Effects of Tobacco Smoking on Post-Liver-Transplant Outcomes
by
, and
Lovepreet Singh
1,*, 
Ramanpreet Bajwa
2,
Sofia Molina Garcia
3,
Kristelle Imperio-Lagabon
4,
Omar T. Sims
2,5,6,* and
Jamak Modaresi Esfeh
2,6 1
Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
2
Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
3
Department of Infectious Diseases, Mayo Clinic, Rochester, MN 55905, USA
4
Department of Gastroenterology and Hepatology, Loma Linda University Medical Center, Loma Linda, CA 92354, USA
5
Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
6
Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
*
Authors to whom correspondence should be addressed.
Transplantology 2024, 5(4), 288-297; https://doi.org/10.3390/transplantology5040029
Submission received: 15 July 2024
/
Revised: 31 October 2024
/
Accepted: 3 December 2024
/
Published: 6 December 2024
(This article belongs to the Section Solid Organ Transplantation)
Abstract
:Background/Objectives: Our study examined 5-year patient and graft survival outcomes among non-smokers, former smokers, and active smokers at the time of liver transplantation (LT) and immediate post-operative complications and short-term outcomes following LT. Methods: This was a retrospective study that examined all liver transplants occurring at Cleveland Clinic Main Campus between January 2015–October 2022. Kaplan–Meier curves examined survival outcomes, and Cox’s multivariate regression analysis was performed. Results: Over the 5-year period, patient survival did not differ statistically between patient groups (all p-values >0.05). However, graft survival was significantly lower in active smokers (p = 0.012). In the multivariate analysis, age (HR = 1.03, 95% CI 1.01–1.05, p = 0.002) and admission to the ICU (HR 1.68, 95% CI 1.13–2.50, p = 0.01) were positively associated with overall mortality. Immediate and short-term complications did not differ statistically between patient groups. Cardiovascular disease (22.5%) was the most common cause of death among all patients. Conclusions: Though our study did not show decreased patient survival outcomes, our findings are in line with previous studies that have shown that pre-transplant smoking is associated with overall reduced graft survival. Combined with the risk for de novo malignancy and cardiovascular events post transplant, smoking cessation before LT should be encouraged to ensure graft longevity.
1. Introduction
Tobacco smoking is the most commonly used substance in the world, and it is the world’s leading cause of preventable premature mortality [1,2]. There are an estimated more than eight million deaths yearly attributed to tobacco smoking [3]. Tobacco smoking is known to contribute to many diseases, including cardiovascular, pulmonary, and autoimmune infections and malignancy [4]. Within organ transplantation, several studies have demonstrated that tobacco use is associated with graft loss and mortality in renal and pancreas transplant patients, cardiovascular disease in renal transplant patients, and cancer in renal, lung, and heart transplant patients [5]. Furthermore, it is associated with poorer surgical outcomes, increased infections, and poor wound healing and has been associated with lower quality-of-life benefit gained from surgical interventions [3,5].
Particularly, in patients with liver transplantation (LT), tobacco smoking has been shown to be associated with serious long-term negative consequences, including de novo malignancies, patient death, and graft failure following liver transplantation [3,5,6]. There have also been studies performed that show tobacco smokers have a higher risk of cirrhosis regardless of alcohol consumption status, and alcohol and smoking can have a synergistic effect when occurring together [3].
Fortunately, liver transplantation is universally accepted as a curative treatment for end-stage liver disease; however, due to increased demand, organ shortage is becoming a concern [7]. LT has undergone tremendous advancements, allowing it to rise from an experimental procedure 50 years ago to becoming a universally accepted curative treatment for virtually all patients with end-stage liver disease [8]. Whether abstinence from smoking should be a transplant selection criterion remains an ethical challenge. Studies have shown that smoking is an absolute contraindication to transplantation at certain programs, but liver transplantation programs are less likely to have smoking be an absolute contraindication when compared to kidney or pancreas transplant programs [9]. With the increasing need for liver transplantation and the challenging organ shortage, post-liver-transplantation outcomes are essential to examine.
Currently, at our institution, active tobacco smoking at the time of transplant is not a contraindication to transplant, but cessation is highly encouraged. We sought out to examine the effects of tobacco smoking on post-LT outcomes. Our study aimed to examine 5-year patient and graft survival outcomes among patients based on pre-transplantation smoking status (i.e., non-smokers, former smokers, and active smokers) at the time of liver transplantation and immediate post-operative complications and short-term outcomes in the first 6 months following liver transplantation.
2. Materials and Methods
2.1. Study Design
We performed a retrospective study that examined all liver transplants occurring at Cleveland Clinic (Main Campus, Cleveland, Ohio) between January 2015–October 2022. Patients were stratified into 3 groups: never smokers, former smokers, and active smokers at the time of LT. Patients who ceased smoking within 90 days of LT were defined as active smokers at the time of LT. Former smokers were defined as any individual that quit smoking more than 90 days prior to LT. Smoking status was determined based on self-reported data in the medical record. Further variables collected for former smokers included duration of time from the cessation date to time of transplant. Pediatric patients, retransplants, combined liver and renal transplants, and liver transplantation with any other surgery concurrently were excluded. This study was approved by Cleveland Clinic’s Institutional Review Board (IRB #22-1049).
