Objectives: How smoking history affects kidney allograft outcomes is unclear in the contemporary era of immunosuppression. Here, we examined a broad range of outcomes after kidney transplant, stratifying patients by smoking status documented at time of transplant, in a well-characterized clinical cohort.
Materials and Methods: This retrospective single-center analysis (2007-2015) included 744 kidney allograft recipients who had documentation of smoking exposure (median follow-up 1327 days posttransplant). Biochemistry, clinical outcome, histopathology, and patient and graft survival data were extracted.
Results: Overall, 264 kidney allograft recipients (35.5%) had smoking exposure (current or ex-smoker) documented at time of transplant; these were more likely to be white male patients. Patients with versus without smoking exposure had higher rates of posttransplant cancer (10.2% vs 4.6%; P = .003) and cardiac events (11.7% vs 4.6%; P < .001) but lower risk of requiring hospitalization with septicemia (5.7% vs 10.0%; P = .027). Patients with versus without smoking exposure had increased rates of 1-year rejection (14.8% vs 10.4%; P = .052), thrombotic microangiopathy (4.2% vs 1.0%; P = .006), recurrent disease (4.2% vs 1.0%; P = .006), and a trend toward more acute tubular injury (16.7% vs 12.3%; P = .063). Overall, smoking exposure was associated with increased risk of death (9.5% vs 4.6%; P = .008), death-censored graft failure (13.6% vs 7.9%; P = .010), and overall graft failure (21.6% vs 11.7%; P < .001). In a Cox regression model of baseline variables, smoking exposure was independently associated with overall graft failure (hazard ratio 1.68; 95% confidence interval, 1.21-2.32; P = .002).
Conclusions: Our results confirm that smoking exposure at time of kidney transplant remains associated with adverse outcomes in the contemporary era. These results reinforce the need to develop robust smoking cessation strategies to encourage kidney transplant candidates to stop smoking to improve posttransplant outcomes.
Key words : Cancer, Graft failure, Kidney transplant, Mortality, Rejection
Smoking is recognized as a major global public health burden and a significant contributor to mortality. Despite public health initiatives, it is estimated that globally there will be an estimated 1.1 billion tobacco smokers by 2025.1 In the United Kingdom, nearly 1 in 5 adults (19%) aged 16 years and over were classified as smokers in 2013, and this rate has remained relatively unchanged over the past few years.2 Smoking is not currently considered a contraindication for potential kidney transplant recipients, although guidelines “recommend that patients should be strongly encouraged to stop smoking before and after transplantation.”3
This recommendation is supported by a recent systematic review highlighting inferior kidney allograft recipient outcomes for smokers after kidney transplant.4 However, although previous studies on this topic have been informative, it is difficult to translate much of this data to the contemporary setting. For example, a recent systematic review was published in 2011, but its most contemporary study reported analyses from a historical cohort between 2000 and 2006.5 Interpretation of clinical outcomes from a different era of immunosuppression and clinical practice to the modern setting is fraught with difficulty for a number of reasons. Tacrolimus has largely replaced cyclosporine as the calcineurin inhibitor of choice since publication of the SYMPHONY study in 2007,6 patient and kidney allograft outcomes have generally improved with time over the past decade,7 and data from the United States (where most of these studies were originally conducted) may not be generalizable due to differences in practices that influence outcomes.8
It therefore is speculative whether kidney allograft recipients with smoking exposure still retain inferior clinical outcomes in contemporary practice. This is important for clinical risk stratification posttransplant and to support an informed process of patient counseling. Indeed, exploring the role of smoking in potential kidney transplant recipients is part of the scope of work for planned Kidney Disease Improving Global Outcomes (KDIGO) guidelines.9 To date, no corroborative study has been conducted to replicate these findings in the contemporary era of immunosuppression. The aim of this study was to analyze data at a large single center regarding kidney allograft recipient outcomes posttransplant for patients with versus without history of smoking exposure. Our hypothesis was that kidney allograft recipients with smoking exposure would continue to retain inferior patient and graft survival after kidney transplant in the contemporary era.
Materials and Methods
This retrospective analyses involved data linkage between a number of electronic patient records to create a comprehensive database of all consecutive kidney transplants performed at a single center between January 2007 and January 2015. This comprehensive database of a well-characterized clinical cohort was utilized for all subsequent analyses. Survival analysis was censored to event or September 2015 (whichever occurred first). We excluded multiple organ transplant recipients, and our cohort only included kidney allograft recipients aged 18 years and older. We excluded kidney allograft recipients from analysis if they had no documentation regarding smoking status. Overall, 1142 patients received kidney transplants over this time period; 398 had no documentation regarding smoking status at time of transplant, leaving a cohort of 744 kidney allograft recipients for analysis.
