- Email: [email protected]
Smoking—Does It “Burn” the Kidney Transplant?
Smoking—Does It “Burn” the Kidney Transplant? Related Article, p. 907
I
n this issue of the American Journal of Kidney Diseases, Nogueira et al1 examine the association between cigarette smoking and transplant outcomes in recipients of a living donor kidney transplant. Smokers, categorized as previous smokers, current smokers, and combined previous and current smokers (referred to as ever smokers), were compared with recipients who never smoked (referred to as never smokers). Both transplant and patient survival in ever smokers were lower than in never smokers, whereas transplant loss was significantly higher in current smokers and marginally higher in previous smokers compared with never smokers. Both previous and current smokers were more likely to die compared with never smokers, although this difference reached statistical significance in only previous smokers. In contrast, death-censored transplant loss was not statistically different among the 3 groups, although there was a nonstatistical increase in death-censored transplant loss in current smokers and a trend toward worse death-censored transplant survival in ever smokers. The risk of acute rejection early after transplant was higher in ever smokers compared with never smokers, and this difference in acute rejection persisted when current and previous smokers were examined separately. During the past half-century, immunosuppressive agents have evolved and multiplied with a corresponding decrease in acute rejection rates. Unfortunately, long-term transplant survival has not improved significantly.2 Many factors contribute to diminished long-term transplant outcomes, including chronic allograft nephropathy, recurrence of original disease, hypertension, and viral infections; additionally, death with a functioning transplant can be considered a poor transplant outcome.3 Nogueira et al’s findings leave us wondering whether smoking also may have a role in decreasing transplant longevity, particularly when one includes death with a functioning transplant as an adverse transplant outcome. Supporting Nogueira et al’s findings are several other studies that have examined this issue. Most found that smoking is associated with decreased transplant survival,1,4-7 whereas 1 study found
no association.8 The explanation for this association is uncertain. One possibility was elaborated by Zitt et al,7 who reported that smoking was associated with increased fibrous intimal thickening of small arteries in the renal transplant, whereas several other investigators4,5 suggest that patients who smoke also might be less adherent to their medications. Cigarette smoking likely accelerates the progression of chronic kidney disease.9 Endothelial dysfunction caused by vascular production of reactive oxygen species,10 as well as transient increases in blood pressure accompanied by a decrease in both glomerular filtration rate and effective renal plasma flow,11 have been implicated. Most likely, these factors also affect transplanted kidneys. Additionally, similar to the findings of Nogueira et al,1 other researchers have found that patient survival is decreased in smokers, with cardiovascular disease (ischemic heart disease and stroke), and malignancies (mainly lung cancer) as the main causes of death.4,5 Nogueria et al1 also present a novel and provocative finding that may be more difficult to explain; specifically, the increased acute rejection rates in ever smokers in their study. Although more ever smokers received a steroid-free regimen, the investigators assert that this is not the cause of the higher rate of acute rejection based on results of multivariable analyses. If confirmed in other studies, this finding implies that smokers have increased short- and long-term risks; early for acute rejection as well as in the long run for death with a functioning transplant. If confirmed, we are left with vexing management questions. For example, should we intensify the early immunosuppressive regimen in smokers or should we perform management biopsies early to detect subclinical rejection? If we intensify their immunosuppressive regimens, we may pay the price later with more infectious Address correspondence to Michelle A. Josephson, MD, Department of Medicine, Section of Nephrology, University of Chicago, 5841 S Maryland Ave, MC5100, Chicago, IL 60637. E-mail: [email protected] © 2010 by the National Kidney Foundation, Inc. 0272-6386/10/5505-0005$36.00/0 doi:10.1053/j.ajkd.2010.01.001
American Journal of Kidney Diseases, Vol 55, No 5 (May), 2010: pp 817-819
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818