Collected recipient data included age at transplant, ethnicity, history of hyperlipidemia, body mass index (BMI) at time of transplantation, history of type 1 or type 2 diabetes, MELD-Na score, history of ascites, and any history of paracentesis. Etiology of cirrhosis was collected from a manual chart review, which included NASH (non-alcoholic steatohepatitis), alcoholic cirrhosis, cholestatic liver disease, including primary biliary sclerosis and primary sclerosing cholangitis, autoimmune, metabolic (alpha 1 antitrypsin deficiency, Wilson’s disease, hemochromatosis, porphyria, and citrullinemia), hepatitis C as the sole diagnosis, hepatitis B cirrhosis, hepatitis C combined with hepatocellular carcinoma, hepatitis C combined with alcohol use, alcohol with hepatocellular carcinoma, hepatocellular carcinoma, NASH and hepatocellular carcinoma, cholangiocarcinoma, cryptogenic, drug-/toxin-induced liver failure, neuroendocrine tumor, and another etiology group that included etiologies not listed above. Donor factors collected included donor after circulatory death, donor after brain death, or living donor. Post-transplant variables collected included length of hospital stay post transplant and intensive care unit (ICU) admission at the time/before LT.
2.2. Primary and Secondary Outcomes
The primary outcome of the study was to examine patient and graft survival at years 1, 3, and 5. Patient survival was defined as either from time of LT to death or last follow-up. Graft survival was defined as graft failure requiring transplantation or resulting in death. Secondary outcomes included the frequency of immediate and short-term complications. Immediate complications were defined as complications that occurred during the LT hospital admission. These included vascular complications such as deep vein thrombosis (DVT) or pulmonary embolism (PE), acute kidney injury, infection (bacteremia, urinary tract infection, wound infection, C. diff infection), arrythmias such as atrial fibrillation or atrial flutter, cardiac arrest, myocardial infarction, pneumonia, cytomegalovirus viremia, graft failure, seizure, and cerebrovascular accident. Short-term complications, characterized as complications that arose within the first 6 months post transplant, were collected, which included infection, arrythmia, renal injury, acute rejection, biliary stricture, pneumonia, myocardial infarction (MI), non-ST segment myocardial infarction (NSTEMI), cerebrovascular accident (CVA), seizure, cardiac arrest, and vascular complications.
2.3. Statistical Analysis
Continuous variables were described as mean ± standard deviation (SD) if normally distributed, median and interquartile range for non-normal variables, and percentages for categorical variables. For the descriptive analysis, the independent samples t-test was used for normally distributed continuous variables, the Kruskal–Wallis test was used for non-normally distributed variables, and was used for categorical variables. Kaplan–Meier graphs with the log-rank test were constructed to examine differences in median mortality between the 3 patient groups. Univariate analysis and multivariate survival analysis were completed using a Cox proportional hazard model. Candidate variables for the multivariate analysis were chosen if the p-value was <0.2 on univariate regression. Results are presented as hazard ratios (HR) with 95% confidence intervals (CI). For all analyses, p values less than 0.05 were considered statistically significant. The data were evaluated with Stata 14.2.
3. Results
3.1. Patients Demographics and Characteristics
A total of 876 patients met the inclusion criteria. There were 492 patients in the never smoker group, 193 patients who were former smokers, and 191 patients who were active smokers at time of LT (56.16% vs. 22.03% vs. 21.8%, p < 0.001) (Table 1). The mean age of patients was 56.02, the mean MELD was 23.73, and the majority of patients were male (63.13%) and White (86.87%). Active smokers were younger (53.74, p < 0.001) and had a higher frequency of a history of paracentesis (60.21%, p = 0.039). Diabetes, hypertension, and hyperlipidemia were more likely to be present in former smokers (all p-values < 0.05). The mean number of pack-years was 22.57 among active smokers and 18.47 among former smokers. Median length of time between date of smoking cessation to date of transplant in the former smoker group was 262.17 days ± 169.27–384.67.
3.2. Etiology of Cirrhosis
The most common etiology of cirrhosis was NASH (21.23%), followed by ETOH (20.66%). Compared to never smokers, a higher proportion of active smokers had ETOH as the etiology or cirrhosis (16.26% vs. 32.98%, p < 0.001) (Table 2).
3.3. Immediate and Short-Term Complications
Acute kidney injury (31.5%) was the most common immediate complication, followed by infection (22.6%) (Table 3). Similarly, the most common short-term complication was acute kidney injury (22.5%), followed by infection (21.9%). However, the frequency of immediate and short-term complications was similar across patient groups.
3.4. Patient and Graft Survival
Though patient survival was lowest at year 1 and year 3 in the former smoking group and the lowest at year 5 in the active smokers group (Table 4), the Kaplan–Meier curve showed survival did not differ statistically between patient groups (log-rank test p = 0.248) (Figure 1). However, graft survival was lowest at years 1, 3, and 5 in the active smoking group (Table 4), with the active smoking group having significantly lower survival over the 5-year interval (log-rank test p = 0.0123) (Figure 1).
3.5. Cox’s Univariate and Multivariate Proportional Regression Analyses
Ascites (HR = 1.71, 95% CI 1.18–2.49, p = 0.005), hypertension (HR = 1.49, 95% CI 1.07–2.07, p = 0.018), history of paracentesis (HR = 1.60, 95% CI 1.15–2.24, p = 0.006), and BMI 40 (HR = 1.84, 95% CI 1.10–3.09, p = 0.019) were risk factors identified in the univariate analysis (Table 5). In the multivariate regression analysis, age (HR = 1.03, 95% CI 1.01–1.05, p = 0.002) and admission to the ICU (HR 1.68, 95% CI 1.13–2.50, p = 0.01) were independent predictors for overall mortality.