Data were initially electronically extracted by the Department of Health Informatics for every consecutive kidney allograft recipient undergoing transplant within our study dates. Electronically extracted data included the following variables: age, sex, ethnicity (white, black, South Asian, other), smoking status (ever or never), donor type (living vs deceased), number of previous transplants, cause of end-stage renal disease, viral serology, socioeconomic deprivation (based on Index of Multiple Deprivation), clinical parameters (weight, body mass index), and biochemical parameters (creatinine, albumin-to-creatinine ratio, liver function tests, full blood count). Biopsy data were manually extracted and classified in accordance to the latest Banff criteria.10 Electronic patient records were then manually linked to admission health records to provide data related to posttransplant outcomes (including cardiovascular events, strokes, septicemia, and cancer) and surgical complications. Patient and graft survival data, based on date of death or graft failure, were acquired from the National Health Service Blood and Transplant and linked to our data.
During the time period encompassing data collection, our immunosuppression protocol remained static. All patients received tacrolimus as their primary immuno-suppressant, with the aim to achieve a target 12-hour trough level of 5 to 8 ng/L. Mycophenolate mofetil was commenced at a dose of 1 g twice daily. Every recipient received an intraoperative dose of intravenous methylprednisolone at the time of transplant (500 mg), which was followed by 10 mg twice daily prednisolone that was subsequently weaned to a maintenance low dose of 5 mg once daily by 3 months posttransplant in the absence of any rejection. Episodes of acute cellular rejection were treated with a bolus of corticosteroids, with T-cell depletion therapy for steroid-resistant rejection. Antibody-mediated rejection was treated with antibody removal by plasmapheresis with or without intravenous immunoglobulin. Standard antibiotic prophylaxis after kidney transplant included nystatin (3 months), cotrimoxazole (12 months), valganciclovir (3 months if deemed high risk, that is, cytomegalovirus-positive donor/cytomegalovirus-negative recipient), and isoniazid/pyridoxine (12 months if high risk of tuberculosis, that is, having previous tuberculosis or being ethnic minority).
Univariate comparisons of transplant outcomes comparing smoking versus nonsmoking recipients were done with chi-square tests for categorical data, t tests for parametric continuous data, and Wilcoxon tests for nonparametric continuous data. All-cause graft failure was taken as the time from transplant to graft nephrectomy or return to dialysis, whichever was earlier, or death of the patient with a functioning graft. Survival of the patient was defined as the time from transplant until death. Follow-up analysis of the entire transplant study cohort included all data up to September 2015. Cox proportional hazard regression models were fitted by a stepwise variable selection method (command “stcox” in STATA; StataCorp LP, College Station, TX, USA) to analyze the combined effects of baseline factors on overall graft failure, reported as hazard ratios (HR). The proportionality assumption was checked for each variable and the whole model; for the main analysis, the proportionality assumption was true for all variables. Variables included in the model were age, sex, ethnicity, donor type (living vs deceased), repeat transplant, socioeconomic deprivation, HLA mismatch, ABO incompatibility, wait list time, cause of end-stage kidney disease (including diabetes, hypertension, glomerulonephritis, polycystic kidney disease, other), and smoking status. Kaplan-Meier curves were used to show patient and graft survival. All tests were two-sided, and P < .05 was judged to be significant.
This study received institutional approval and was registered as an audit with University Hospitals Birmingham National Health Service Trust (audit identifier; CARMS-12578). The corresponding author had full access to all data.
In total, data were extracted and linked for 740 patients who received a kidney transplant during the study period, with median follow-up for the study cohort of 1327 days (interquartile range, 649-2203 d). Overall, 264 kidney allograft recipients (35.5%) had documented smoking exposure (active or ex-smoking). A comparison of baseline characteristics is shown in Table 1, highlighting the greater proportion of kidney allograft recipients with smoking exposure who were male and/or white.
Table 2 highlights a number of comparisons for kidney allograft recipients with versus without smoking exposure for graft-related outcomes. Histopathologically, although rates of biopsies were similar between groups, kidney allograft biopsies from patients with smoking exposure were more likely to show rejection within the first year, thrombotic microangiopathy, recurrent disease, and borderline trend toward more acute tubular injury.
