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Effect of Obesity on the Outcome of Kidney Transplantation: A 20-Year Follow-Up

Hoogeveen, Ellen K.1,2,7; Aalten, Jeroen3; Rothman, Kenneth J.4; Roodnat, Joke I.5; Mallat, Marko J. K.1; Borm, George6; Weimar, Willem5; Hoitsma, Andries J.3; de Fijter, Johan W.1

doi: 10.1097/TP.0b013e3182100f3a
Clinical and Translational Research
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Background. Cardiovascular disease is both a major threat to the life expectancy of kidney transplant recipients and an important determinant of late allograft loss. Obesity is an important risk factor for cardiovascular disease.

Methods. We investigated the relation between both pretransplant and 1-year posttransplant body mass index (BMI) with patient and renal graft survival in a cohort of 1810 adult patients. Sixty-one percent of all patients were men; median age (interquartile range [IQR]) was 46 years (35–56 years); median (IQR) pretransplant BMI was 23.0 kg/m2 (20.8–25.6 kg/m2); 1 year after transplantation, the median (IQR) BMI had increased 1.6 kg/m2 (0.3–3.2 kg/m2) and median (IQR) follow-up time was 8.3 years (5.3–12.0 years). We categorized BMI as follows: less than or equal to 20, more than 20 to less than or equal to 25 (normal), more than 25 to less than or equal to 30, and more than 30 (obesity) kg/m2.

Results. Using a Cox proportional hazards model, after adjustment for cardiovascular risk factors, the relative risks (95% confidence intervals) of death and death-censored graft failure during all follow-up for pretransplant obesity compared with normal BMI were 1.22 (0.86–1.74) and 1.34 (1.02–1.77), respectively; for obesity 1 year after transplantation compared with normal BMI, it was 1.39 (1.05–1.86) and 1.39 (1.10–1.74), respectively; and for change in BMI (per 5 kg/m2 increment) during the first year after transplantation, it was 1.23 (1.01–1.50) and 1.18 (1.01–1.38), respectively.

Conclusions. One year posttransplant BMI and BMI increment are more strongly related to death and graft failure than pretransplant BMI among kidney transplant recipients. Patients with BMI more than 30 kg/m2 compared with a normal BMI have approximately 20% to 40% higher risk for death and graft failure.

1 Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

2 Department of Internal Medicine, Jeroen Bosch Hospital, Den Bosch, The Netherlands.

3 Department of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

4 RTI Health Solutions, RTI International, Research Triangle Park, NC.

5 Department of Nephrology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.

6 Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

This work was supported by a grant from Roche Netherlands BV (for data management).

7 Address correspondence to: Ellen K. Hoogeveen, M.D., Ph.D., Department of Internal Medicine, Jeroen Bosch Hospital, Post Box 90153, 5200 ME Den Bosch, The Netherlands.

E-mail: ellen.hoogeveen@planet.nl

E.K.H., J.I.R., G.B., W.W., A.J.H., and J.W.d.F. participated in research design; E.K.H., K.J.R., J.W.d.F., and J.A. participated in the writing of the manuscript; E.K.H., J.A., J.I.R., and M.J.K.M. participated in data collection; and E.K.H., K.J.R., M.J.K.M., and J.W.d.F. participated in the statistical analyses.

Received 11 October 2010. Revision requested 10 November 2010.

Accepted 12 January 2011.

End-stage renal disease is increasing globally in prevalence. Kidney transplantation is, for most patients with end-stage renal disease, the preferred modality of renal replacement therapy, which has resulted in a shortage of donor kidneys. Both patient and renal allograft survival at 1 year are more than 90% in most transplant centers. The half-lives for grafts from cadaveric and living donors are approximately 14 and 22 years, respectively (1). The success of kidney transplantation has increased both the demand for organs and waiting time. Although more potent immunosuppressive strategies have improved short-term graft survival, long-term graft survival has not improved dramatically. This lack of improvement is due, at least in part, to continued graft failure caused by allograft fibrosis and atrophy (chronic allograft nephropathy [CAN]), and death with a functioning graft (1).