3.6. Causes of Death
There were 61 post-transplant deaths in year 1, with 33 occurring in the never smoking group, 15 in the former smoking group, and 13 in the active smoking group. Cardiovascular causes were the most common cause of death, with most occurring in the never smoking group. Graft failure and malignancy were the most common in the active smoking group (23.08%, 23.08%, p = 0.036) (Table 6). The most common cause of death overall in the group was cardiovascular, accounting for 22.5% of deaths.
4. Discussion
Our study examined patient and graft survival over a 5-year period and immediate and short-term complications between non-smokers, former smokers, and active smokers at the time of LT. Our study results demonstrate that active tobacco smoking at the time of liver transplantation increases the probability of graft failure, similar to findings published in previous studies [6]. Studies in kidney transplants have shown that active smoking was associated with greater than 50% graft loss [10], and in orthotopic heart transplant, animal studies have demonstrated that exposure to cigarette smoke pre transplant is associated with increased allograft rejection and reduces graft survival, ranging from 33% to 57% [11]. Additionally, compared to non-smoking donors, tobacco smoking in renal transplant donors is known to reduce graft survival and increase the likelihood of death in LT recipients [12]. Smoking affects both innate and adaptive immunity; however, the molecular effects of smoking on graft rejection are not well identified [4]. The mechanisms by which cigarette smoking affects allografts are suggested to include the stimulation of T or B cell memory, the suppression of dendritic cell development, and the downregulation of Treg cell numbers [4]. Cigarette smoke also contains reactive nitrogen species, reactive oxygen species, and free radicals, which contribute to inflammation, oxidative stress, and DNA damage. Thus, smoking should be discouraged at the time of liver transplantation to ensure organ longevity. Prospective studies are encouraged to further examine other factors that may play a role in immunity and graft survival.
Five-year patient survival outcomes and immediate and short-term complications did not differ by tobacco smoking status. This is different compared to other studies within renal transplantation that have shown that smoking doubled mortality after the first year of transplantation [6]. Furthermore, smoking greater than 25 years is associated with increased mortality in renal transplantation [13]. Within liver transplantation, studies have demonstrated that active smokers had an increased risk of all-cause mortality [6]. There are differing results in the published literature as to whether active smokers experience higher levels of immediate and short-term complications post transplantation [1]. Li et al., in 2007, demonstrated that smokers did not have a higher rate of biliary complications, acute kidney disease, or the need for ventilation post-operatively after LT, and there was also no difference in hospital stay or ICU stay [1]. Despite our study not showing a significant difference in patient survival among the three groups, it is still advisable for smoking cessation to be encouraged among active smokers given the other consequences associated with smoking.
Cox’s multivariate regression analysis did not show that active smoking was an independent risk factor for mortality. Risk factors for overall mortality included age and admission to the ICU. Certain studies have shown that older age at transplantation is associated with higher post-transplant mortality [14,15]. Studies have also demonstrated that length of stay in the ICU prior to LT is associated with decreased patient survival post LT as well as reduced survival in patients hospitalized in the ICU compared to in regular wards prior to LT [16,17]. Thus, patients with these risk factors need to be closely monitored during the transplantation process.
The most common cause of death within our study was cardiovascular disease, accounting for 22.5% of overall deaths. Within the first year post LT, cardiovascular death was the most common cause of death. Historically, early mortality after LT was thought to be due to graft failure and infections; however, emerging data have shown that early cardiovascular death post LT is surpassing graft failure and death from infections [18]. Smoking cessation should be encouraged to decrease cardiovascular death for our LT patients.
Within the first year post LT, there were 61 deaths, and cardiovascular events were the most common, followed by respiratory causes. Malignancy had the highest occurrence in the active smoking group. Previous studies have identified that recipient smoking history significantly increased de novo malignancy after transplant and post-transplant cardiovascular events [19]. Furthermore, de novo malignancies have been shown to occur at higher rates in kidney and liver recipients than in the general population [20]. Increased cancer risk is thought to be due immune suppression from medications post LT [20]. Within our group, malignancies after LT had the highest rate in the active smoking group compared to the other groups. Lung cancer screening is advised in patients who undergo LT with any history of smoking, as tumors detected can be quite aggressive [21].
Our study had notable limitations. The use of self-reported smoking status data in the medical record is not as reliable as the use of biological measures of smoking status. In this regard, the self-reported data may be vulnerable to bias or underreporting of active smoking. Future studies should include measures of cotinine levels in plasma or urine to minimize reliance on self-reported smoking status data [14]. Post-LT tobacco smoking status was not included in the analysis, which could have influenced the survival estimates, especially among the former smokers who may have resumed smoking post LT. Equally important is the fact that future studies are encouraged to examine and compare survival in larger sample sizes based on stratifications of pack-years. Data were not available on pack-years nor on the duration of smoking, which would be helpful to include in future studies. Furthermore, cardiovascular deaths were the highest among the never smoker group, which was an unexpected result. Future studies are encouraged to determine the underlying causes that may have contributed to this, which our data did not include. It may also be helpful to complete a study comparing smoking vs. non-smoking groups. In addition, etiology of cirrhosis and graft survival was not assessed, which could be examined in future studies. Assessing short-term outcomes such as rejection and biliary strictures could be examined at 1 year post transplant in future studies. Lastly, our study did not examine concurrent tobacco smoking and substance use nor other psychosocial factors that commonly co-occur among active smokers that may negatively impact patient and graft survival [3].
