e72
www.transplantjournal.com
most studies reported, obesity was generally assessed by BMI, which reflects both increased visceral and abdominal fat and/or muscle mass. More recent studies in the dialysis population and in kidney transplant recipients showed a survival benefit in patients with higher BMI who have higher muscle mass (5, 7). In a prospective cohort study of 993 kidney transplant recipients, higher BMI was associated with lower mortality after adjustment for waist circumference (0.48 [0.34, 0.69], PG0.001), whereas higher waist circumference was strongly associated with higher mortality after adjustment for BMI (2.18 [1.55Y3.08], PG0.001). The associations of waist circumference with mortality remained significant on multivariate analyses (7). Hence, assessing patient and graft outcomes in obese transplant recipients based on BMI alone may be misleading. We agree with Heinbokel et al. that waist-to-hip ratio may more adequately represent the immunologically active visceral adipose tissue. Similar to the general population, studies in the dialysis population and in kidney transplant recipients suggest that obesity as assessed by waist circumference or waistto-hip ratio is a stronger independent predictor of cardiovascular disease and cardiovascular death than BMI (7Y9). Future studies in obese transplant recipients should incorporate waist-to-hip ratio or waist circumference. Whether increased visceral and/or abdominal adiposity is associated with heightened
Transplantation
& Volume 96, Number 10, November 27, 2013
alloimmune responses and whether the addition of leptin level measurement improves overall graft outcome remain to be studied. Nonetheless, arbitrary limits on transplantation in obese transplant candidates should be reconsidered. The clinically relevant issue for determining whether or not to list an obese patient for transplant should not be risk relative to nonobese patients but rather risk compared with their higher-risk waitlisted counterparts such as highly sensitized transplant candidates or those with diabetes. Furthermore, the risk that accrues from remaining on dialysis should not be overlooked (5). Phuong-Thu T. Pham1 Gabriel M. Danovitch1 Phuong-Chi T. Pham2
Received 23 August 2013. Accepted 3 September 2013. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0041-1337/13/9610-00 DOI: 10.1097/01.TP.0000436929.53768.93
REFERENCES 1.
2.
3.
4.
1
Department of Medicine Nephrology Division Kidney Transplant Program David Geffen School of Medicine at UCLA, Los Angeles, CA 2 Department of Medicine Division of Nephrology and Hypertension UCLA-Olive View Medical Center David Geffen School of Medicine at UCLA, Los Angeles, CA The authors declare no funding or conflicts of interest. Address correspondence to: Phuong-Thu T. Pham, MD, Department of Medicine, Nephrology Division, Kidney Transplant Program David Geffen School of Medicine at UCLA, Los Angeles, CA 90095. E-mail: [email protected] P.-T.T.P. participated in writing the article. G.M.D. and P.-C.T.P. participated in the critical review and revision of the article.
5.
6.
7.
8. 9.
Heinbokel T, Floerchingr B, Schmiderer A, et al. Obesity and its impact on transplantation and alloimmunity. Transplantation 2013; 96: 10. Moraes-Vieira PMM, Bassi EJ, Larocca RA, et al. Leptin modulates allograft survival by favoring a TH2 and a regulatory immune profile. Am J Transplant 2013; 13: 36. Chang SH, Coates PT, McDonald SP. Effects of body mass index at transplant on outcomes of kidney transplantation. Transplantation 2007; 84: 981. Gore JL, Pham PT, Danovitch GM, et al. Obesity and outcome following renal transplantation. Am J Transplant 2006; 6: 357. Pham PT, Danovitch GM, Pham PC. Kidney transplantation in the obese transplant candidates: to transplant or not to transplant? Semin Dial 2013; 26: 568. Lord GM, Matarese G, Howard JK, et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998; 394: 897. Kalamtar-Zadeh K, Streja E, Molnar MZ, et al. Mortality prediction by surrogates of body composition: an examination of the obesity paradox in hemodialysis patients using composite ranking score analysis. Am J Epidemiol 2012; 175: 793. Bigaard J, Frederiksen K, Tjonneland A, et al. Body fat and fat-free mass and allcause mortality. Obes Res 2004; 12: 1042. Kovesdy CP, Czira ME, Rudas A, et al. Body mass index, waist circumference and mortality in kidney transplant recipients. Am J Transplant 2010; 10: 2644.