complications or even cancers (which smokers are more prone to). In addition, considering the evidence that steroid avoidance may be associated with early acute rejections,9 should we even offer steroid-free immunosuppressive regimens to smokers? Another interesting finding in Nogueira et al’s study is that the increased risks apply not only to current smokers, but also extend to previous smokers. If ever having smoked is a risk factor for acute rejection and death with a functioning transplant, does that mean smoking is not a modifiable risk factor? In the most blunt sense, can we question whether there is a point in counseling patients to quit? The answer is that numerous reasons remain to encourage and promote smoking cessation because many adverse outcomes beyond transplant survival are associated with current smoking status.12 Even Nogueira et al1 show that previous smokers fare better with respect to transplant loss than current smokers. In contrast to the findings of Nogueira et al,1 2 other studies have shown that smoking is a modifiable risk,5,6 with Kasiske and Klinger5 describing better outcomes in individuals who quit smoking at least 5 years before transplant compared with those who continued smoking. Perhaps because the average waiting time for a deceased donor kidney transplant is ⬃4 years in the United States,13 an integral part of the transplant evaluation should be to counsel patients to stop smoking. A last important question is whether smoking, including even a history of smoking, should be factored into organ allocation scheme proposals? Perhaps denying smokers transplants seems extreme, but this is an exclusion criterion currently applied at some centers.14 What about living donors? Given the findings of this study, do we have an obligation to inform potential living donors that their “gift of life” may be at increased risk of failure because of the recipient’s smoking habit? There is precedent for this approach, which is considered in other settings, such as human immunodeficiency virus (HIV)-positive recipients, high-risk recipients, and individuals with a high likelihood of recurrent glomerular disease.15-17 However, does smoking really constitute enough of a risk to the transplant to inform our potential living donors? This is difficult to answer. However, if yes, where should we draw the line? After all, many
Kadambi, Chon, and Josephson
factors are associated with increased long-term risk to transplant function, including obesity,18 nonadherent behavior,19 and even prior dialysis.20 Perhaps the most useful way to conceptualize the findings by Nogueira et al1 is that they provide more information to motivate our patients to quit smoking or, even better, never start. As the nephrology community focuses on educating about optimal care for patients with chronic kidney disease using evidence-based findings, our message must include the association of smoking and decreased kidney and kidney transplant survival. Perhaps with earlier intervention, larger numbers of our patients could quit smoking long before they need a kidney transplant. It even is possible that quitting could decrease the need for that transplant. Of course, we need to involve our pediatrician colleagues who are on the front line of smoking prevention. The study has several limitations and weaknesses, including retrospective design, reliance on patient report, limitation to living donor recipients, and variable time between assessment of smoking status and transplant. The study also lacks quantification of smoking amount and provides no information for exposure to secondhand smoke for recipients and smoking behavior of donors. The lack of quantification of the time since quitting in previous smokers and unknown amount of smoking recidivism is problematic. This last issue is key because individuals who reported that they were previous smokers could have restarted and been current smokers at the time of transplant, although for study purposes, they were counted as previous smokers. Reflecting these limitations, it is important to confirm the findings of Nogueira et al, with particular attention to differences between current and previous smokers, as well as the issue of increased rejection rates. If confirmed, the study provides yet more good reasons for our patients not to smoke, lest their kidney transplants go up in smoke! Pradeep V. Kadambi, MD W. James Chon, MD Michelle A. Josephson, MD University of Chicago Chicago, Illinois
Editorial
819
ACKNOWLEDGEMENTS Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Nogueira JM, Haririan A, Jacobs SC, Cooper M, Weir MR. Cigarette smoking, kidney function, and mortality after live donor kidney transplantation. Am J Kidney Dis. 2010; 55(5):907-915. 2. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004;4(3):378-383. 3. Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int. 2000;57(1):307313. 4. Cosio FG, Falkenhain ME, Pesavento TE, et al. Patient survival after renal transplantation: II The impact of smoking. Clin Transplant. 1999;13(4):336-341. 5. Kasiske BL, Klinger D. Cigarette smoking in renal transplant recipients. J Am Soc Nephrol. 2000;11(4):753759. 6. Sung RS, Althoen M, Howell TA, Ojo AO, Merion RM. Excess risk of renal allograft loss associated with cigarette smoking. Transplantation. 2001;71(12):17521757. 7. Zitt N, Kollerits B, Neyer U. et al. Cigarette smoking and chronic allograft nephropathy. Nephrol Dial Transplant. 2007;22(10):3034-3039. 8. Mohamed Ali AA, Abraham G, Mathew M. et al. Can serial eGFR, body mass index and smoking predict renal allograft survival in south Asian patients. Saudi J Kidney Dis Transpl. 2009;20(6):984-990. 9. Orth SR, Hallan SI. Smoking: a risk factor for progression of chronic kidney disease and for cardiovascular morbidity and mortality in renal patients—absence of evidence or evidence of absence? Clin J Am Soc Nephrol. 2008;3(1):226236.