Despite these limitations, our study had several strengths. The strengths of our study included the inclusion of a relatively large sample size from a large, high-volume tertiary care center. The large sample size allowed for the examination of immediate and short-term complications across all three patient groups. The exclusion criteria were minimal, which allowed for the inclusion of the majority of LT patients at this respective study site, thereby increasing generalizability of the study’s findings to other large, high-volume sites.
In conclusion, as liver transplant needs increase and organ shortage is occurring, further optimization of our patient population is required. Though our study did not show decreased patient survival outcomes, active tobacco smoking does result in decreased graft survival, which, in turn, can negatively impact long-term survival outcomes. Thus, smoking cessation should be greatly encouraged for our liver transplant recipients, as active smoking has the potential to reduce graft longevity.
Author Contributions
Conceptualization, L.S., R.B., S.M.G., K.I.-L. and J.M.E.; methodology, L.S., S.M.G. and O.T.S.; formal analysis, L.S., R.B., S.M.G. and O.T.S.; investigation, L.S., R.B., S.M.G., K.I.-L., O.T.S. and J.M.E.; data curation, L.S., R.B., S.M.G. and K.I.-L.; data interpretation, L.S., R.B., S.M.G., K.I.-L., O.T.S. and J.M.E.; writing—original draft preparation, L.S., R.B., S.M.G., K.I.-L., O.T.S. and J.M.E.; writing—review and editing, L.S., R.B., O.T.S. and J.M.E.; supervision, O.T.S. and J.M.E. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
This study was conducted in accordance with the Declaration of Helsinki and approved by Cleveland Clinic’s Institutional Review Board (protocol code #22-1049; 26 September 2022).
Informed Consent Statement
Patient consent was waived due to the retrospective nature of this study.
Data Availability Statement
The patient data presented in this article are not readily available because of ethical IRB-related privacy reasons. Consideration for access to the data can be submitted to the corresponding author.
Acknowledgments
O.T.S and J.M.E. were co-senior authors.
Conflicts of Interest
The authors declare no conflicts of interest.
References
- Li, Q.; Wang, Y.; Ma, T.; Liu, X.; Wang, B.; Wu, Z.; Lv, Y.; Wu, R. Impact of cigarette smoking on early complications after liver transplantation: A single-center experience and a meta-analysis. PLoS ONE 2017, 12, e0178570. [Google Scholar] [CrossRef] [PubMed]
- Leithead, J.A.; Ferguson, J.W.; Hayes, P.C. Smoking-related morbidity and mortality following liver transplantation. Liver Transplant. 2008, 14, 1159–1164. [Google Scholar] [CrossRef]
- López-Lazcano, A.I.; Gual, A.; Colmenero, J.; Caballería, E.; Lligoña, A.; Navasa, M.; Crespo, G.; López, E.; López-Pelayo, H. Active Smoking Before Liver Transplantation in Patients with Alcohol Use Disorder: Risk Factors and Outcomes. J. Clin. Med. 2020, 9, 2710. [Google Scholar] [CrossRef] [PubMed]
- Qiu, F.; Fan, P.; Nie, G.D.; Liu, H.; Liang, C.L.; Yu, W.; Dai, Z. Effects of Cigarette Smoking on Transplant Survival: Extending or Shortening It? Front. Immunol. 2017, 8, 127. [Google Scholar] [CrossRef] [PubMed]
- Ehlers, S.L.; Rodrigue, J.R.; Widows, M.R.; Reed, A.I.; Nelson, D.R. Tobacco use before and after liver transplantation: A single center survey and implications for clinical practice and research. Liver Transplant. 2004, 10, 412–417. [Google Scholar] [CrossRef]
- Anis, K.H.; Weinrauch, L.A.; D’Elia, J.A. Effects of Smoking on Solid Organ Transplantation Outcomes. Am. J. Med. 2019, 132, 413–419. [Google Scholar] [CrossRef]
- Jadlowiec, C.C. Liver transplantation: Current status and challenges. World J. Gastroenterol. 2016, 22, 4438. [Google Scholar] [CrossRef]
- Zarrinpar, A.; Busuttil, R.W. Liver transplantation: Past, present and future. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 434–440. [Google Scholar] [CrossRef]
- Cote, D.; Chirichella, T.; Noon, K.; Shafran, D.; Augustine, J.; Schulak, J.; Sanchez, E.; Woodside, K. Abdominal Organ Transplant Center Tobacco Use Policies Vary by Organ Program Type. Transplant. Proc. 2016, 48, 1920–1926. [Google Scholar] [CrossRef]
- Weinrauch, L.; Claggett, B.; Liu, J.; Finn, P.V.; Weir, M.; Weiner, D.; D’Elia, J. Smoking and outcomes in kidney transplant recipients: A post hoc survival analysis of the FAVORIT trial. Int. J. Nephrol. Renov. Dis. 2018, 11, 155–164. [Google Scholar] [CrossRef]
- Ohiomoba, R.; Youmans, Q.; Akanyirige, P.; Ezema, A.; Anderson, A.; Bryant, A.; Jackson, K.; Mandieka, E.; Pham, D.; Raza, Y.; et al. History of cigarette smoking and heart transplant outcomes. IJC Heart Vasc. 2020, 30, 100599. [Google Scholar] [CrossRef] [PubMed]
- Aref, A.; Sharma, A.; Halawa, A. Smoking in Renal Transplantation; Facts Beyond Myth. World J. Transplant. 2017, 7, 129. [Google Scholar] [CrossRef] [PubMed]
