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NDT Advance Access originally published online on May 21, 2007
Nephrology Dialysis Transplantation 2007 22(10):3034-3039; doi:10.1093/ndt/gfm275
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Cigarette smoking and chronic allograft nephropathy

Nina Zitt1,2, Barbara Kollerits3, Ulrich Neyer2, Walter Mark4, Dorothea Heininger1, Gert Mayer1, Florian Kronenberg3 and Karl Lhotta1

1Clinical Division of Nephrology, Innsbruck Medical University, Innsbruck, 2Department of Nephrology and Dialysis, Academic Teaching Hospital Feldkirch, Feldkirch, 3Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology and 4Clinical Division of Transplant Surgery, Innsbruck Medical University, Innsbruck, Austria

Correspondence and offprint requests to: Dr Karl Lhotta, Clinical Division of Nephrology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria, Email: Karl.lhotta{at}uki.at.



   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. Smoking has been demonstrated to decrease patient and graft survival after kidney transplantation. Data on histological changes associated with smoking in renal allografts are lacking.

Methods. Smoking habits before and after renal transplantation were evaluated by questionnaire in 279 patients. A transplant biopsy was performed more than 1 year after transplantation in 76 of them. Histological changes were classified according to Banff 97 criteria. Linear regression analysis and proportional odds models for histological changes including the factors age, gender, diabetes, body mass index, donor age, time since transplantation, history of acute rejection and smoking status were calculated.

Results. Overall 22% of patients continued smoking after transplantation, with the proportion decreasing from 38% of those transplanted before 1990 to 13% of those transplanted after 2000. Serum creatinine was non-significantly higher in smokers (2.3 ± 2.7 mg/dl vs 1.8 ± 1.4 mg/dl, P = 0.21). A renal biopsy was performed in 24% of non-smokers and 39% of smokers (P = 0.02), and smokers were biopsied on average 1.5 years earlier. Among biopsied patients current smokers tended to suffer more often from diabetes (25.0% vs 13.5%, P = 0.33), to develop transplant failure (33.3% vs 21.2%, P = 0.25) or experience a cardiovascular event (29.2% vs 15.4%, P = 0.16). The frequency of acute rejection was comparable between smokers and non-smokers (25.0% vs 34.6%, P = 0.40). Glomerular sclerosis was associated with diabetes (P = 0.03). Severity of vascular intimal fibrous thickening was associated with current smoking (P = 0.004), whereas the degree of arteriolar hyalinosis (P < 0.001) and chronic/sclerosing nephropathy (P = 0.05) were associated with time since transplantation.

Conclusions. The number of patients who continue cigarette smoking after renal transplantation has decreased in recent years. The main allograft lesion associated with smoking is fibrous intimal thickening of small arteries.

Keywords: arteriolar hyalinosis; arteriopathy; cigarette smoking; chronic allograft nephropathy; kidney transplantation



   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Chronic allograft nephropathy has become the leading cause of late kidney transplant failure [1]. Its histological hallmarks are tubular atrophy, interstitial fibrosis, microvascular changes and glomerulosclerosis [2]. The prevalence and severity of chronic allograft pathology increase with time elapsed after transplantation [3,4]. Chronic allograft nephropathy is driven by a number of immunological and non-immunological factors such as pre-existing donor pathology, ischaemia reperfusion injury, acute tubular necrosis, acute rejection, hypertension or calcineurin inhibitor toxicity (reviewed in [5]).

Cigarette smoking has been identified as a progression factor in various kidney diseases, for example, diabetic nephropathy [6], hypertensive kidney disease [7], lupus nephritis [8], IgA nephropathy and autosomal dominant polycystic kidney disease [9]. Because progression factors of native kidney disease usually also aggravate chronic allograft nephropathy, we hypothesized that this is also the case for cigarette smoking. The present study was undertaken to investigate any potential impact of smoking on both function of and morphological changes in renal allografts.



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
All 272 prevalent transplant patients older than 18 years with a functioning kidney allograft and under regular control at the Nephrology Departments in Innsbruck and Feldkirch were included in the study. In addition, seven patients who had been included in the renal biopsy study (see further) but were back on dialysis were also enrolled. Patients under investigation had undergone kidney transplantation between 1974 and 2004. The investigation was performed during the summer of 2005. After informed consent was obtained, patients were asked to fill out a questionnaire about their smoking habits during a control visit at the out-patient department. They were asked in detail whether they were non-smokers, ex-smokers or current smokers. Smokers were asked the number of cigarettes per day and the years of smoking before and after transplantation. In addition, ex-smokers were asked when they quit smoking. Current laboratory parameters as well as age, height, weight, blood pressure, immunosuppressive medication and other therapies were determined from the patient chart. Patients were classified as having experienced an acute rejection episode if this was confirmed by transplant biopsy or if it was clinically diagnosed and followed by anti-rejection therapy.