Cardiovascular disease (CVD) is the leading cause of death among kidney transplant recipients and an important determinant of late renal allograft loss. CVD accounts for approximately 40% of deaths among kidney transplant recipients (2), occurring more frequently in these patients than in the general population. Identification of modifiable pretransplant and posttransplant cardiovascular risk factors may improve survival of the allograft and life expectancy of the patient. Obesity contributes to an adverse cardiovascular risk profile and may also be involved in the pathogenesis of allograft dysfunction (3).

Obesity is an established risk factor for decline in kidney function in both healthy individuals and individuals with chronic kidney disease (4–6). The mechanisms by which obesity is related to kidney disease are uncertain, but it may promote kidney damage through both hemodynamic and hormonal effects (6). The deleterious effects of obesity on the kidney are in part mediated by associated cardiovascular risk factors such as diabetes mellitus, hypertension, dyslipidemia, and insulin resistance. In addition, accumulation of visceral fat can increase inflammatory mediators produced by adipocytes, such as tumor necrosis factor-α and interleukin-6, and contribute to glomerular and interstitial fibrosis. Moreover, obesity is associated with an increased single-nephron glomerular filtration rate, which may lead to glomerulosclerosis and subsequent loss of renal function over time. The higher blood pressures associated with obesity, caused by activation of the sympathetic nervous system and renin-angiotensin system, may also accelerate loss of kidney function. Finally, obesity may increase the risk of delayed graft function, a risk factor for chronic rejection and decreased graft survival.

Trends in obesity prevalence among renal transplant recipients mirror trends in the general population. The prevalence of obesity, measured as a body mass index (BMI) of greater than 30 kg/m2 (7), has increased over the last decade among kidney transplant candidates in The Netherlands from 6% to 11% and in the United States from 26% to 34% (8, 9). After transplantation, patients gain an average weight of approximately 10 kg during the first year, partly due to corticosteroid therapy.

Obesity may have adverse effects on CVD and wound healing. We previously showed that 1- and 5-year graft and patient survival were substantially lower in obese renal transplant recipients (8). A 7-year follow-up study among more than 25,000 primary kidney recipients showed a similar result (10). However, the effect of obesity on long-term graft and patient survival has not been reported. Nevertheless, the likelihood of receiving a kidney transplant is known to decrease with increasing degree of obesity (11), although there is no consensus whether obesity should be an exclusion criterion for kidney transplantation. Therefore, we investigated the effect of obesity on survival of kidney grafts and their recipients in a cohort followed up for 20 years.

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RESULTS

From 1984 to 1988, 518 patients (28%) received their first kidney transplant; from 1989 to 1993, 704 (38%) patients and from 1994 to 1997, 614 (34%) patients. Initial immunosuppressive therapy consisted of corticosteroids and a calcineurin inhibitor in all three transplantation centers. Since 1994, most (57%) patients have also received azathioprine or mycophenolate mofetil.

The median (interquartile range [IQR]) age of the study cohort (n=1810) was 46 years (35–56 years), and 61% of the patients were men, 92% were white, 3% black, 4% Asian, and 1% other ethnicity. The median (IQR) duration of dialysis treatment pretransplantation was 636 days (364–1049 days). The median (IQR) pretransplant BMI was 23.0 kg/m2 (20.8–25.6 kg/m2), with an approximately normal distribution. The distribution of the primary kidney recipients per category of BMI at baseline was: less than or equal to 20 (17%), more than 20 to less than or equal to 25 (53%), more than 25 to less than or equal to 30 (24%), and more than 30 (6%). Table 1 presents the baseline characteristics of the four BMI categories of the kidney recipients and the weight gain 1 year after transplantation.