- Khalil, M.A.M.; Tan, J.; Khamis, S.; Khalil, M.A.; Azmat, R.; Ullah, A.R. Cigarette Smoking and Its Hazards in Kidney Transplantation. Adv. Med. 2017, 2017, 6213814. [Google Scholar] [CrossRef]
- Gil, E.; Kim, J.M.; Jeon, K.; Park, H.; Kang, D.; Cho, J.; Suh, G.Y.; Park, J. Recipient Age and Mortality After Liver Transplantation: A Population-based Cohort Study. Transplantation 2018, 102, 2025–2032. [Google Scholar] [CrossRef] [PubMed]
- Durand, F.; Levitsky, J.; Cauchy, F.; Gilgenkrantz, H.; Soubrane, O.; Francoz, C. Age and liver transplantation. J. Hepatol. 2019, 70, 745–758. [Google Scholar] [CrossRef]
- Bittermann, T.; Makar, G.; Goldberg, D.S. Early post-transplant survival: Interaction of MELD score and hospitalization status. J. Hepatol. 2015, 63, 601–608. [Google Scholar] [CrossRef] [PubMed]
- Wiering, L.; Öllinger, R.; Kruppa, J.; Schoeneberg, U.; Dziodzio, T.; Jara, M.; Biebl, M.; Dargie, R.; Raschzok, N.; Schöning, W.; et al. Hospitalization Before Liver Transplantation Predicts Posttransplant Patient Survival: A Propensity Score–Matched Analysis. Liver Transplant. 2020, 26, 628–639. [Google Scholar] [CrossRef]
- VanWagner, L.B.; Lapin, B.; Levitsky, J.; Wilkins, J.T.; Abecassis, M.M.; Skaro, A.I.; Lloyd-Jones, D.M. High early cardiovascular mortality after liver transplantation. Liver Transplant. 2014, 20, 1306–1316. [Google Scholar] [CrossRef]
- Abbasoglu, O.; Levy, M.F.; Brkic, B.B.; Testa, G.; Jeyarajah, D.R.; Goldstein, R.M.; Husberg, B.S.; Gonwa, T.A.; Klintmalm, G.B. Ten years of liver transplantation. Transplantation 1997, 64, 1801–1807. [Google Scholar] [CrossRef]
- Park, B.; Yoon, J.; Choi, D.; Kim, H.J.; Jung, Y.K.; Kwon, O.J.; Lee, K.G. De novo cancer incidence after kidney and liver transplantation: Results from a nationwide population based data. Sci. Rep. 2019, 9, 17202. [Google Scholar] [CrossRef]
- Lantuejoul, L.R.; Toffart, A.-C.; Ghelfi, J.; Decaens, T.; Hilleret, M.N.; Brichon, P.Y.; Stefanov, O.; Jankowski, A.; Reymond, E.; Ferretti, G.R. Liver transplantation-associated lung cancer in smokers: Results of an early CT detection program. J. Liver Transplant. 2022, 5, 100050. [Google Scholar] [CrossRef]
Figure 1.
Kaplan–Meier survival curve of patient (left) and graft (right) survival by smoking status.
Figure 1.
Kaplan–Meier survival curve of patient (left) and graft (right) survival by smoking status.
Table 1.
Patient demographics and clinical characteristics.
| Total (N = 876) | Never Smoker (N = 492 56.16%) | Former Smoker (N = 193 22.03%) | Active Smoker (N = 191 21.8%) | p-Value | |
|---|---|---|---|---|---|
| Age, years (SD) | 56.02 (11.46) | 54.98 (12.25) | 60.93 (7.76) | 53.74 (11.15) | <0.001 |
| MELD-Na | 23.73 (8.37) | 23.93 (8.74) | 22.85 (7.67) | 24.08 (8.08) | 0.079 |
| Male | 553 (63.13%) | 299 (60.77%) | 136 (70.47%) | 118 (61.78%) | 0.055 |
| Ethnicity | 0.294 | ||||
| White | 761 (86.87%) | 423 (85.98%) | 167 (86.53%) | 171 (89.53%) | |
| Black | 44 (5.02%) | 27 (5.49%) | 7 (3.63%) | 10 (5.24%) | |
| Hispanic | 41 (4.68%) | 20 (4.07%) | 13 (6.74%) | 8 (4.19%) | |
| Asian | 17 (1.94%) | 10 (2.03%) | 5 (2.59%) | 2 (1.05%) | |
| Middle Eastern | 10 (1.14%) | 9 (1.83%) | 1 (0.52%) | 0 | |
| Other | 3 (0.34%) | 3 (0.61%) | 0 | 0 | |
| Comorbidity | |||||
| Diabetes mellitus | 357 (40.75%) | 181 (36.79%) | 101 (52.33%) | 75 (39.27%) | 0.001 |
| Hypertension | 455 (51.94%) | 229 (46.54%) | 121 (62.69%) | 105 (54.97%) | <0.001 |
| Hyperlipidemia | 369 (42.12%) | 198 (40.24%) | 106 (54.92%) | 65 (34.03%) | <0.001 |
| History of ascites | 575 (65.71%) | 320 (65.17%) | 123 (63.73%) | 132 (69.11%) | 0.502 |
| History of paracentesis | 471 (53.89%) | 246 (50.20%) | 110 (56.99%) | 115 (60.21%) | 0.039 |
| BMI | 0.777 | ||||
| <30 | 477 (54.45%) | 266 (54.07%) | 104 (53.89%) | 107 (56.02%) | |
| 30–34.9 | 217 (24.77%) | 117 (23.78%) | 54 (27.98%) | 46 (24.08%) | |
| 35–39.9 | 117 (13.36%) | 68 (13.82%) | 22 (11.40%) | 27 (14.14%) | |
| >40 | 65 (7.42%) | 41 (8.33%) | 13 (6.74%) | 11 (5.76%) | |
| Length of hospital stay | 12 (9–20) | 13 (9–20) | 11 (8–20) | 9 (9–19) | 0.343 |
| ICU admission | 210 (23.97%) | 122 (24.80%) | 42 (21.76%) | 46 (24.08%) | 0.704 |
| Pack-years (SD) | 20.53 (20.21) | 18.47 (17.55) | 22.57 (22.37) | 0.104 | |
| Time from quitting to transplant date | 262.17 (169.27–384.67) |
For continuous variables age, MELD-NA, and pack-years, table shows mean (standard deviation); length of hospital stay and time from quitting to transplant were not normally distributed, so median (interquartile range) is shown. One-way ANOVA was used for variables showing means, and Kruskal–Wallis’ test was used for those showing medians. MELD-NA: Model of End-Stage Liver disease-—Sodium; BMI: body mass index; ICU: intensive care unit.
