for the 206 who had quit more than 5 yr pretransplant, 30.8 (95% CI, 25.8 to 35.8) for those who had quit within 5 yr of transplant, and 20.9 (95% CI, 18.9 to 22.9) for those who still smoked at the time of transplant (P < 0.001). The prevalence of cigarette smoking was comparable to what has been observed in the United States and in Minnesota (Tables 1 and 2).
Smoking prevalence by eraa
Smoking prevalence by agea
Characteristics of Patients Who Smoked
There were differences in age, race, gender, the proportion with renal disease from diabetes, and the transplant era for patients who smoked, did not smoke, or had smoked and quit before transplantation (Table 3). Those who smoked at the time of transplantation compared to those who did not were younger (38.7 yr [37.4 to 40.0] versus 43.3 yr [42.5 to 44.1], P < 0.001), more likely to be black (8.2% versus 2.2%, P < 0.001), less likely to have renal disease caused by type 2 diabetes (4.6% versus 10.0%, P = 0.002), and more likely to have been transplanted before August 1992 (30.3% versus 18.5%, P < 0.001). There were no major differences in total cholesterol or systolic BP in those who smoked, did not smoke, or had smoked and quit at some time before transplantation (Table 3). Posttransplant cholesterol was 249 mg/dl (95% CI, 243 to 255) versus 254 mg/dl (95% CI, 250 to 258) for the 274 patients with cholesterol values who did, and the 847 who did not smoke at the time of transplantation, respectively (P = 0.172). Posttransplant systolic BP was 138 mmHg (95% CI, 136 to 140) versus 140 mmHg (95% CI, 139 to 141) for the 286 patients with BP readings who did and the 870 who did not smoke at the time of transplant, respectively (P = 0.140).
Characteristics of patients who smokeda
Outcomes Associated with Cigarette Smoking
While smoking per se was associated with increased mortality and decreased graft survival, the total number of pack-years smoked at the time of transplantation was a stronger predictor of outcomes. In univariate analysis, smoking more than 25 pack-years at transplantation was associated with increased graft failure and higher mortality (Figures 1 and 2). After adjusting for multiple predictors of graft failure, smoking more than 25 pack-years (compared to smoking less than 25 pack-years or never having smoked) was associated with a 30% higher risk of graft failure (Table 4). This was abrogated largely by having quit more than 5 yr before transplantation, which reduced the relative risk by 34% (Table 4). These effects appeared to be additive, i.e., there was no interaction between the number of pack-years smoked and having quit 5 yr before transplant.
The effects on graft survival of smoking more than 25 pack-years at the time of transplantation (n = 207) compared to smoking 25 pack-years or less and never having smoked (n = 1026).
The effects on mortality of smoking more than 25 pack-years at the time of transplantation (n = 207) compared to smoking 25 pack-years or less and never having smoked (n = 1026).
Effects of cigarette smoking on graft failurea
Most of the effects of smoking on graft survival seemed to be due to its effects on mortality (Table 5). In contrast, smoking had no statistically significant effect on patients returning to dialysis. Indeed, after adjusting for the same variables shown in Table 5, the relative risk of returning to dialysis with smoking 1 to 10 pack-years (compared to 0 pack-years at transplant) was 1.35 (95% CI, 0.97 to 1.87; P = 0.071); with 11 to 25 pack-years it was 1.07 (95% CI, 0.74 to 1.55; P = 0.702) and with greater than 25 pack-years it was 1.01 (95% CI, 0.74 to 1.66; P = 0.616). In addition, we could discern no effect of smoking on serum creatinine for patients who survived with a functioning graft during the first posttransplant year. For example, the average serum creatinine at 3, 6, and 12 mo was 1.56 mg/dl (95% CI, 1.50 to 1.61) for patients smoking no more than 25 pack-years at transplant, and 1.55 mg/dl (95% CI, 1.44 to 1.65) for patients smoking more than 25 pack-years at transplant (P = 0.886).
Cigarette smoking and mortalitya
Smoking more than 25 pack-years at the time of transplantation was associated with an increased risk of cardiovascular disease (n = 207 events) after adjusting for multiple risk factors in a multivariate analysis (Table 6). Specifically, the adjusted relative risk for ischemic heart disease (n = 159 events) with smoking 1 to 10 pack-years (compared to 0 pack-years at transplant) was 0.90 (95% CI, 0.53 to 1.52; P = 0.686); with 11 to 25 pack-years it was 1.68 (95% CI, 1.09 to 2.59; P = 0.018) and with greater than 25 pack-years it was 2.05 (95% CI, 1.36 to 3.09; P < 0.001). Similarly, the adjusted relative risk for cerebral vascular disease (n = 75 events) with smoking 1 to 10 pack-years was 1.36 (95% CI, 0.70 to 2.66; P = 0.369); with 11 to 25 pack-years it was 1.29 (95% CI, 0.64 to 2.61; P = 0.470) and with greater than 25 pack-years it was 1.88 (95% CI, 1.00 to 3.55; P = 0.052). Unlike what was found for graft failure and mortality, having quit smoking more than 5 yr before transplantation did not significantly reduce the risk of cardiovascular disease.
