Our study supports the evidence that even in patients without a history of smoking, incident smoking after transplant is associated with allograft failure and decreased patient survival. Prior studies have suggested that prior and/or active smoking may play an important role in transplant loss and mortality (Table 3). Kasiske and Klinger reported that it might be too late to improve posttransplant outcomes by convincing transplant candidates to quit smoking because of smoking history at the time of the transplant predicted graft failure. The authors suggested that this may be possible as patients who smoked before transplant would continue to smoke after transplantation, but additional studies are warranted to support this conclusion. They also found that smoking cessation 5 years before transplant decreased the relative risk of graft failure by 34% (P=0.001) (9). This notion is also supported by our findings in a sensitivity analysis in which prior smokers had a lower AHR of allograft loss than new smokers.
Sung et al. reported similar results to those of Kasiske and Klinger. They concluded that pretransplant smoking was a strong and independent risk factor for transplant loss during follow-up of 10 years (P<0.005). Patients who smoked at the time of listing had a graft survival of 84%, 65%, and 48% at 1, 5, and 10 years, respectively, compared with nonsmokers who had graft survival of 88%, 78%, and 62% (P=0.007), respectively. Smoking also adversely affected death-censored graft survival in recipients of cadaveric (P=0.02) and living donor kidneys (P=0.02). They showed that the adverse effects of pretransplant smoking on graft survival were primarily secondary to graft loss than to death with a functioning graft (14). Cosio et al. found that the most common cause of transplant failure in smokers was patient death. They found that graft survival was significantly reduced in smokers, patients with diabetes, or patients older than 40 years compared with patients without diabetes or a history of smoking and the cause was increased mortality. They concluded that active smoking may be an important risk factor for mortality rather than transplant loss (8). A similar conclusion was made by Kheradmand and Shahbazian (10), who concluded that pretransplant smoking was associated with reduced overall graft survival (P=0.01), but interestingly, smoking cessation after transplantation did not increase graft survival. Nogueira et al. found that smokers had a graft and patient survival rate that was worse than that of the patients who never smoked (P=0.01 and P=0.02, respectively). In addition, rejection-free survival at 1 year in smokers was significantly worse (P=0.03) and risk of rejection was much higher (P=0.02) (12). Compared with the aforementioned studies, Doyle et al. (15) reported that survival of patients who smoked but quit at least 2 months before the transplant was equivalent to the survival of nonsmokers.
Furthermore, it is recommended that transplant programs should have smoking cessation programs and encourage patients to stop smoking before being wait-listed. Tobacco use is the single most preventable cause of death and disease in the United States. In 2007, CDC published “Best Practices for Comprehensive Tobacco Control Programs,” a document that provides guidelines that can strengthen the implementation of comprehensive tobacco smoking cessation programs. The CDC concluded that the most effective population-based approaches contain the following components: State and Community Interventions; Health Communication Interventions; Cessation Interventions; Surveillance and Evaluation; and Administration and Management (16). Unfortunately, even though there are general guidelines for smoking interventions, there is little literature that describes the implementation of smoking cessation programs in the United States in the transplant population or addresses the safety and utility of pharmacologic interventions to promote smoking cessation.
Ehlers et al. discussed development and implementation of a smoking cessation program at the Mayo Clinic. They recommend that during the pretransplant evaluation, patients should be encouraged to quit smoking and should be referred to a tobacco cessation program. The establishment of a successful smoking cessation program at the Mayo Clinic used a multistep approach; team awareness of the potential impact of tobacco on the patients and the donated organs; creation of a multidisciplinary team to provide a team support; to find out the most efficient way to increase patient accessibility to the program; provision of resources to support the program; and finally, the development of a system to select patients who might benefit from the program (17).