Table 2.
Etiology of cirrhosis.
| Total (N = 876) | Never Smoker (N = 492 56.16%) | Former Smoker (N = 193 22.03%) | Active Smoker (N = 191 21.8%) | p-Value | |
|---|---|---|---|---|---|
| Cause | <0.001 | ||||
| NASH | 186 (21.23%) | 120 (24.39%) | 46 (23.83%) | 20 (10.47%) | |
| ETOH | 181 (20.66%) | 80 (16.26%) | 38 (19.69%) | 63 (32.98%) | |
| Cholestatic | 92 (10.50%) | 72 (14.63%) | 14 (7.25%) | 6 (3.14%) | |
| Autoimmune | 27 (3.08%) | 19 (3.86%) | 2 (1.04%) | 6 (3.14%) | |
| Metabolic | 26 (2.97%) | 21 (4.27%) | 2 (1.04%) | 3 (1.57%) | |
| HCV | 28 (3.20%) | 12 (2.44%) | 7 (3.63%) | 9 (4.71%) | |
| HBV | 7 (0.80%) | 4 (0.81%) | 0 | 3 (1.57%) | |
| HCV + HCC | 67 (7.65%) | 23 (4.67%) | 27 (13.99%) | 17 (8.90%) | |
| HCV + ETOH | 20 (3.42%) | 7 (1.42%) | 6 (3.11%) | 17 (8.90%) | |
| HCC + ETOH | 28 (3.20%) | 8 (1.63%) | 12 (6.22%) | 8 (4.19%) | |
| HCC | 7 (0.80%) | 6 (1.22%) | 1 (0.52%) | 0 | |
| NASH + HCC | 39 (4.45%) | 24 (4.88%) | 13 (6.74%) | 2 (1.05%) | |
| Cholangiocarcinoma | 11 (1.26%) | 10 (2.03%) | 0 | 1 (0.52%) | |
| Cryptogenic | 34 (3.88%) | 19 (3.86%) | 8 (4.15%) | 7 (3.66%) | |
| Drug/Toxin | 11 (1.26%) | 5 (1.02%) | 2 (1.04%) | 4 (2.09%) | |
| Neuroendocrine | 4 (0.46%) | 1 (0.20%) | 3 (1.55%) | 0 | |
| Other | 95 (10.84%) | 59 (11.99%) | 12 (6.22%) | 24 (22.57%) |
NASH: non-alcoholic steatohepatitis; ETOH: alcohol, HCV: hepatitis C virus, HBV: hepatitis B virus, HCV + HCC: hepatitis C virus and hepatocellular carcinoma; HCV + ETOH: hepatitis C virus and alcohol; HCC + ETOH: hepatocellular carcinoma and alcohol; NASH + HCC: non-alcoholic steatohepatitis and hepatocellular carcinoma. Of note: hepatocellular carcinoma (HCC), cholangiocarcinoma, and neuroendocrine tumors were listed as causes of cirrhosis.
Table 3.
Immediate and short-term complications.