10. Raij L, DeMaster EG, Jaimes EA. Cigarette smokeinduced endothelium dysfunction: role of superoxide anion. J Hypertens. 2001;19(5):891-897. 11. Halimi JM, Philippon C, Mimran A. Contrasting renal effects of nicotine in smokers and non-smokers. Nephrol Dial Transplant. 1998;13(4):940-944. 12. Gratziou C. Respiratory, cardiovascular and other physiological consequences of smoking cessation. Curr Med Res Opin. 2009;25(2):535-545. 13. US Renal Data System. Transplantation. In: USRDS 2009 Annual Data Report: Atlas of End Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2009;282-295. 14. Siddqi N, Hariharan S, Danovitch G. Evaluation and preparation of renal transplant candidates. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:169192. 15. Bright PD, Nutt J. The ethics surrounding HIV, kidney donation and patient confidentiality. J Med Ethics. 2009;35(4):270-271. 16. O’Hara JF Jr, Bramstedt K, Flechner S, Goldfarb D. Ethical issues surrounding high-risk kidney recipients: implications for the living donor. Prog Transplant. 2007;17(3):180182. 17. Spasovski G, Ivanovski N, Masin-Spasovska J, et al. Recurrent glomerulonephritis in living kidney transplantation. Prilozi. 2005;26(2):79-90. 18. Meier-Kriesche HU, Arndorfer JA, Kaplan B. The impact of body mass index on renal transplant outcomes: a significant independent risk factor for graft failure and patient death. Transplantation. 2002;73(1):70-74. 19. Butler JA, Roderick P, Mullee M, Mason JC, Peveler RC. Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. Transplantation. 2004;77(5):769-776. 20. Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: a paired donor kidney analysis. Transplantation. 2002;74(10):1377-1381.
I
n this issue of the American Journal of Kidney Diseases, Nogueira et al1 examine the association between cigarette smoking and transplant outcomes in recipients of a living donor kidney transplant. Smokers, categorized as previous smokers, current smokers, and combined previous and current smokers (referred to as ever smokers), were compared with recipients who never smoked (referred to as never smokers). Both transplant and patient survival in ever smokers were lower than in never smokers, whereas transplant loss was significantly higher in current smokers and marginally higher in previous smokers compared with never smokers. Both previous and current smokers were more likely to die compared with never smokers, although this difference reached statistical significance in only previous smokers. In contrast, death-censored transplant loss was not statistically different among the 3 groups, although there was a nonstatistical increase in death-censored transplant loss in current smokers and a trend toward worse death-censored transplant survival in ever smokers. The risk of acute rejection early after transplant was higher in ever smokers compared with never smokers, and this difference in acute rejection persisted when current and previous smokers were examined separately. During the past half-century, immunosuppressive agents have evolved and multiplied with a corresponding decrease in acute rejection rates. Unfortunately, long-term transplant survival has not improved significantly.2 Many factors contribute to diminished long-term transplant outcomes, including chronic allograft nephropathy, recurrence of original disease, hypertension, and viral infections; additionally, death with a functioning transplant can be considered a poor transplant outcome.3 Nogueira et al’s findings leave us wondering whether smoking also may have a role in decreasing transplant longevity, particularly when one includes death with a functioning transplant as an adverse transplant outcome. Supporting Nogueira et al’s findings are several other studies that have examined this issue. Most found that smoking is associated with decreased transplant survival,1,4-7 whereas 1 study found
no association.8 The explanation for this association is uncertain. One possibility was elaborated by Zitt et al,7 who reported that smoking was associated with increased fibrous intimal thickening of small arteries in the renal transplant, whereas several other investigators4,5 suggest that patients who smoke also might be less adherent to their medications. Cigarette smoking likely accelerates the progression of chronic kidney disease.9 Endothelial dysfunction caused by vascular production of reactive oxygen species,10 as well as transient increases in blood pressure accompanied by a decrease in both glomerular filtration rate and effective renal plasma flow,11 have been implicated. Most likely, these factors also affect