Authors’ Reply e appreciate the comments of Pham et al. (1). Indeed, with an endemic incidence, consequences of obesity on immune responses are of emerging interest with implications far beyond organ transplantation. The work by Moraes-Vieira et al. (2) represents an elegant experimental study linking concepts of obesity-related inflammation with altered alloimmune responses. These data stress the importance of future experimental studies with translational potential to foster our understanding of the complex network of obesity-related consequences. Moreover, those studies will have the potential to define novel targets of immune modulation.
W
While obesity has been linked to increased incidences of delayed graft function (DGF) (3), this correlation may not necessarily reflect a clear correlation of cause and effect. Of note, DGF is in general considered a major risk factor for acute rejection and graft survival (4). Moreover, it remains unclear, as pointed out by Pham et al., if obesity is linked to more frequent rates of acute rejections. Indeed, more frequent utilization of lymphocyte-depleting agents in patients expected to develop DGF may play a role. Although of critical clinical significance, several confounding factors including obesity-related aspects of pharmacokinetics, immunosuppressive
regimens, and thresholds for biopsies in obese recipients may play an additional role. We agree that arbitrary body mass index (BMI) limits may not represent an appropriate approach in stratifying transplant candidacy. Moreover, as mentioned by Pham et al., effects of obesity on mortality when remaining on dialysis need to be part of a risk assessment before renal transplantation. While we are aware that clear cause-andeffect correlations of obesity on clinical transplant outcomes are currently missing, there is compelling evidence from elegant studies outside transplantation linking obesity to immunity.
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Correspondence
* 2013 Lippincott Williams & Wilkins
Direct effects of obesity need to be distinguished from obesity-related comorbidities and immune responses. As much as it will be critical to analyze individual risk factors in this complex interplay, it may not always be possible to draw straight lines of cause and effects. Previous clinical studies by others have been unable to link transplant outcomes with obesity-related comorbid conditions. When adjusting BMI for ascites, Leonard et al. (5) were unable to link BMI to patient or graft survival after liver transplantation. Along the same lines, a single-center retrospective analysis was unable to link BMI to renal transplant outcome when rigorously screening for cardiovascular risk factors (6). While those studies are in contrast with others supporting an association between obesity and transplant outcome, it seems critical to better understand the complex pathophysiology of obesity. Moreover, on a clinical level, it will be critical to use clinical parameters best reflecting the consequences of obesity. We are therefore in agreement with Pham et al. that assessing patient survival based on BMI solely may be misleading. Indeed, an appropriate risk analysis also needs to account for muscle mass and visceral adipose tissue. Further
clinical studies using clinically most relevant surrogate markers are therefore warranted. Moreover, efforts are in need of exploring the associations of waist-tohip ratio, waist circumference, muscle mass, body fat, and fat-free mass with transplant outcome. Consequences of obesity on inflammation and alloimmune responses indeed seem intriguing. Dissecting those mechanisms will be of critical clinical significance in the future for clinical evaluation as well as treatment before and after transplantation. Timm Heinbokel1,2 Markus Quante1 Stefan G. Tullius1 1 Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women’s Hospital Harvard Medical School Boston, MA 2 Institute of Medical Immunology Charite´ Y Universita¨tsmedizin Berlin Berlin, Germany
The authors declare no funding or conflicts of interest. Address correspondence to: Stefan G. Tullius, M.D., Ph.D., Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. E-mail: [email protected]
e73
Received 26 August 2013. Accepted 3 September 2013. T.H. participated in writing the article. M.Q. participated in writing and critical review of the article. S.G.T. participated in critical review and revision of the article. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0041-1337/13/9610-00 DOI: 10.1097/01.tp.0000435597.96492.05
REFERENCES 1. 2.
3.
4. 5.
6.
Pham PT, Danovitch GM, Pham PC. Obesity and its impact on transplantation and alloimmunity. Transplantation 2013; 96: e72. Moraes-Vieira PMM, Bassi EJ, Larocca RA, et al. Leptin modulates allograft survival by favoring a TH2 and a regulatory immune profile. Am J Transplant 2013; 13: 36. Meier-Kriesche H-U, 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: 70. Boom H, Mallat MJ, de Fijter JW, et al. Delayed graft function influences renal function, but not survival. Kidney Int 2000; 58: 859. Leonard J, Heimbach JK, Malinchoc M, et al. The impact of obesity on long-term outcomes in liver transplant recipientsV results of the NIDDK liver transplant database. Am J Transplant 2008; 8: 667. Johnson DW, Isbel NM, Brown AM, et al. The effect of obesity on renal transplant outcomes. Transplantation 2002; 74: 675.
