Letter
Uncovering of Body Mass Index as a Risk Factor for Poor Long-term Outcome After Renal Transplantation Petronella E. Deetman,1 Jan-Stephan F. Sanders,1 Marc A.J. Seelen,1 Reinold O.B. Gans,1 Gerjan Navis,1 and Stephan J.L. Bakker1,2
W
e read with great interest the article by Nicoletto et al1 on obesity and outcome after renal transplantation. They found that, beyond the year 2000, obesity (ie, body mass index [BMI] ≥ 30 kg/m2) is a risk factor for neither graft failure nor mortality.1 The authors hypothesized that advances in immunosuppressive therapy, better control of obesity-related comorbidities, and increasing experience in kidney transplantation underlie absence of increased risk associated with obesity.1 It is important to realize that BMI is determined not only by fat mass but also by other constituents, particularly muscle mass. Muscle mass could confound the association of BMI with long-term outcomes because it has associations with long-term outcome opposite of those hypothesized for BMI. This is true not only for renal transplant recipients (RTR)2 but also for other populations.3,4 We therefore investigated whether muscle mass, determined by 24-hour urinary creatinine excretion (UCE), confounds associations of BMI with graft failure and mortality in RTR. To this end, we prospectively investigated 916 RTR transplanted between 1993 and 2008 (of which 67% were transplanted after 2000) in the University Medical Center Groningen, the Netherlands. Details of the cohort and its design have been published previously.5 Baseline BMI was determined at 1 year after transplantation. Urinary creatinine excretion was determined from 24-hour urine collections gathered between 6 and 18 months after transplantation. Cox regression analyses were applied. At baseline, median age was 50 years (interquartile range, 39–59 years), and 58% were male. Mean (SD) BMI was 26 (4) kg/m2, mean (SD) estimated glomerular filtration rate Accepted 11 August 2014.
was 54 (18) mL/min per 1.73 m2, and mean (SD) UCE was 12.3 (3.0) mmol per 24 hours. A total of 77 RTR (8%) experienced graft failure during 4.6 years (2.5–7.9 years) of follow-up. In a univariable analysis, BMI was not associated with graft failure (hazard ratio [HR], 1.09 [0.87–1.36]; P = 0.45). The association of BMI with graft failure remained nonsignificant after adjustment for age and sex (HR, 1.20 [0.96–1.50]; P = 0.10) but became uncovered by further adjustment for UCE (HR, 1.44 [1.14–1.82]; P = 0.003; Figure 1). This uncovering effect remained after further adjustment for systolic blood pressure, use of antihypertensive drugs, cholesterol, use of lipid lowering drugs, diabetes, smoking status, and estimated glomerular filtration rate (HR, 1.44 [1.09–1.91]; P = 0.012). A total of 153 RTR (17%) died during 4.9 years (2.7–8.4 years) of follow-up. In a univariable Cox regression analysis, BMI tended to be positively associated with mortality (HR, 1.16 [0.99–1.35]; P = 0.067). This trend disappeared after adjustment for age and sex (HR, 1.06 [0.90–1.25]; P = 0.50) but became uncovered by adjustment for UCE (HR, 1.35 [1.13–1.62]; P = 0.001; Figure 1). This uncovering effect remained after further adjustment for potential confounders (HR, 1.35 [1.10–1.66]; P = 0.004). After exclusion of subjects who were transplanted before 2000, results were essentially similar. To our knowledge, we are the first to report an uncovering effect by UCE on associations of BMI with graft failure and mortality in RTR. Adjustment for UCE seems to uncover an adverse association of high fat mass, for which BMI became a better measure after adjustment for UCE, with both graft failure and mortality. These findings provide an additional potential explanation for the absence of increased risk associated with obesity observed by Nicoletto et al.1
Received 7 August 2014. 1 Division of Nephrology, Department of Medicine, University Medical Center Groningen and University of Groningen, the Netherlands. 2
Top Institute Food and Nutrition, Wageningen, the Netherlands.