Renal biopsies
Biopsies performed at least 1 year after transplantation were evaluated. All biopsies were done at the discretion of the treating physician. Relevant laboratory variables and immunosuppressive treatment at the time of biopsy were retrieved from patient charts. According to the Banff 97 working classification of renal allograft pathology, chronic/sclerosing allograft nephropathy was graded as mild, moderate or severe. In addition, quantitative criteria for vascular fibrous intimal thickening and arteriolar hyaline thickening were determined as described in the Banff 97 classification [2].

The study protocol was approved by the institutional review boards of both institutions.

Statistical analysis
Statistical analysis was performed with the Statistical Package for the Social Sciences (SPSS) for Windows 12.01. Univariate comparisons of continuous variables between various groups were performed using an unpaired t-test or the non-parametric Wilcoxon rank sum test for non-normally distributed variables. Dichotomized variables were compared using Pearson's {chi}2 test. Differences were considered significant at P < 0.05. Data are presented as mean ± SD and as 25th, 50th and 75th percentile for skewed variables where appropriate. Multiple adjusted risk estimates for glomerulosclerosis were calculated using linear regression analysis. Odds ratios derived from ordinal logistic regression analysis for arteriopathy, arteriolopathy and chronic sclerosing allograft nephropathy refer to the odds of being lower or higher on the outcome variable across the entire range of the outcome. The proportional odds assumption was tested.



   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Smoking habits of patients
In total 279 prevalent patients at the two participating units were included in this study. Overall 62 (22%) patients continued smoking after transplantation, 106 (38%) were ex-smokers (that means they quit prior to or at the time of transplantation), and 111 (40%) patients never smoked. The percentage of patients who continued smoking decreased with the time when transplantation was performed. Of those transplanted before 1990, 11 (38%) continued smoking, of those transplanted between 1990 and 1999, 36 (26%) continued, and the proportion of smokers further decreased to 13% (n = 15) in those transplanted after 2000. This decrease was paralleled by an increase in patients who quit smoking before or at the time of transplantation. The proportion of non-smokers remained constant over time. The number of pack years smoked before transplantation was identical for ex-smokers (18.6 ± 17.2) and current smokers (18.2 ± 17.0). Current smokers had smoked 4.0 ± 4.1 pack-years since renal transplantation.

The clinical and laboratory data of all 279 patients with further stratification for current smokers and non/ex-smokers are shown in Table 1. Current smokers were younger, had higher triglyceride levels and a lower body mass index. Smokers tended to have higher serum creatinine levels. This trend towards higher serum creatinine in smokers was also observed after stratification for gender and for transplantation before 1990, between 1990 and 2000, and after 2000, however, without being significant in any subgroup. The time elapsed since transplantation was longer in smokers. This was reflected in a shift in immunosuppression from azathioprine to mycophenolic acid and in a higher proportion of non-smokers treated with tacrolimus. Target trough levels within the first year were 150–200 ng/ml for cyclosporin A and 8–12 ng/ml for tacrolimus, and thereafter 80–120 ng/ml for cyclosporin A and 5–8 ng/ml for tacrolimus.


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  		Table 1. Clinical and laboratory data and immunosuppression of 279 transplant patients with further stratification into non/ex-smokers and smokers

 
A transplant biopsy was more often performed in smokers than in non-smokers (39% vs 24%, P = 0.02). Smokers with biopsy had smoked 3.1 ± 4.0 pack-years from transplantation until biopsy.