transplanted kidneys. Additionally, similar to the findings of Nogueira et al,1 other researchers have found that patient survival is decreased in smokers, with cardiovascular disease (ischemic heart disease and stroke), and malignancies (mainly lung cancer) as the main causes of death.4,5 Nogueria et al1 also present a novel and provocative finding that may be more difficult to explain; specifically, the increased acute rejection rates in ever smokers in their study. Although more ever smokers received a steroid-free regimen, the investigators assert that this is not the cause of the higher rate of acute rejection based on results of multivariable analyses. If confirmed in other studies, this finding implies that smokers have increased short- and long-term risks; early for acute rejection as well as in the long run for death with a functioning transplant. If confirmed, we are left with vexing management questions. For example, should we intensify the early immunosuppressive regimen in smokers or should we perform management biopsies early to detect subclinical rejection? If we intensify their immunosuppressive regimens, we may pay the price later with more infectious Address correspondence to Michelle A. Josephson, MD, Department of Medicine, Section of Nephrology, University of Chicago, 5841 S Maryland Ave, MC5100, Chicago, IL 60637. E-mail: [email protected] © 2010 by the National Kidney Foundation, Inc. 0272-6386/10/5505-0005$36.00/0 doi:10.1053/j.ajkd.2010.01.001
American Journal of Kidney Diseases, Vol 55, No 5 (May), 2010: pp 817-819
817
818
complications or even cancers (which smokers are more prone to). In addition, considering the evidence that steroid avoidance may be associated with early acute rejections,9 should we even offer steroid-free immunosuppressive regimens to smokers? Another interesting finding in Nogueira et al’s study is that the increased risks apply not only to current smokers, but also extend to previous smokers. If ever having smoked is a risk factor for acute rejection and death with a functioning transplant, does that mean smoking is not a modifiable risk factor? In the most blunt sense, can we question whether there is a point in counseling patients to quit? The answer is that numerous reasons remain to encourage and promote smoking cessation because many adverse outcomes beyond transplant survival are associated with current smoking status.12 Even Nogueira et al1 show that previous smokers fare better with respect to transplant loss than current smokers. In contrast to the findings of Nogueira et al,1 2 other studies have shown that smoking is a modifiable risk,5,6 with Kasiske and Klinger5 describing better outcomes in individuals who quit smoking at least 5 years before transplant compared with those who continued smoking. Perhaps because the average waiting time for a deceased donor kidney transplant is ⬃4 years in the United States,13 an integral part of the transplant evaluation should be to counsel patients to stop smoking. A last important question is whether smoking, including even a history of smoking, should be factored into organ allocation scheme proposals? Perhaps denying smokers transplants seems extreme, but this is an exclusion criterion currently applied at some centers.14 What about living donors? Given the findings of this study, do we have an obligation to inform potential living donors that their “gift of life” may be at increased risk of failure because of the recipient’s smoking habit? There is precedent for this approach, which is considered in other settings, such as human immunodeficiency virus (HIV)-positive recipients, high-risk recipients, and individuals with a high likelihood of recurrent glomerular disease.15-17 However, does smoking really constitute enough of a risk to the transplant to inform our potential living donors? This is difficult to answer. However, if yes, where should we draw the line? After all, many
Kadambi, Chon, and Josephson