The authors declare no funding or conflicts of interest. P.E.D. analyzed the data and drafted the article. J.-S.F.S. participated in the data collection. M.A.J.S. participated in the data collection. R.O.B.G. participated in the protocol development and article revisions. G.N. participated in the article revisions and intellectual contributions. S.J.L.B. initiated the study, supervised the data collection, participated in the subject care, and edited the article. Correspondence: Petronella E. Deetman, University Medical Center Groningen, Division of Nephrology (AA 53), PO Box 30.001, 9700 RB Groningen, the Netherlands. ([email protected]) Copyright © 2014 Wolkers Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9901-e5 DOI: 10.1097/TP.0000000000000484
Transplantation
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January 15, 2015
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Volume 99
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Number 1
REFERENCES 1. Nicoletto BB, Fonseca NK, Manfro RC, Gonçalves LF, Leitão CB, Souza GC. Effects of obesity on kidney transplantation outcomes: a systematic review and meta-analysis. Transplantation. 2014;98:167–176. 2. Oterdoom LH, van Ree RM, de Vries AP, et al. Urinary creatinine excretion reflecting muscle mass is a predictor of mortality and graft loss in renal transplant recipients. Transplantation. 2008;86:391–398. 3. Oterdoom LH, Gansevoort RT, Schouten JP, de Jong PE, Gans RO, Bakker SJ. Urinary creatinine excretion, an indirect measure of muscle mass, is an independent predictor of cardiovascular disease and mortality in the general population. Atherosclerosis. 2009;207:534–540. 4. Sinkeler SJ, Kwakernaak AJ, Bakker SJ, et al. Creatinine excretion rate and mortality in type 2 diabetes and nephropathy. Diabetes Care. 2013;36: 1489–1494. 5. Deetman PE, Said MY, Kromhout D, et al. Urinary urea excretion and long-term outcome after renal transplantation. Transplantation. 2014; November 12 [Epub ahead of print].
www.transplantjournal.com
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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e6
Transplantation
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January 15, 2015
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Volume 99
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Number 1
www.transplantjournal.com
FIGURE 1. Uncovering of the association of BMI with mortality and graft failure by adjustment for urinary creatinine excretion. A, The age- and sex-adjusted association of BMI with graft failure. B, Additional adjustment for urinary creatinine excretion. C, The age- and sex-adjusted association of BMI with mortality. D, Additional adjustment for urinary creatinine excretion. BMI indicates body mass index.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Uncovering of Body Mass Index as a Risk Factor for Poor Long-term Outcome After Renal Transplantation Petronella E. Deetman,1 Jan-Stephan F. Sanders,1 Marc A.J. Seelen,1 Reinold O.B. Gans,1 Gerjan Navis,1 and Stephan J.L. Bakker1,2
W
e read with great interest the article by Nicoletto et al1 on obesity and outcome after renal transplantation. They found that, beyond the year 2000, obesity (ie, body mass index [BMI] ≥ 30 kg/m2) is a risk factor for neither graft failure nor mortality.1 The authors hypothesized that advances in immunosuppressive therapy, better control of obesity-related comorbidities, and increasing experience in kidney transplantation underlie absence of increased risk associated with obesity.1 It is important to realize that BMI is determined not only by fat mass but also by other constituents, particularly muscle mass. Muscle mass could confound the association of BMI with long-term outcomes because it has associations with long-term outcome opposite of those hypothesized for BMI. This is true not only for renal transplant recipients (RTR)2 but also for other populations.3,4 We therefore investigated whether muscle mass, determined by 24-hour urinary creatinine excretion (UCE), confounds associations of BMI with graft failure and mortality in RTR. To this end, we prospectively investigated 916 RTR transplanted between 1993 and 2008 (of which 67% were transplanted after 2000) in the University Medical Center Groningen, the Netherlands. Details of the cohort and its design have been published previously.5 Baseline BMI was determined at 1 year after transplantation. Urinary creatinine excretion was determined from 24-hour urine collections gathered between 6 and 18 months after transplantation. Cox regression analyses were applied. At baseline, median age was 50 years (interquartile range, 39–59 years), and 58% were male. Mean (SD) BMI was 26 (4) kg/m2, mean (SD) estimated glomerular filtration rate Accepted 11 August 2014.