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
www.transplantjournal.com
most studies reported, obesity was generally assessed by BMI, which reflects both increased visceral and abdominal fat and/or muscle mass. More recent studies in the dialysis population and in kidney transplant recipients showed a survival benefit in patients with higher BMI who have higher muscle mass (5, 7). In a prospective cohort study of 993 kidney transplant recipients, higher BMI was associated with lower mortality after adjustment for waist circumference (0.48 [0.34, 0.69], PG0.001), whereas higher waist circumference was strongly associated with higher mortality after adjustment for BMI (2.18 [1.55Y3.08], PG0.001). The associations of waist circumference with mortality remained significant on multivariate analyses (7). Hence, assessing patient and graft outcomes in obese transplant recipients based on BMI alone may be misleading. We agree with Heinbokel et al. that waist-to-hip ratio may more adequately represent the immunologically active visceral adipose tissue. Similar to the general population, studies in the dialysis population and in kidney transplant recipients suggest that obesity as assessed by waist circumference or waistto-hip ratio is a stronger independent predictor of cardiovascular disease and cardiovascular death than BMI (7Y9). Future studies in obese transplant recipients should incorporate waist-to-hip ratio or waist circumference. Whether increased visceral and/or abdominal adiposity is associated with heightened
Transplantation
& Volume 96, Number 10, November 27, 2013
alloimmune responses and whether the addition of leptin level measurement improves overall graft outcome remain to be studied. Nonetheless, arbitrary limits on transplantation in obese transplant candidates should be reconsidered. The clinically relevant issue for determining whether or not to list an obese patient for transplant should not be risk relative to nonobese patients but rather risk compared with their higher-risk waitlisted counterparts such as highly sensitized transplant candidates or those with diabetes. Furthermore, the risk that accrues from remaining on dialysis should not be overlooked (5). Phuong-Thu T. Pham1 Gabriel M. Danovitch1 Phuong-Chi T. Pham2
Received 23 August 2013. Accepted 3 September 2013. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0041-1337/13/9610-00 DOI: 10.1097/01.TP.0000436929.53768.93
REFERENCES 1.
2.
3.
4.
1
Department of Medicine Nephrology Division Kidney Transplant Program David Geffen School of Medicine at UCLA, Los Angeles, CA 2 Department of Medicine Division of Nephrology and Hypertension UCLA-Olive View Medical Center David Geffen School of Medicine at UCLA, Los Angeles, CA The authors declare no funding or conflicts of interest. Address correspondence to: Phuong-Thu T. Pham, MD, Department of Medicine, Nephrology Division, Kidney Transplant Program David Geffen School of Medicine at UCLA, Los Angeles, CA 90095. E-mail: [email protected] P.-T.T.P. participated in writing the article. G.M.D. and P.-C.T.P. participated in the critical review and revision of the article.
5.
6.
7.
8. 9.
Heinbokel T, Floerchingr B, Schmiderer A, et al. Obesity and its impact on transplantation and alloimmunity. Transplantation 2013; 96: 10. Moraes-Vieira PMM, Bassi EJ, Larocca RA, et al. Leptin modulates allograft survival by favoring a TH2 and a regulatory immune profile. Am J Transplant 2013; 13: 36. Chang SH, Coates PT, McDonald SP. Effects of body mass index at transplant on outcomes of kidney transplantation. Transplantation 2007; 84: 981. Gore JL, Pham PT, Danovitch GM, et al. Obesity and outcome following renal transplantation. Am J Transplant 2006; 6: 357. Pham PT, Danovitch GM, Pham PC. Kidney transplantation in the obese transplant candidates: to transplant or not to transplant? Semin Dial 2013; 26: 568. Lord GM, Matarese G, Howard JK, et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998; 394: 897. Kalamtar-Zadeh K, Streja E, Molnar MZ, et al. Mortality prediction by surrogates of body composition: an examination of the obesity paradox in hemodialysis patients using composite ranking score analysis. Am J Epidemiol 2012; 175: 793. Bigaard J, Frederiksen K, Tjonneland A, et al. Body fat and fat-free mass and allcause mortality. Obes Res 2004; 12: 1042. Kovesdy CP, Czira ME, Rudas A, et al. Body mass index, waist circumference and mortality in kidney transplant recipients. Am J Transplant 2010; 10: 2644.