| Total | Never Smoker | Former Smoker | Active Smoker | p-Value | |
|---|---|---|---|---|---|
| Immediate complications | |||||
| Vascular (%) | 41 (4.7) | 24 (4.9) | 11 (5.7) | 6 (3.1) | 0.470 |
| Acute kidney injury (%) | 276 (31.5) | 165 (33.6) | 53 (27.5) | 58 (30.4) | 0.275 |
| Infection (%) | 198 (22.6) | 111 (22.6) | 44 (22.8) | 43 (22.5) | 0.998 |
| Arrythmia (%) | 79 (9.0) | 49 (10.0) | 19 (9.8) | 11 (5.8) | 0.204 |
| Cardiac arrest (%) | 28 (3.2) | 19 (3.9) | 5 (2.6) | 4 (2.1) | 0.428 |
| MI (%) | 8 (0.9) | 4 (0.8) | 2 (1.0) | 2 (1.1) | 0.801 |
| Respiratory (%) | 50 (5.7) | 23 (4.7) | 15 (7.8) | 12 (6.3) | 0.273 |
| CMV viremia (%) | 39 (4.5) | 22 (4.5) | 6 (3.1) | 11 (5.8) | 0.453 |
| Acute rejection (%) | 53 (6.1) | 32 (6.5) | 10 (5.2) | 11 (5.8) | 0.790 |
| Graft failure (%) | 13 (1.5) | 7 (1.4) | 2 (1.0) | 4 (2.1) | 0.683 |
| Seizure (%) | 31 (3.5) | 18 (3.7) | 3 (1.6) | 10 (5.2) | 0.145 |
| CVA (%) | 11 (1.3) | 8 (1.6) | 2 (1.0) | 1 (0.5) | 0.604 |
| Short-term complications at 6 months | |||||
| Infection (%) | 187 (21.9) | 107 (22.4) | 42 (22.1) | 38 (20.4) | 0.858 |
| Arrythmia (%) | 29 (3.4) | 15 (3.1) | 7 (3.7) | 7 (3.8) | 0.895 |
| Renal injury (%) | 192 (22.5) | 96 (20.1) | 46 (24.2) | 50 (26.9) | 0.137 |
| Acute rejection (%) | 115 (13.5) | 69 (14.4) | 19 (10) | 27 (14.5) | 0.284 |
| Biliary stricture (%) | 91 (10.7) | 51 (10.7) | 21 (11.1) | 19 (10.2) | 0.966 |
| CMV viremia (%) | 168 (19.7) | 94 (19.7) | 42 (22.1) | 32 (17.2) | 0.490 |
| Respiratory (%) | 53 (6.2) | 23 (4.8) | 18 (9.5) | 12 (6.5) | 0.078 |
| MI, N-stemi (%) | 11 (1.3) | 9 (1.9) | 2 (1.1) | 0 | 0.155 |
| CVA (%) | 6 (0.8) | 4 (1.0) | 1 (0.6) | 1 (0.6) | 0.840 |
| Seizure (%) | 16 (1.9) | 8 (1.7) | 4 (2.1) | 4 (2.2) | 0.888 |
| Vascular (%) | 48 (5.6) | 24 (5.0) | 14 (7.4) | 10 (5.4) | 0.480 |
| Cardiac arrest (%) | 5 (0.6) | 3 (0.6) | 2 (1.1) | 0 | 0.398 |
Fisher’s exact was used for variables with less than 20 total events. AKI: acute kidney injury; MI: myocardial infarction; CMV Viremia: cytomegalovirus viremia; CVA: cerebrovascular accident; MI: myocardial infarction; NSTEMI: non-ST-elevation myocardial infarction.
Table 4.
Patient and graft survival based on recipient smoking status.
| Smoking Status | No. of Patients | 1-Year Patient Survival% (95% CI) | 3-Year Patient Survival% (95% CI) | 5-Year Patient Survival% (95% CI) | p-Value by Log-Rank |
| Never smoker | 492 | 93.3 (90.7–95.2) | 88.1 (84.6–90.8) | 82.1 (77.3–85.9) | |
| Former smoker | 193 | 92.6 (87.9–95.6) | 85.0 (78.6–89.6) | 78.6 (70.9–84.5) | |
| Active smoker | 191 | 93.1 (88.5–96) | 85.9 (79.5–90.3) | 78.0 (70.2–84.1) | |
| p-Value | 0.25 | ||||
| Smoking Status | No. of Patients | 1-Year Graft Survival% (95% CI) | 3-Year Graft Survival% (95% CI) | 5-Year Graft Survival% (95% CI) | p-Value by Log-Rank |
| Never smoker | 492 | 99.0 (97.6–99.6) | 98.0 (96.3–99.0) | 98.0 (96.3–99.0) | |
| Former smoker | 193 | 99.0 (95.9–99.7) | 99.0 (95.9–99.7) | 99.0 (95.9–99.7) | |
| Active smoker | 191 | 96.3 (92.4–98.2) | 95.1 (90.7–97.4) | 94.1 (89.0–96.8) | |
| p-Value | 0.012 |
Table 5.
Cox’s univariate and multivariate models for overall mortality.