TABLE 1

TABLE 1

Approximately 41% of deaths were due to cardiovascular causes, 16% due to infection, and 16% due to malignancy. The crude median (IQR) patient survival, conditional on being alive with a functioning graft 3 months after transplantation, was 8.3 years (5.3–12.0 years). The crude 1- and 5-year survival proportions (95% confidence interval [CI]) were 98% (97%–98%) and 88% (86%–89%) and for death-censored graft survival proportions (95% CI) were 97% (96%–98%) and 79% (76%–80%), respectively. The results were similar for obese and nonobese patients. Figure 1 shows the crude patient survival curves according to the category of BMI at baseline. Patient survival was lowest among obese patients. We used four categories of BMI as previously mentioned and used the second category as the reference for comparison (Table 2). It has been suggested that adequate adjustment for smoking would result in an almost linear relation between BMI and mortality (4). Nevertheless, as shown in Table 2, after additional adjustment for smoking, the U-shaped relation between BMI and both mortality and graft failure persisted. Additional adjustment for baseline hypertension, diabetes, hypercholesterolemia, and CVD attenuated the association between BMI and survival or graft failure slightly. The relative risk (RR) of 7-year mortality for patients with a low BMI (≤20 kg/m2) was 1.36 (1.03–1.81) after adjustment for recipient age and sex, diabetes, hypertension, smoking, hypercholesterolemia, history of CVD, and transplantation era. Obesity compared with normal weight increased the risk of mortality approximately 20% and for death-censored graft failure approximately 30%.

FIGURE 1.

FIGURE 1.

TABLE 2

TABLE 2

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1-Year Posttransplantation BMI and Change of BMI

For the following analyses, the first year of follow-up after kidney transplantation was excluded. One year after transplantation, the median (IQR) BMI had increased 1.6 kg/m2 (0.3–3.2 kg/m2) compared with baseline. During this period, the percentage of patients with obesity increased from 5.6% to 11.5%. After multivariable adjustment, each 5 kg/m2 increment in BMI in the first year after transplantation increased the risk of death and death-censored graft failure with an RR of 1.23 (1.01–1.50) and 1.18 (1.01–1.38), respectively (Table 2). Additional adjustment for baseline BMI led to similar results. After stratifying by the four baseline BMI categories and adjustment for age, sex, and smoking, the RR (95% CI) for each 5 kg/m2 increase in BMI during the first year posttransplantation were 1.51 (0.87–2.60), 1.31 (1.08–1.59), 1.31 (1.08–1.59), and 1.94 (1.17–3.20), respectively, for mortality and 1.18 (0.81–1.74), 1.21 (1.03–1.41), 1.21 (1.03–1.41), and 1.31 (0.90–1.96), respectively, for graft failure.

After multivariable adjustment, the RRs for BMI more than 30 kg/m2 for mortality and graft failure were 1.39 (1.05–1.86) and 1.39 (1.10–1.74), respectively (Table 2). Thus, obesity 1-year posttransplantation compared with normal weight increased the risk of mortality and graft failure approximately 40%.

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DISCUSSION

Our study shows that obesity (BMI >30 kg/m2) both pretransplant and 1-year posttransplantation is a risk factor for both patient mortality and death-censored graft failure independent of other cardiovascular risk factors. Primary kidney transplant recipients with a BMI more than 30 kg/m2 have approximately 20% to 40% higher risk for death and graft failure compared with patients with a normal BMI. A high BMI (>30 kg/m2) posttransplantation compared with pretransplant was more strongly related to death and graft failure. Weight gain within 1 year after transplantation, independent of pretransplant BMI, is also a risk factor for both mortality and graft failure, and the risk increased 23% and 18% for each 5 kg/m2 BMI increment, respectively. In addition, the risks were greater for patients who were obese at baseline, implying a greater individual risk. Obesity has been reported to be associated with patient death and (death censored) graft failure after renal transplantation by some (10, 12–14) but not others (15, 16). However, in contrast to our study, these results were not adjusted for diabetes and other cardiovascular risk factors.