Authors’ Reply e appreciate the comments of Pham et al. (1). Indeed, with an endemic incidence, consequences of obesity on immune responses are of emerging interest with implications far beyond organ transplantation. The work by Moraes-Vieira et al. (2) represents an elegant experimental study linking concepts of obesity-related inflammation with altered alloimmune responses. These data stress the importance of future experimental studies with translational potential to foster our understanding of the complex network of obesity-related consequences. Moreover, those studies will have the potential to define novel targets of immune modulation.
W
While obesity has been linked to increased incidences of delayed graft function (DGF) (3), this correlation may not necessarily reflect a clear correlation of cause and effect. Of note, DGF is in general considered a major risk factor for acute rejection and graft survival (4). Moreover, it remains unclear, as pointed out by Pham et al., if obesity is linked to more frequent rates of acute rejections. Indeed, more frequent utilization of lymphocyte-depleting agents in patients expected to develop DGF may play a role. Although of critical clinical significance, several confounding factors including obesity-related aspects of pharmacokinetics, immunosuppressive
regimens, and thresholds for biopsies in obese recipients may play an additional role. We agree that arbitrary body mass index (BMI) limits may not represent an appropriate approach in stratifying transplant candidacy. Moreover, as mentioned by Pham et al., effects of obesity on mortality when remaining on dialysis need to be part of a risk assessment before renal transplantation. While we are aware that clear cause-andeffect correlations of obesity on clinical transplant outcomes are currently missing, there is compelling evidence from elegant studies outside transplantation linking obesity to immunity.
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Correspondence
* 2013 Lippincott Williams & Wilkins
Direct effects of obesity need to be distinguished from obesity-related comorbidities and immune responses. As much as it will be critical to analyze individual risk factors in this complex interplay, it may not always be possible to draw straight lines of cause and effects. Previous clinical studies by others have been unable to link transplant outcomes with obesity-related comorbid conditions. When adjusting BMI for ascites, Leonard et al. (5) were unable to link BMI to patient or graft survival after liver transplantation. Along the same lines, a single-center retrospective analysis was unable to link BMI to renal transplant outcome when rigorously screening for cardiovascular risk factors (6). While those studies are in contrast with others supporting an association between obesity and transplant outcome, it seems critical to better understand the complex pathophysiology of obesity. Moreover, on a clinical level, it will be critical to use clinical parameters best reflecting the consequences of obesity. We are therefore in agreement with Pham et al. that assessing patient survival based on BMI solely may be misleading. Indeed, an appropriate risk analysis also needs to account for muscle mass and visceral adipose tissue. Further
clinical studies using clinically most relevant surrogate markers are therefore warranted. Moreover, efforts are in need of exploring the associations of waist-tohip ratio, waist circumference, muscle mass, body fat, and fat-free mass with transplant outcome. Consequences of obesity on inflammation and alloimmune responses indeed seem intriguing. Dissecting those mechanisms will be of critical clinical significance in the future for clinical evaluation as well as treatment before and after transplantation. Timm Heinbokel1,2 Markus Quante1 Stefan G. Tullius1 1 Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women’s Hospital Harvard Medical School Boston, MA 2 Institute of Medical Immunology Charite´ Y Universita¨tsmedizin Berlin Berlin, Germany
The authors declare no funding or conflicts of interest. Address correspondence to: Stefan G. Tullius, M.D., Ph.D., Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. E-mail: [email protected]
e73
Received 26 August 2013. Accepted 3 September 2013. T.H. participated in writing the article. M.Q. participated in writing and critical review of the article. S.G.T. participated in critical review and revision of the article. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0041-1337/13/9610-00 DOI: 10.1097/01.tp.0000435597.96492.05
REFERENCES 1. 2.
3.
4. 5.
6.
Pham PT, Danovitch GM, Pham PC. Obesity and its impact on transplantation and alloimmunity. Transplantation 2013; 96: e72. Moraes-Vieira PMM, Bassi EJ, Larocca RA, et al. Leptin modulates allograft survival by favoring a TH2 and a regulatory immune profile. Am J Transplant 2013; 13: 36. Meier-Kriesche H-U, 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: 70. Boom H, Mallat MJ, de Fijter JW, et al. Delayed graft function influences renal function, but not survival. Kidney Int 2000; 58: 859. Leonard J, Heimbach JK, Malinchoc M, et al. The impact of obesity on long-term outcomes in liver transplant recipientsV results of the NIDDK liver transplant database. Am J Transplant 2008; 8: 667. Johnson DW, Isbel NM, Brown AM, et al. The effect of obesity on renal transplant outcomes. Transplantation 2002; 74: 675.
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