factors are associated with increased long-term risk to transplant function, including obesity,18 nonadherent behavior,19 and even prior dialysis.20 Perhaps the most useful way to conceptualize the findings by Nogueira et al1 is that they provide more information to motivate our patients to quit smoking or, even better, never start. As the nephrology community focuses on educating about optimal care for patients with chronic kidney disease using evidence-based findings, our message must include the association of smoking and decreased kidney and kidney transplant survival. Perhaps with earlier intervention, larger numbers of our patients could quit smoking long before they need a kidney transplant. It even is possible that quitting could decrease the need for that transplant. Of course, we need to involve our pediatrician colleagues who are on the front line of smoking prevention. The study has several limitations and weaknesses, including retrospective design, reliance on patient report, limitation to living donor recipients, and variable time between assessment of smoking status and transplant. The study also lacks quantification of smoking amount and provides no information for exposure to secondhand smoke for recipients and smoking behavior of donors. The lack of quantification of the time since quitting in previous smokers and unknown amount of smoking recidivism is problematic. This last issue is key because individuals who reported that they were previous smokers could have restarted and been current smokers at the time of transplant, although for study purposes, they were counted as previous smokers. Reflecting these limitations, it is important to confirm the findings of Nogueira et al, with particular attention to differences between current and previous smokers, as well as the issue of increased rejection rates. If confirmed, the study provides yet more good reasons for our patients not to smoke, lest their kidney transplants go up in smoke! Pradeep V. Kadambi, MD W. James Chon, MD Michelle A. Josephson, MD University of Chicago Chicago, Illinois
Editorial
819
ACKNOWLEDGEMENTS Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Nogueira JM, Haririan A, Jacobs SC, Cooper M, Weir MR. Cigarette smoking, kidney function, and mortality after live donor kidney transplantation. Am J Kidney Dis. 2010; 55(5):907-915. 2. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004;4(3):378-383. 3. Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int. 2000;57(1):307313. 4. Cosio FG, Falkenhain ME, Pesavento TE, et al. Patient survival after renal transplantation: II The impact of smoking. Clin Transplant. 1999;13(4):336-341. 5. Kasiske BL, Klinger D. Cigarette smoking in renal transplant recipients. J Am Soc Nephrol. 2000;11(4):753759. 6. Sung RS, Althoen M, Howell TA, Ojo AO, Merion RM. Excess risk of renal allograft loss associated with cigarette smoking. Transplantation. 2001;71(12):17521757. 7. Zitt N, Kollerits B, Neyer U. et al. Cigarette smoking and chronic allograft nephropathy. Nephrol Dial Transplant. 2007;22(10):3034-3039. 8. Mohamed Ali AA, Abraham G, Mathew M. et al. Can serial eGFR, body mass index and smoking predict renal allograft survival in south Asian patients. Saudi J Kidney Dis Transpl. 2009;20(6):984-990. 9. Orth SR, Hallan SI. Smoking: a risk factor for progression of chronic kidney disease and for cardiovascular morbidity and mortality in renal patients—absence of evidence or evidence of absence? Clin J Am Soc Nephrol. 2008;3(1):226236.
10. Raij L, DeMaster EG, Jaimes EA. Cigarette smokeinduced endothelium dysfunction: role of superoxide anion. J Hypertens. 2001;19(5):891-897. 11. Halimi JM, Philippon C, Mimran A. Contrasting renal effects of nicotine in smokers and non-smokers. Nephrol Dial Transplant. 1998;13(4):940-944. 12. Gratziou C. Respiratory, cardiovascular and other physiological consequences of smoking cessation. Curr Med Res Opin. 2009;25(2):535-545. 13. US Renal Data System. Transplantation. In: USRDS 2009 Annual Data Report: Atlas of End Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2009;282-295. 14. Siddqi N, Hariharan S, Danovitch G. Evaluation and preparation of renal transplant candidates. In: Danovitch GM, ed. Handbook of Kidney Transplantation. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:169192. 15. Bright PD, Nutt J. The ethics surrounding HIV, kidney donation and patient confidentiality. J Med Ethics. 2009;35(4):270-271. 16. O’Hara JF Jr, Bramstedt K, Flechner S, Goldfarb D. Ethical issues surrounding high-risk kidney recipients: implications for the living donor. Prog Transplant. 2007;17(3):180182. 17. Spasovski G, Ivanovski N, Masin-Spasovska J, et al. Recurrent glomerulonephritis in living kidney transplantation. Prilozi. 2005;26(2):79-90. 18. Meier-Kriesche HU, Arndorfer JA, Kaplan B. The impact of body mass index on renal transplant outcomes: a significant independent risk factor for graft failure and patient death. Transplantation. 2002;73(1):70-74. 19. Butler JA, Roderick P, Mullee M, Mason JC, Peveler RC. Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. Transplantation. 2004;77(5):769-776. 20. Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: a paired donor kidney analysis. Transplantation. 2002;74(10):1377-1381.