The mechanism by which obesity reduces graft survival is unknown. One possibility is that obese patients are more likely to have also, or develop in the future, diabetes and hypertension, steps in the causal pathway linking increased BMI to graft failure or death (5, 17). Therefore, the World Health Organization suggests that to prevent underestimation of the risk associated with high BMI, factors closely related, such as hypertension, hypercholesterolemia, and hyperglycemia, should not be considered confounding and adjustment should not be made (7). Adjustment for intermediates in the pathway may attenuate the strength of the effect as we found in our analyses.

Another possibility is that obesity may lead to renal failure also through other mechanisms independent of hypertension and diabetes (5). In our study, even after multivariable adjustment of cardiovascular risk factors, the relation between obesity and patient death and graft failure persists, showing indeed that, in addition, direct mechanisms are involved. There is an increasing evidence that adipose tissue is “an endocrine organ” that secretes biologically active substances that could contribute to focal and segmental glomerulosclerosis (6, 18). Finally, normal kidneys adapt to the increased metabolic load of obesity with an increase in size and glomerular filtration. Glomerulomegaly and focal segmental glomerulosclerosis are the most common histologic lesions in patients with obesity-related glomerulopathy (19–21). These factors may also play a role in accelerating the progression of CAN in obese kidney transplant recipients.

In the general population, overweight is associated with long-term increased risk of death, whereas underweight is associated with short-term mortality (22). This pattern was also present among our transplant population. Our finding that underweight is also a risk factor for patient death and graft failure has been reported by others, in the absence of adjustment for cardiovascular risk factors (12, 23). Another study found no relation after adequate adjustment (24). The factors influencing body composition are manifold in prekidney transplant patients, including infection, and impaired nutritional status (25). This so-called malnutrition-inflammation-complex probably leads to the activation of T cells through interleukin-2 and may contribute to CAN. Although we controlled for smoking, we found U-shaped relation between BMI and both mortality and graft failure. We cannot rule out residual confounding because of insufficient adjustment for smoking. But, if anything, this would tend to underestimate the effect of obesity. Obesity increases risk of death through an accumulated effect over years. The negative effect of obesity on life expectancy is probably greater at a young age, whereas by the age of 70 years, there is hardly any effect of obesity on life expectancy (26).

A limitation of this study is that we used the BMI as a proxy for obesity, known imprecisely to reflect the risk contained by the metabolic effects of an increased fat mass (27). Moreover, BMI does not reflect the changes that occur with age: the proportion of body fat increases with age, whereas muscle mass decreases (27). Finally, we used the same cutoff point to define obesity in our mixed ethnic cohort. The cutoff point to define obesity is approximately 6 kg/m2 lower among nonEuropean groups compared with Europeans (28).

In our study, both BMI increment and BMI posttransplantation were more strongly related to outcome than pretransplant BMI. Most likely, the altered hydration status associated with dialysis resulted in a relatively high BMI and therefore results in misclassification of some patients as obese pretransplantation. Posttransplantation BMI (>30 kg/m2) and increment of BMI are probably more accurate measures of enlargement of adipose tissue. The possible misclassification of obesity in this study was most likely nondifferential when using BMI. In general, nondifferential misclassification would likely bias the findings toward effect attenuation (i.e., underestimation of the strength of the relation between obesity and graft failure or death) (29). In conclusion, we found that obesity, especially posttransplantation, is a risk factor for graft failure and death.

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MATERIALS AND METHODS

The transplantation cohort comprised 2161 patients at least 18 years of age, at three transplantation centers in The Netherlands. Included patients received a first kidney transplant between January 1, 1984, and December 31, 1997, and survived with no graft loss for at least 3 months. We thus excluded surgical- and immunologic-related graft loss. Primary endpoints were graft failure and all-cause mortality. We defined patient survival as the time between transplantation and the date of death from any cause. We defined graft survival as the time between the date of transplantation and the date of graft failure or death. Patient survival was censored at the date of graft failure if the patient was still alive. Follow-up ended January 1, 2004. Baseline and follow-up data from these centers were stored in the Netherlands Organ Transplantation Registration (30).