Kidney allograft function, determined from estimated glomerular filtration rate or urine albumin-to-creatinine ratio, was not different between groups at 1 or 3 years posttransplant in surviving kidney allografts. Anti-HLA antibodies were only checked in the context of transplant dysfunction (acute or gradual decline in kidney allograft function). From available results (73.6% of patients), no significant differences were detected regarding detection of anti-HLA antibody (both donor-specific and non-specific) when comparing kidney allograft recipients with versus without smoking exposure (25.0% vs 28.5%; P = .497).
Unadjusted Kaplan-Meier survival analysis showed that kidney allograft recipients with versus without smoking exposure had increased risk of both death-censored and overall graft losses (see Table 2 and Figure 1).
Risk for posttransplant complications is shown in Table 3. Kidney allograft recipients with versus without smoking exposure had increased rates of developing vascular thrombosis, cardiac events, peripheral vascular disease, and cancer. However, they were less likely to be admitted to hospital secondary to septicemia.
When we focused on posttransplant cancer, there were no differences in time to cancer for kidney allograft recipients with versus without smoking exposure. The mean number of days to developing posttransplant cancer (any type of cancer) in patients with smoking exposure was 1014 ± 735 days compared with 961 ± 979 days for those who had never smoked (P = .859). There was no significant difference in types of cancer between kidney allograft recipients with versus without smoking exposure. In the Cox regression model, smoking exposure was shown to be an independent risk factor for development of posttransplant cancer (HR 2.24; 95% confidence interval [CI], 1.02-4.93; P = .045).
Kidney allograft recipients with versus without history of smoking exposure had increased risk of death posttransplant (9.5% vs 4.6%; P = .008) (see Table 3 and Figure 1). Death from cancer, cardiovascular events, and cerebrovascular accident was more common among kidney allograft recipients with versus without smoking exposure respectively (16.7% vs 4.8% for cancer, 29.2% vs 19.0% for cardiovascular events, and 4.2% vs 0.0% for cerebrovascular accident), but death from infection was less common (12.5% vs 23.8%).
After adjustment for baseline variables in our Cox proportional hazards regression model, smoking exposure at time of kidney transplant was shown to be a significant risk factor for death-censored graft loss (HR 1.58, 95% CI, 1.01-2.49; P = .048). When we repeated the analysis for overall graft survival, the independent effect of smoking status remained statistically significant on adjusted models (see Table 4).
This study, a contemporary analysis of the effects of smoking exposure on outcomes after kidney transplant, suggests inferior clinical and allograft outcomes for kidney allograft recipients with active or previous smoking history at time of transplant. Our findings suggest that smoking exposure continues to have adverse outcomes for kidney allograft recipients in the present day and reinforces efforts to encourage patients to either quit or remain smoking-free after kidney transplant. This study should guide the current development of KDIGO guidelines looking at potential kidney transplant candidates and provide some up-to-date data of the effects of smoking exposure in kidney allograft recipients.
Previous literature has consistently shown adverse outcomes for smokers after kidney transplant. One of the largest population-based cohort studies was conducted by Hurst and colleagues, a retrospective analysis of the US Renal Data Systems data, using institutional claim forms reported to Medicare between January 2001 and December 2006.5 Smoking status was identified by ICD-9 diagnosis codes for tobacco use disorder (305.1X) and/or “toxic effect of other substances, tobacco” (989.84). In their analysis of 41 705 adult Medicare primary kidney allograft recipients, 9.9% of patients (n = 4117) were classified as prior smokers and 4.6% (n = 11715) were new claims for smoking after kidney transplant among previous never-smokers. Compared with never-smokers, incident smoking after kidney transplant was associated with increased risk of death-censored graft loss (adjusted HR 1.46; 95% CI, 1.19-1.79; P < .001) and death (adjusted HR 2.32; 95% CI, 1.98-2.72; P < .001). After further adjustments in sensitivity analysis (excluding recipients with emphysema and drug or alcohol problems), the independent risk of both death-censored graft loss and death persisted. Limitations of this analysis are the use of administrative data for data extraction, which is a recognized flaw with any analysis of this type. Although obtaining larger numbers for analysis is valuable, the lack of more granular data means that analyses of posttransplant outcomes, graft function, and histopathology are absent. Additional caveats to this study analyses are the restriction to Medicare patients, meaning study results may not be translatable to other kidney transplant cohorts. Similar to our study, Hurst and colleagues were unable to quantify the smoking exposure; therefore, no dose-dependent effects to correlate smoking with adverse clinical outcomes were possible. However, the major limitation is the time frame for this analysis (2001-2006), which predates significant changes to immunosuppression. Therefore, it is unclear whether the observations from this registry analysis are relevant to the contemporary setting. No other analyses have been published within the past 5 years; specifically, no study has looked at a cohort of patients beyond 2007 since publication of the SYMPHONY study. Therefore, our findings are important as they reinforce the adverse outcomes associated with smoking exposure for kidney allograft recipients in the setting of current immunosuppression.