Evaluation of transplant biopsies
All patients with a renal biopsy were further stratified into non-smokers after transplantation and current smokers (Table 2). Smokers were biopsied on average 19 months earlier than non-smokers, however, this difference was not significant (P = 0.16). There was also a trend towards more cardiovascular events in smokers (29.2 vs 15.4%, P = 0.16), and they tended to have diabetes more frequently (25.0% vs 13.5%, P = 0.33). The proportion of patients who had experienced transplant failure by the end of 2006 was 33.3% in smokers and 21.2% in non-smokers (P = 0.25). The frequency of acute rejection episodes was not significantly different between non-smokers and smokers (34.6% vs 25.0%, P = 0.40). Exact information on arteriolar hyalinosis was available from 69 biopsies (48 non-smokers, 21 smokers), on arteriopathy from 43 biopsies (31 non-smokers, 12 smokers) and on chronic/sclerosing allograft nephropathy from 68 patients (46 non-smokers, 22 smokers). Severe fibrous intimal thickening of small arteries cv3 was more frequently found in smokers (25.0 vs 9.7%, P = 0.01). Of the smokers, none had cv0 but 25% had cv3. None of the smokers had cv0 compared with 52% of the non-smokers. The presence of severe arteriolar hyaline thickening ah3 and grade III chronic/sclerosing allograft nephropathy and the percentage of sclerotic glomeruli tended to be higher in smokers than in non-smokers, which, however, did not reach significance. A history of acute rejection was not associated with any of the investigated parameters of chronic allograft nephropathy.


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  		Table 2. Clinical and laboratory data and markers of chronic allograft nephropathy of 76 transplant patients with biopsy, with further stratification into non/ex-smokers and smokers

 
The results of linear regression analysis and proportional odds models for histological changes including the factors age, gender, diabetes, body mass index, donor age, time since transplantation, smoking status and acute rejection are shown in Table 3. Diabetes, current smoking and time since transplantation were identified as the most important factors associated with the severity of chronic allograft changes. Diabetes showed a strong correlation with the percentage of sclerotic glomeruli (P = 0.03). Current smoking was significantly associated with a more than 4-fold probability of a 1° increase in vascular fibrous intimal thickening (P = 0.004). The time between transplantation and biopsy was significantly associated with the severity of arteriolar hyaline thickening (P < 0.001) and chronic/sclerosing nephropathy (P = 0.05).


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  		Table 3. Association of different variables with glomerulosclerosis, arteriopathy, arteriolopathy and chronic sclerosing allograft nephropathy using linear regression analysis and ordinal logistic regression analysis (proportional odds models)

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
Our study underscores the view that cigarette smoking is a modifiable risk factor for chronic allograft nephropathy. We found that smokers are more likely to undergo a transplant biopsy later than 1 year after grafting than are non-smokers. Histological analysis revealed that smoking was associated with the severity of vascular fibrous intimal thickening. Smoking increased the probability of a 1° increase in the severity of arteriopathy by a factor > 4.

Only few studies have investigated the impact of smoking on patient and graft survival in renal transplant recipients, and none of them included data on allograft histology. In most reports smoking status was determined only prior to or at the time of transplantation and an exact quantification of post-transplant smoking is largely lacking. In the ALERT trial, smoking was a risk factor for graft loss in the unadjusted analysis (RR 2.33). In the adjusted analysis, it was a risk factor for the combined renal end points and death [10]. Sung reported a relative risk of 2.3 for graft loss in patients with pre-transplant smoking, of whom 90% continued smoking after transplantation [11]. Overall, smoking seems to more than double the risk for graft loss within 5–10 years. This is in line with the almost twice as high number of biopsied smokers with transplant failure compared with non-smokers. Having smoked more than 25 pack-years at time of transplantation was associated with a 30% increase in graft failure mainly due to patient death, more cardiovascular complications and invasive malignancies [12]. Another study identified smoking prior to transplantation as a risk factor for reduced patient survival [13]. In elderly patients smoking at the time of transplantation is associated with reduced patient and graft survival [14]. Interestingly, donor smoking also has a small but significant negative impact on both graft and recipient survival [15].

According to our data, the main target of smoking in a renal allograft seems to be the small arteries. Vascular fibrous intimal thickening was strongly associated with smoking after transplantation. This is even more remarkable, since the time between transplantation and biopsy in our patients was mostly in the range of 4–6 years and patients had smoked on average 3.1 pack-years during that period. This indicates that a relatively small dose of smoking may induce vascular changes rather rapidly in the renal allograft. The results after renal transplantation are in line with our observations in patients with primary glomerular disease, in whom we also found fibrointimal hyperplasia of small arteries in association with smoking [16]. The kidneys of these patients, however, were exposed to a far greater number of pack-years (on average 28) than were the grafts of the transplant patients. An additional effect of donor smoking cannot be excluded. Data from the United Network for Organ Sharing show a history of cigarette smoking in 42% of kidney donors [15]. Unfortunately, our study included no information on donor smoking habits. It seems unlikely, however, that kidneys of smokers were allocated only to smokers and vice versa, and we, therefore, believe that the observed difference was indeed caused by post-transplant smoking.