Briefly, at baseline the following information was collected: age and sex of recipient; sex, age, and type of donor (deceased vs. living); cold ischemic time; delayed graft function; immunosuppressive and other medication; weight; height; blood pressure; serum cholesterol; HbA1c; and history of dialysis treatment, CVD, cigarette smoking, and diabetes. During follow-up (3 months and yearly after transplantation), the following data were collected: weight, blood pressure, use of medication, date of graft loss and death, and cause of death.

Weight or height at baseline was missing for 351 patients. The main analyses were therefore performed on 1810 subjects (83%) with sufficient data to compute baseline BMI. We measured adiposity using BMI (weight in kilograms divided by the square of height in meters), categorizing BMI as follows: less than or equal to 20, more than 20 to less than or equal to 25, more than 25 to less than or equal to 30, and more than 30 kg/m2. The cutoff points of 25 and 30 correspond to those endorsed by the World Health Organization as the transition between healthy weight and overweight (BMI of 25 kg/m2) and the transition between overweight and obesity (BMI of 30 kg/m2) (7).

We defined hypertension as use of blood pressure reducing medication, a diastolic blood pressure greater than or equal to 90 mm Hg, or a systolic blood pressure greater than or equal to 140 mm Hg. Hypercholesterolemia was defined as total cholesterol more than 5 mmol/L or the use of statins. Patients were classified as current smokers or nonsmokers. History of CVD was defined as any history of coronary artery, cerebrovascular, or peripheral arterial disease.

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Statistical Analyses

We assessed the relation between BMI and the primary endpoint using proportional hazards regression. Patient and graft survival analyses were performed conditional on being alive with a functioning graft 3 months after kidney transplantation. Death-censored graft survival was defined as graft survival conditional on patient survival. We constructed Kaplan-Meier curves for the primary endpoints. To study the relation between BMI and outcome, we categorized BMI values to correspond approximately to those characterized as low weight, normal weight, moderately overweight, and obese. We evaluated the effect of pretransplant BMI and BMI at 1 year after transplant on subsequent patient and graft survival. We also investigated the effect of the change in BMI from just before transplantation to 1 year after transplantation to subsequent patient and graft survival. Overweight is in the general population associated with long-term increased risk of death, whereas underweight is associated with short-term mortality (22). Therefore, we also investigated the relation between low BMI (≤20 kg/m2) and 7-year mortality (short-term follow-up). Causes of death were extracted from medical records to calculate the fraction of cardiovascular deaths. We examined the relation between all-cause mortality and BMI, adjusting for recipient age and sex, diabetes, hypertension, smoking, hypercholesterolemia, history of CVD, and transplantation era (1984–1988, 1989–1993, and 1994–1997). Graft failure was adjusted in addition for cold ischemic time, donor age, and whether donor was deceased.

Number of missing values for variables used in the analyses are as follows: BMI (0%), recipient sex (0%), recipient age (0%), transplantation era (0%), current smoking (50%), history of CVD (0%), diabetes (0%), hypertension (23%), hypercholesterolemia (64%), deceased donor (0%), and cold ischemic time (0%). Missing values for data of smoking, hypertension, and hypercholesterolemia were imputed using multiple imputations. Handling missing data using other methods is more likely to introduce bias, because the missing values are typically not missing randomly (31). Calculations were carried out using SPSS version 18.0 (SPSS Inc., Chicago, IL).

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ACKNOWLEDGMENT

The authors thank Dr. W. Lemmens for his data management support.

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Keywords:

Kidney transplantation; Graft failure; Mortality; Obesity; Epidemiology

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