There is clear and compelling evidence that there is a negative association between history of smoking and graft and recipient survival, including history of smoking by the donor (18, 19). Zitt et al., in a study of 272 patients, found that 22% were active and 38% were former smokers. Active smokers were more likely to develop graft failure (33.3% vs. 21.2%, P=0.25). Serum creatinine was higher in smokers (2.3±2.7 mg/dL vs. 1.8±1.4 mg/dL, P=0.21). Main allograft lesion associated with smoking was fibrous intimal thickening (20). Lentine et al. examined the risks, predictors, and mortality implications of cerebrovascular disease events after kidney transplantation in the USRDS. They found that the cumulative, 3-year incidence of de novo cerebrovascular disease events after transplantation was 6.8% and was lower than adjusted 3-year estimates of 11.8% on the waiting list and 11.2% after graft loss. They found that smoking was a potentially preventable correlate of posttransplant cerebrovascular events (21).
Adverse outcomes have also been demonstrated in other solid-organ transplants. van der Heide et al. investigated 401 adult patients with a follow-up of at least 2 years after orthotopic liver transplantation (OLT). A questionnaire about smoking habits at four time points before and after OLT was sent to all 326 patients, out of 301 (92%) patients responded. Both before and after OLT, 53% of patients never used tobacco and 17% were active smokers. Of the active smokers during the evaluation for OLT, almost one-third succeeded in cessation. Twelve percent of former smokers restarted smoking. At 10 years, the cumulative rate of malignancies was 12.7% in active smokers vs. 2.1% in nonsmokers (P=0.019). No effect on skin cancer or cardiovascular disease was found. They concluded that smoking was a serious problem after OLT and increased the risk for malignancy (22).
Our study was unable to directly measure tobacco exposure including an assessment of second-hand smoke exposure. Omoloja et al. conducted a cross-sectional study in which adolescents aged 13 to 18 years with chronic kidney disease were asked to complete a single anonymous self-administered survey. In addition, a single freshly voided urine sample for cotinine measurement was obtained from eligible subjects. Of 182 subjects, 60 (34%) were transplant recipients. Twenty-four percent of all respondents had smoked at some point in their lives and 13% had smoked within the last 30 days of taking the survey. In addition, 52% reported living with an adult who smoked and 54% reported having friends who smoked. Forty-seven percent and 44% of those who had never smoked lived with an adult and had friends who smoked, respectively. The highest cotinine/creatinine levels among the nonsmokers were observed in those who lived with a smoker and had friends who smoked (23).
The limitations of using an administrative data of Medicare patients are well described (24). We used claims to identify new tobacco abuse, which may not capture all patients who are actively smoking. We were also unable to quantify the extent of tobacco abuse, but one would expect it to be a clinically relevant amount if a claim was submitted. However, we were unable to assess the impact of tobacco “dose” using this method. It is possible that patients may have been misclassified as “new” smokers even if they had a history of tobacco use given limitations of claims. We attempted to exclude anyone with claims before transplant or with Centers for Medicare and Medicaid Services (CMS) Form 2728 evidence of tobacco abuse. As this pertains to allograft and patient outcomes, we excluded patients with history of COPD and/or drug and alcohol abuse in an attempt to exclude any patients who were potentially misclassified as “new” smokers. We were also unable to capture claims for smoking cessation. There are now several unique International Classification of Diseases—9th Revision (ICD-9) codes for this service, but most were enacted after the dates used in this cohort. Codes used for counseling prior are not specific to tobacco cessation counseling. This is the largest study of this kind, with the caveat that this is a cohort of Medicare patients; results may not be generalizable to the entire kidney transplant population.
There is compelling evidence that there is a negative association between history of smoking and graft and recipient survival, including history of smoking by the donor. We have demonstrated that there is also increased risk in those who start smoking after transplant. Our study reports that some demographic factors were associated with new smoking including male gender, African American ethnicity, white ethnicity, history of drug or alcohol use, history of COPD, and later year of transplant. These patients may be targeted for smoking cessation programs. Cessation of smoking should be part of a multimodal strategy which should include strict blood pressure control, tight glucose control for diabetes, strict blood pressure control, renin-angiotensin system blockade to reduce proteinuria, and statins for hyperlipidemia with emphasis on adherence to improve long-term graft outcomes (25, 26). The pathogenesis of the smoking-related renal damage is inferred from clinical observations and trials. A retrospective multicenter European case-control study showed that smoking was an independent risk factor for end-stage renal failure in patients with inflammatory and noninflammatory renal disease. The intermittent increase in blood pressure during smoking, intraglomerular pressure, and endothelial cell dysfunction seems to play a major role in causing renal damage (27, 28).