Cigarette smoking and cardiovascular diseasea
Cigarette smoking was also associated with an increased risk for 71 invasive malignancies, and having quit smoking more than 5 yr before transplantation did not reduce the risk of cancer (Table 7). The adjusted relative risk for lung neoplasms (n = 11) with smoking 1 to 10 pack-years was 1.13 (95% CI, 0.10 to 12.71; P = 0.922); with 11 to 25 pack-years it was 1.32 (95% CI, 0.12 to 14.71; P = 0.821) and with greater than 25 pack-years it was 8.48 (95% CI, 1.64 to 43.92; P = 0.011). In contrast, smoking had no statistically significant effect on non-lung malignancies. The adjusted relative risk for non-lung neoplasms (n = 60) with smoking 1 to 10 pack-years was 0.96 (95% CI, 0.46 to 2.03; P = 0.925); with 11 to 25 pack-years it was 1.05 (95% CI, 0.51 to 2.19; P = 0.889) and with greater than 25 pack-years it was 1.37 (95% CI, 0.69 to 2.73; P = 0.372).
Cigarette smoking and the risk for invasive cancera
Discussion
The prevalence of cigarette smoking in our cohort of transplant recipients resembles that seen in the general population (Tables 1 and 2). It is encouraging that the prevalence of smoking at the time of transplantation has declined over the past 30 yr. Although the number of transplant patients in this study is relatively small, it appears that the prevalence of smoking in recent years may be slightly lower in transplant recipients compared to the general population (Table 1).
Cigarette smoking at the time of transplantation was associated with increased graft failure, which, in turn, was largely due to increased mortality. A fatalistic interpretation of these results might be that it is too late to improve posttransplant outcomes by exhorting transplant candidates to quit smoking, since it was smoking history at the time of transplantation that predicted graft failure. However, it is possible that a history of pretransplant smoking may only be associated with adverse outcomes because the patients who smoked the most pretransplant were those most likely to continue smoking posttransplant. In other words, it is possible that pretransplant smoking history was a surrogate for smoking behavior after transplantation. Unfortunately, we did not have adequate information on posttransplant smoking habits to analyze its effects on outcome, and additional studies are warranted.
In examining the additive effects of covariates, patients who smoked but quit more than 5 yr before transplantation appeared to have better outcomes than patients who had never smoked. The reason for this is unclear. This effect was independent of other, major determinants of graft survival posttransplant. We might speculate that patients who were able to quit smoking were also patients who had other attributes that led to improved survival, attributes that were not taken into account in the multivariate analysis. For example, patients who were able to quit smoking may have been more adherent to medications. It is also possible that patients who were able to quit smoking adopted other lifestyles and habits that improved their survival after transplantation. In any case, this result should be interpreted with caution, given the relatively small number of end points for the relatively large number of variables entered into the models. Although we looked for interactions between variables, the number of patients and end points may have been too small to allow us to detect significant interactions. Thus, the apparent benefit from having quit smoking may largely be the result of a benefit in a subpopulation of patients who were heavy smokers, even though we were unable to discern this with the statistical models.
It is encouraging that the reduced graft and patient survival associated with heavy smoking seemed to be abrogated by quitting more than 5 yr before transplantation. The 5-yr interval was arbitrary. However, other studies in nontransplant populations have also found that the effects of smoking on mortality dissipate over a number of years after having quit (4,5,6,7).
There was no discernible effect of smoking on the rate of return to dialysis. In addition, smoking had no effect on serum creatinine during the first posttransplant year. Thus, there was no evidence from this study that smoking affected graft function after renal transplantation. However, these results do not eliminate the possibility that smoking may have an effect on posttransplant renal function detectable by better measures or renal function and/or longer follow-up. Indeed, studies in nontransplant populations have shown that smoking has an adverse effect on renal function (8,9). A longer follow-up or a greater number of patients may be required to detect an adverse effect of smoking on graft function.
Few studies have examined the effects of smoking in organ transplant recipients. In one investigation, the effects of smoking in 84 heart transplant recipients were examined (10). Despite the small sample size, smoking was associated with decreased patient survival and an increased rate of cancer. In another study of 210 cardiac transplant recipients, smoking correlated significantly with the occurrence of posttransplant coronary artery disease (11). Data from these retrospective, observational studies can never prove cause-and-effect relationships. However, it is difficult if not impossible to conduct randomized, controlled intervention trials to establish that quitting smoking will improve survival after organ transplantation.
There is a growing shortage of organs that are suitable for transplantation, and waiting times for cadaveric transplants continue to increase. It can be argued that we (society) should attempt to maximize the potential improvement in patient survival that may result from each organ that is transplanted. In particular, we should attempt to maximize the overall benefit from cadaveric organs by reducing modifiable risk factors that negatively affect graft survival. Smoking may be such a risk factor. Evidence suggests that when appropriate interventions are used, many patients can quit smoking (12,13). Thus, every effort should be made to encourage transplant candidates to quit smoking. Indeed, it may even be in the public interest to deny renal transplantation to patients who do not make a serious attempt to quit smoking. The interests of both the individual and society may be best served by such an approach.
Footnotes
American Society of Nephrology
- © 2000 American Society of Nephrology
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