Hypertension is another prominent inducer of renal fibrointimal hyperplasia. Blood pressure levels were identical and in an acceptable range for smokers and non-smokers, which makes hypertension an unlikely cause of the vascular changes we observed. Levels of total cholesterol and triglycerides were comparable between smokers and non-smokers who had undergone biopsy. Thus, lipid levels also do not explain the differences in vascular damage found in our study population. In addition, diabetes did not affect small arteries, but was associated with the development of glomerulosclerosis.

Arteriolar hyaline thickening and overall chronic/sclerosing nephropathy, on the contrary, were mainly consequences of the time elapsed since transplantation, that means total exposure to calcineurin inhibitors, which is a well-described phenomenon [17]. We also observed at least a trend towards severe chronic/sclerosing allograft nephropathy in smokers. Overall it seems that continued smoking after transplantation is a risk factor for the development of chronic allograft changes. Because smokers were biopsied on average 1.5 years earlier than non-smokers, smoking may also have an accelerating effect on chronic allograft nephropathy.

Somewhat unexpected we did not find an influence of acute rejection on histological parameters of chronic allograft nephropathy. Such an association has been described mainly in protocol biopsy studies [3,18]. These biopsies were taken considerably earlier compared with the biopsies in our patients. Over time changes induced by acute rejection may become veiled through other lesions caused by calcineurin inhibitor toxicity, smoking or diabetes. Furthermore, our patients were biopsied because of some renal problem and represent a selected group, which differs substantially from a protocol biopsy cohort.

The mechanisms by which cigarette smoking causes renal, and especially renal vascular, damage are still speculative. Nicotine stimulates the sympathetic nervous system. It causes acute renal vasoconstriction, which seems to be irreversible in smokers [19,20,21]. The fact that sympathetic activity plays a role in the nephrotoxic effect of smoking is supported by the finding made by Odoni that in a renal ablation model in rats renal denervation precluded tissue injury induced by cigarette smoke condensate [22]. Our results, however, would suggest that the denervated renal transplant is by no means protected from smoking-induced injury. Recently, the focus of smoking-induced vasotoxicity has shifted from nicotine to oxidative stress (reviewed in [23]). Cigarette smoke itself not only contains large amounts of free radicals [24], but also induces free radical production in various ways. In addition, smoking is directly toxic to endothelial cells, has numerable proinflammatory effects, modifies the lipid profile and causes insulin resistance [23].

The main limitation of this study is that it included only prevalent patients. Many of our patients lived with a functioning transplant for years and they thus represent a somewhat positive selection. Given the fact that smoking increases graft loss and mortality, more smokers than non-smokers may have returned to dialysis or died, and therefore were not included in our study. Thus, the actual proportion of patients who continue smoking after transplantation is probably higher than calculated in our population and the deleterious consequences on graft function may in fact be underestimated. Another limitation is the recently reported relatively high inter-observer variation (low {kappa}-values) in renal allograft pathology [25]. However, it is known that the misclassification in the outcomes (e.g. histological grading) usually does not induce a bias of the estimates (odds ratios) but might increase the standard error of the estimates [26]. This would mean that the odds ratios are unbiased and correct on average and that the confidence interval might be even smaller if the outcome measurement would be more precisely. For example the observed adjusted odds ratio of smoking with a 4-fold probability of a 1° increase in vascular fibrous intimal thickening would still be 4.12, but the relatively wide 95% confidence interval of 1.42–11.94 would become more narrow.

In summary, both pre- and post-transplant smoking reduce patient and allograft survival following renal transplantation. Continued smoking after transplantation causes vascular fibrous intimal thickening in transplanted kidneys, and is therefore a modifiable risk factor for the development of chronic/sclerosing allograft nephropathy. Every effort should be made to convince and help smokers to stop tobacco consumption prior to kidney transplantation. It is encouraging to see that the proportion of patients who continue to smoke after transplantation is decreasing, as shown by a previous [12] and our study.



   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
The study was supported by grants from the ‘Austrian Nationalbank’ (Project 9331) and the Austrian Heart Fund to F. Kronenberg as well as by a grant from Hans Drexel and Herwig Wallmann to VIVIT (Vorarlberg Institute of Vascular Investigation and Treatment).

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Received for publication: 29. 1.07
Accepted in revised form: 13. 4.07


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