| Variable | Univariate HR (95% CI) | Univariate p-Value | Multivariate HR (95% CI) | Multivariate p-Value |
|---|---|---|---|---|
| Active Smoking at LT | 1.20 (0.84–1.73) | 0.321 | ||
| Former Smoker | 1.20 (0.84–1.73) | 0.320 | ||
| Age | 1.03 (1.01–1.05) | 0.001 | 1.03 (1.01–1.05) | 0.002 |
| Sex | ||||
| Female | 1.00 | |||
| Male | 1.05 (0.75–1.47) | 0.771 | ||
| MELD | 1.02 (1.00–1.04) | 0.117 | 1.01 (0.99–1.03) | 0.464 |
| Diabetes | 1.30 (0.95–1.79) | 0.106 | 1.06 (0.76–1.49) | 0.735 |
| Hypertension | 1.49 (1.07–2.07) | 0.018 | 1.21 (0.86–1.73) | 0.275 |
| Hyperlipidemia | 1.20 (0.87–1.65) | 0.262 | ||
| Ascites | 1.71 (1.18–2.49) | 0.005 | 1.34 (0.84–2.13) | 0.225 |
| Paracentesis | 1.60 (1.15–2.24) | 0.006 | 1.26 (0.83–1.90) | 0.279 |
| Alcoholic cirrhosis | 1.07 (0.74–1.55) | 0.709 | ||
| NASH | 1.20 (0.81–1.77) | 0.357 | ||
| HCV | 1.23 (0.79–1.90) | 0.359 | ||
| Combined etiology | 1.21 (0.80–1.83) | 0.359 | ||
| Admitted to the ICU | 1.76 (1.23–2.51) | 0.002 | 1.68 (1.13–2.50) | 0.010 |
| Donor status | 0.357 | |||
| Living | 1.00 | |||
| DBD | 1.39 (0.80–2.42) | 0.947 | ||
| DCD | 1.60 (0.82–3.13) | 0.169 | ||
| BMI | 0.129 | |||
| <30 | 1.00 | 1.00 | ||
| 30–34.9 | 0.92 (0.61–1.38) | 0.688 | 0.81 (0.53–1.23) | 0.324 |
| 35–39.9 | 0.94 (0.56–1.58) | 0.815 | 0.77 (0.45–1.31) | 0.331 |
| >40 | 1.84 (1.10–3.06) | 0.019 | 1.60 (0.94–2.74) | 0.084 |
| Pack-Years | 1.00 (0.99–1.02) | 0.455 | ||
| Time since quitting | 1.00 (1.00–1.00) | 0.372 |
MELD-NA: Model of End-Stage Liver disease—Sodium; NASH: non-alcoholic steatohepatitis, HCV: hepatitis C virus; DBD: donor after brain death; DCD: donor after circulatory death.
Table 6.
Causes of death in first year post LT and overall cause of death.
| Cause of Death in First Year | Total (N = 61) | Never Smoker (N = 33, 54%) | Former Smoker (N = 15, 25%) | Active Smoker (N = 13, 21%) | p-Value |
| Cardiovascular | 16 (26.23%) | 10 (30.3%) | 4 (26.67%) | 2 (15.38%) | |
| Graft failure | 3 (4.92%) | 0 | 0 | 3 (23.08%) | |
| Malignancy | 5 (8.20%) | 1 (3.03%) | 1 (6.67%) | 3 (23.08%) | |
| Multi-organ failure | 7 (11.48%) | 4 (12.12%) | 2 (13.33%) | 1 (7.69%) | |
| Neurological | 3 (4.92%) | 3 (9.09%) | 0 | 0 | |
| Respiratory | 11 (18.03%) | 5 (15.15%) | 3 (20%) | 3 (23.08%) | |
| Sepsis | 8 (13.11%) | 4 (12.12%) | 4 (26.67%) | 0 | |
| Other | 8 (13.11%) | 6 (18.18%) | 1 (6.67%) | 1 (7.69%) | |
| p-Value | 0.036 | ||||
| Overall Cause of Death | Total (n = 151) | Never Smoker (n = 73, 48%) | Former Smoker (n = 36, 24%) | Active Smoker (n = 39, 0.06%) | p-Value |
| Cardiovascular | 34 (22.5%) | 20 (27.4%) | 6 (15.4%) | 8 (20.5%) | |
| Graft failure | 5 (3.3%) | 1 (1.4%) | 0 | 4 (10.3%) | |
| Malignancy | 21 (13.9%) | 8 (11%) | 6 (15.4%) | 7 (18%) | |
| Multi-organ failure | 10 (6.6%) | 4 (5.5%) | 3 (7.7%) | 3 (7.7%) | |
| Neurological | 8 (5.3%) | 7 (9.6%) | 0 | 1 (2.6%) | |
| Respiratory | 29 (19.2%) | 13 (17.8%) | 9 (23.1%) | 7 (18%) | |
| Sepsis | 13 (8.6%) | 5 (6.9%) | 5 (12.8%) | 3 (7.7%) | |
| Other | 31 (20.5%) | 15 (20.6%) | 10 (25.6%) | 6 (15.4%) | |
| p-Value | 0.187 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Singh, L.; Bajwa, R.; Molina Garcia, S.; Imperio-Lagabon, K.; Sims, O.T.; Modaresi Esfeh, J. Effects of Tobacco Smoking on Post-Liver-Transplant Outcomes. Transplantology 2024, 5, 288-297. https://doi.org/10.3390/transplantology5040029
AMA Style
Singh L, Bajwa R, Molina Garcia S, Imperio-Lagabon K, Sims OT, Modaresi Esfeh J. Effects of Tobacco Smoking on Post-Liver-Transplant Outcomes. Transplantology. 2024; 5(4):288-297. https://doi.org/10.3390/transplantology5040029
Chicago/Turabian StyleSingh, Lovepreet, Ramanpreet Bajwa, Sofia Molina Garcia, Kristelle Imperio-Lagabon, Omar T. Sims, and Jamak Modaresi Esfeh. 2024. "Effects of Tobacco Smoking on Post-Liver-Transplant Outcomes" Transplantology 5, no. 4: 288-297. https://doi.org/10.3390/transplantology5040029
APA StyleSingh, L., Bajwa, R., Molina Garcia, S., Imperio-Lagabon, K., Sims, O. T., & Modaresi Esfeh, J. (2024). Effects of Tobacco Smoking on Post-Liver-Transplant Outcomes. Transplantology, 5(4), 288-297. https://doi.org/10.3390/transplantology5040029