was 54 (18) mL/min per 1.73 m2, and mean (SD) UCE was 12.3 (3.0) mmol per 24 hours. A total of 77 RTR (8%) experienced graft failure during 4.6 years (2.5–7.9 years) of follow-up. In a univariable analysis, BMI was not associated with graft failure (hazard ratio [HR], 1.09 [0.87–1.36]; P = 0.45). The association of BMI with graft failure remained nonsignificant after adjustment for age and sex (HR, 1.20 [0.96–1.50]; P = 0.10) but became uncovered by further adjustment for UCE (HR, 1.44 [1.14–1.82]; P = 0.003; Figure 1). This uncovering effect remained after further adjustment for systolic blood pressure, use of antihypertensive drugs, cholesterol, use of lipid lowering drugs, diabetes, smoking status, and estimated glomerular filtration rate (HR, 1.44 [1.09–1.91]; P = 0.012). A total of 153 RTR (17%) died during 4.9 years (2.7–8.4 years) of follow-up. In a univariable Cox regression analysis, BMI tended to be positively associated with mortality (HR, 1.16 [0.99–1.35]; P = 0.067). This trend disappeared after adjustment for age and sex (HR, 1.06 [0.90–1.25]; P = 0.50) but became uncovered by adjustment for UCE (HR, 1.35 [1.13–1.62]; P = 0.001; Figure 1). This uncovering effect remained after further adjustment for potential confounders (HR, 1.35 [1.10–1.66]; P = 0.004). After exclusion of subjects who were transplanted before 2000, results were essentially similar. To our knowledge, we are the first to report an uncovering effect by UCE on associations of BMI with graft failure and mortality in RTR. Adjustment for UCE seems to uncover an adverse association of high fat mass, for which BMI became a better measure after adjustment for UCE, with both graft failure and mortality. These findings provide an additional potential explanation for the absence of increased risk associated with obesity observed by Nicoletto et al.1
Received 7 August 2014. 1 Division of Nephrology, Department of Medicine, University Medical Center Groningen and University of Groningen, the Netherlands. 2
Top Institute Food and Nutrition, Wageningen, the Netherlands.
The authors declare no funding or conflicts of interest. P.E.D. analyzed the data and drafted the article. J.-S.F.S. participated in the data collection. M.A.J.S. participated in the data collection. R.O.B.G. participated in the protocol development and article revisions. G.N. participated in the article revisions and intellectual contributions. S.J.L.B. initiated the study, supervised the data collection, participated in the subject care, and edited the article. Correspondence: Petronella E. Deetman, University Medical Center Groningen, Division of Nephrology (AA 53), PO Box 30.001, 9700 RB Groningen, the Netherlands. ([email protected]) Copyright © 2014 Wolkers Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9901-e5 DOI: 10.1097/TP.0000000000000484
Transplantation
■
January 15, 2015
■
Volume 99
■
Number 1
REFERENCES 1. Nicoletto BB, Fonseca NK, Manfro RC, Gonçalves LF, Leitão CB, Souza GC. Effects of obesity on kidney transplantation outcomes: a systematic review and meta-analysis. Transplantation. 2014;98:167–176. 2. Oterdoom LH, van Ree RM, de Vries AP, et al. Urinary creatinine excretion reflecting muscle mass is a predictor of mortality and graft loss in renal transplant recipients. Transplantation. 2008;86:391–398. 3. Oterdoom LH, Gansevoort RT, Schouten JP, de Jong PE, Gans RO, Bakker SJ. Urinary creatinine excretion, an indirect measure of muscle mass, is an independent predictor of cardiovascular disease and mortality in the general population. Atherosclerosis. 2009;207:534–540. 4. Sinkeler SJ, Kwakernaak AJ, Bakker SJ, et al. Creatinine excretion rate and mortality in type 2 diabetes and nephropathy. Diabetes Care. 2013;36: 1489–1494. 5. Deetman PE, Said MY, Kromhout D, et al. Urinary urea excretion and long-term outcome after renal transplantation. Transplantation. 2014; November 12 [Epub ahead of print].
www.transplantjournal.com
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
e5
e6
Transplantation
■
January 15, 2015
■
Volume 99
■
Number 1
www.transplantjournal.com
FIGURE 1. Uncovering of the association of BMI with mortality and graft failure by adjustment for urinary creatinine excretion. A, The age- and sex-adjusted association of BMI with graft failure. B, Additional adjustment for urinary creatinine excretion. C, The age- and sex-adjusted association of BMI with mortality. D, Additional adjustment for urinary creatinine excretion. BMI indicates body mass index.
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