Although the negative effects of smoking exposure on mortality are plausible, there is no clear explanation for the underlying pathophysiology of how smoking exposure is directly detrimental to the kidney allograft. Nogueira and colleagues reported smoking at time of transplant evaluation to be associated with worse first-year rejection-free survival (adjusted HR 1.46; 95% CI, 1.05-2.03; P = .003), and patients with smoking exposure had worse allograft function (based on estimated glomerular filtration rate).11 This was similar to our findings, although we did not identify any difference in kidney allograft function after transplant. Mechanistically, Wan and colleagues have demonstrated smoking exposure suppresses expression and activity of indoleamine 2,3-dihydrogenase, which is an enzyme expressed on antigen-presenting cells.12 Indoleamine 2,3-dihydrogenase-mediated tryptophan catabolism plays an important role in immune tolerance due to its role in inducing and expanding regulatory T cells.13 However, all death-censored kidney allograft losses may not be directly linked to increased risk of rejection within the first year as we identified an increased risk of a number of histopathologic abnormalities for kidney allograft recipients with smoking exposure. This can be understood in the context of well-documented pathophysiologic effects of smoking exposure on the kidney, which include vasoconstriction, endothelial dysfunction, and hypoxic damage.14 Therefore, it is likely that the detrimental effects of smoking on kidney allografts are multifactorial in nature.
Although many of our results were predictable, we were surprised to observe less risk of hospital-ization with septicemia for kidney allograft recipients with known smoking exposure. This also mirrored the lower percentage of deaths secondary to infection for patients with versus without smoking exposure. The general literature has consistently shown that smoking increases the risk of infection, by blunting the immune system and compromising the ability to mount appropriate immune and inflammatory responses.15 A review of the literature also suggests a dose-dependent effect of smoking exposure and risk of infection.16 It appears paradoxical for the cancer and infection-related outcomes to be diametrically opposed for kidney allograft recipients with versus without smoking exposure, considering both are manifestations of over-immunosuppression-related complications. Although pharmacologic therapy can act as prophylaxis for certain infections after kidney transplant, it is unclear why kidney allograft recipients with smoking exposure would benefit more from such prophylaxis. Further details regarding smoking exposure, especially a dose-dependent calculation and separation of active versus ex-smokers, are important to tease out more granular data.
On the basis that smoking exposure is detrimental to outcomes after kidney transplant, it becomes imperative for the transplant community to devise strategies to help potential and current kidney allograft recipients to both stop smoking and remain off smoking. This is important as approximately one-third of kidney allograft recipients are smokers, with 90% of patients continuing to smoke postoperatively.4 Although the overwhelming benefits of smoking cessation are well documented in the general population, there are no data to support similar efficacy of smoking cessation after kidney transplant. Before transplant, Kasiske and Klinger reported the benefits of having quit smoking 5 years before transplant, with a reduction in overall graft failure (adjusted relative risk of 0.66; 95% CI, 0.52-0.85; P < 0.001) primarily driven by less deaths.17 Further support of the benefits of smoking cessation comes from Opelz and Dohler, who explored data from the Collaborative Transplant Study and observed that patients who stopped smoking before kidney transplant only had a modest increased risk of all-cause graft failure (HR 1.1; 95% CI, 1.0-1.1; P < .001) or death (HR 1.1; 95% CI, 1.0-1.2; P < .001) compared with nonsmokers but no difference in death-censored graft loss.18 This is in contrast to the dramatically higher risks of death and graft failure among kidney allograft recipients who continued to smoke.18 In the general population, Cahill and colleagues demon-strated in a recent systematic review and network meta-analysis that pharmacologic interventions improve the chances of quitting smoking, with none of the treatments displaying an excess incidence of adverse events.19
A major recent development concerning inter-ventions to stop smoking is the use of e-cigarettes. Rahman and colleagues undertook a systematic review and meta-analysis of the efficacy of e-cigarettes in the general population (6 studies incorporating 7551 participants).20 They concluded that the use of e-cigarettes was associated with smoking cessation and reduction but reflected critically on the quality and heterogeneity of the included studies. Perhaps surprisingly, in the context of lack of robustness from available data, Public Health England reported overwhelmingly in favor of the use of e-cigarettes, citing that they were 95% less harmful than smoking.21 However, this report has been criticized for the lack of critical appraisal of the empirical evidence,22,23 and recent systematic reviews and meta-analyses of real-world clinical scenarios are less supportive of the effectiveness of e-cigarettes.24 We currently have no data on the use of e-cigarettes in the setting of solid-organ transplant, and further clarification is warranted before robust recom-mendations can be made for the use of safe and effective smoking cessation strategies.