MATERIALS AND METHODS
Patients and Sources
This study used the USRDS database, which incorporates extensive baseline and follow-up demographic and clinical data on all patients accessing the Medicare End Stage Renal Disease program in the United States. The variables included in the USRDS standard analysis files (SAFs) and methods and validation studies are published and listed at the USRDS website, under “Researcher's Guide to the USRDS Database,” Section E, “Contents of all the SAFs.” The demographics of the renal transplant population have been previously described (2008 USRDS report). The files SAF.TXUNOS were used as the primary data set. We used an inception cohort (based on date of transplant) with patients older than 18 years who underwent renal transplantation between January 1, 2001, and June 30, 2006, and had Medicare primary insurance (parts A and B).
The outcome variables were based on Institutional claims reported to Medicare from January 1, 2001, to December 31, 2006. Claims were identified as “Smoking” by ICD9 Diagnosis Codes for tobacco use disorder (305.1×) and/or toxic effect of other substances, tobacco (989.84). We assessed the earliest Medicare claim for smoking after transplantation.
Time to smoking was calculated as the time from transplant date until the date of first Medicare claim for smoking, with recipients censored at time of death, loss to follow-up, or the end of the study period (October 1, 2006).
Patient characteristics were those at the date of transplant, with the exception of data from the CMS Form 2728, which includes demographic and comorbidity data obtained at the first treatment of End Stage Renal Disease, whether dialysis or transplant. The duration of dialysis (dialysis vintage) pretransplant was defined as the time from first recorded dialysis treatment until the date of transplantation. Other variables assessed included donor and recipient age, race, gender, induction/maintenance immunosuppressant, graft loss, delayed graft function, human leukocyte antigen match status, PRA, cold ischemic time, expanded donor criteria, and cadaver renal transplant. Data from CMS form 2728 included information on comorbid conditions including diabetes mellitus, COPD, hypertension, cancer, and tobacco use.
Tobacco use pretransplant was a combination of CMS2728 data and ICD9 claims for smoking before date of transplant.
All analyses were performed using SPSS 12.0 (SPSS, Inc., Chicago, IL). Files were merged and converted to SPSS files using DBMS/Copy (Conceptual Software, Houston, TX). Bivariate analysis of factors associated with smoking was performed with χ2 testing for categorical variables (Fisher's exact test was used for violations of Cochran's assumptions) and Student's t test for continuous variables (Mann-Whitney U test used for non-normally distributed variables). Statistical significance for bivariate comparisons was defined as P less than 0.05.
The independent associations between patient factors and smoking were examined using multivariate analysis with forward stepwise Cox regression. Variables with P less than 0.10 tested in bivariate analysis for a relationship were entered into multivariate analysis as covariates because of the possibility of negative confounding. Variables thought to have a known clinical association with outcomes were also introduced into multivariate models even if bivariate P values were more than 0.10, in accordance with established principles of model development.
The association between renal allograft loss and death and smoking as a time-dependent variable was assessed with Cox nonproportional hazards regression. Variables found to be independently associated with smoking in the above Cox regression were included in the model as were factors known to be independently associated with allograft loss. The model included age, gender, race, diabetes, drug use, alcohol use, COPD, donor type, expanded donor criteria, delayed graft function, tacrolimus at discharge, mycophenolate at discharge, induction immunosuppression, elevated PRA, human leukocyte antigen mismatch, year of transplant, and prolonged cold ischemic time.
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Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
Smoking; Smoking cessation; USRDS; Graft survival; Patient survival