Overall, further studies are warranted to assess the benefits of smoking cessation strategies posttransplant but, in its absence, it would seem rationale to encourage smoking cessation for kidney allograft recipients.
There are several limitations of this analysis that must be appreciated in the interpretation of our results. There are likely to be numerous confounders that have an impact on mortality after kidney transplant that we were unable to factor in. Missing data (and misclassification bias) also have implications on the analyses performed; these represent an inherent bias in epidemiologic analyses. A significant pro-portion of kidney allograft recipients had no documentation regarding smoking exposure but, on the assumption that they were random in nature, underwent list-wise deletion from further analysis. Our major limitation was the inability to classify whether smoking exposure was active or what was the overall smoking pack-year history, as this documentation was retrospectively extracted from administrative databases. Having a greater under-standing of this is important to examine the benefits of smoking cessation on posttransplant outcomes and to determine the dose-dependent correlation of smoking exposure with adverse clinical outcomes.
To conclude, this is the first study corroborating dated literature to report a strong link between smoking exposure among kidney allograft recipients and adverse posttransplant outcomes, including increased risk of cancer, cardiac events, rejection within the first year, kidney allograft loss, and death. In a Cox regression model, smoking exposure was found to be an independent risk factor for overall graft loss after kidney transplant. These study findings provide contemporary evidence in the development of the current KDIGO guidelines for the assessment of potential kidney transplant recipients, providing evidence for the detrimental effects of smoking exposure on kidney transplant outcomes. Further investigation is warranted to determine the dose-dependent effects of smoking on posttransplant outcomes and the benefits of smoking cessation. Efforts to support kidney transplant candidates and recipients from smoking should be encouraged, but further work is required to determine the optimal strategy to help smokers quit. However, by encouraging smoking cessation, we will likely be successful in improving their posttransplant outcomes, and patients should be appropriately counselled to that effect.
Volume : 16
Issue : 3
Pages : 274 - 281
DOI : 10.6002/ect.2016.0310
From the 1University of Birmingham, the 2Department of Health Informatics,
Queen Elizabeth Hospital, the 3School of Immunology and Inflammation, University
of Birmingham, and the 4Department of Nephrology and Transplantation, Queen
Elizabeth Hospital, Birmingham, United Kingdom
Acknowledgements: We are grateful for the funding in support of the BMedSci intercalated degrees for H. Gillott (from Arthur Thomson Trust) and F. Jackson Spence and S. Tahir (from Kidney Research UK). The authors have no conflicts of interest to disclose. This work was presented as a Free Communication at the American Transplant Congress in Boston, Massachusetts, USA (June 2016). FJS, JN, and AS designed the study; FJS, HG, ST, JM, and FE performed data extraction; FJS, JM, and FE performed data analyses; FJS, JN, and AS performed data interpretation; FJS and AS wrote the original draft; all authors reviewed the manuscript.
Corresponding author: Adnan Sharif, Department of Nephrology and Transplantation, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2WB, UK
Phone: +44 121 371 5861
Table 1. Comparison of Baseline Demographics in Kidney Allograft Recipients on the Basis of Smoking Status
Table 2. Difference in Graft-Related Outcomes Comparing Kidney Allograft Recipients With Versus Without Smoking Exposure
Table 3. Difference in Posttransplant Complications Comparing Kidney Allograft Recipients With Versus Without Smoking Exposure
Table 4. Cox Proportional Hazards Modeling of Overall Graft Loss in Kidney Allograft Recipients Using Baseline Variables
Figure 1. Unadjusted Kaplan-Meier Plots of Mortality (A), Death-Censored Graft Loss (B), and Overall Graft Loss (C) Comparing Kidney Allograft Recipients With Versus Without Smoking Exposure