New-onset Obesity After Lung Transplantation: Incidence, Risk Factors, and Clinical Outcomes : Transplantation

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Original Clinical Science—General

New-onset Obesity After Lung Transplantation: Incidence, Risk Factors, and Clinical Outcomes

Jomphe, Valérie MSc, RD1; Bélanger, Noémie MSc, RD2; Beauchamp-Parent, Caroline RD2; Poirier, Charles MD1,3; Nasir, Basil S. MD1,4; Ferraro, Pasquale MD1,4; Lands, Larry C. MD, PhD1,5; Mailhot, Geneviève PhD, RD2,6

Author Information
doi: 10.1097/TP.0000000000004222

Abstract

INTRODUCTION

Lung transplantation (LTx) comes at the expense of lifelong immunosuppressive therapy associated with a range of metabolic effects, including an inevitable weight gain. We previously reported that 77% of recipients gained weight in the first 2 y following transplant.1 In 41% of these cases, weight gain led to an upward shift in body mass index (BMI), placing approximately one third of individuals in the obese BMI range.1 Consistent obesity throughout the pre- and post-LTx periods was found to be associated with poor survival and worse clinical outcomes, including longer mechanical ventilation duration and intensive care unit stay and higher rates of surgical complications, primary graft dysfunction, and new-onset diabetes after transplantation.2-7 Yet, the impact of obesity developing post-LTx (new-onset) on morbidity and mortality remains ill defined. Moreover, when posttransplant obesity was studied, the distinction between consistent obesity over the pre- and post-LTx periods and new-onset obesity occurring after LTx was not made.

To address these gaps, we assessed the incidence and associated risk factors of new-onset obesity in a large single-center cohort of LTx recipients. In addition, we investigated whether new-onset obesity was associated with overall survival and post-LTx outcomes, more specifically, posttransplant diabetes mellitus (PTDM) and metabolic syndrome (MS). Outcomes of recipients with new-onset obesity were compared with those of nonobese recipients, consistently obese recipients throughout the pre- and post-LTx period, and obese recipients who lost weight after LTx. We hypothesized that new-onset obesity was associated with mortality and risk of post-LTx PTDM and MS similar to that of consistently obese recipients but greater than nonobese recipients.

MATERIALS AND METHODS

Study Population

This was a retrospective study of all individuals aged ≥18 y who underwent a single or bilateral LTx at the Centre Hospitalier de l’Université de Montréal (CHUM) in Montreal, Canada, between December 6, 1999, and December 31, 2018. The CHUM is the referral center for LTx in Eastern Canada (Maritimes, Quebec, and Eastern Ontario). Patients were included if they had data on weight and BMI available at pretransplant evaluation, transplant, and at least 6 mo after transplant. The exclusion criteria were retransplantation, multiple solid organ transplants, post-LTx pregnancy, and lack of weight measures after transplantation, primarily because of early death. The CHUM Research Ethics Committee approved this study and waived the requirement for consent.

Data Collection

Data extracted from medical charts and our institutional transplant database included demographics, anthropometrics, and clinical data, including underlying lung diseases, type of transplant, comorbidities (eg, diabetes, hypertension, and dyslipidemia), survival status, systolic and diastolic blood pressure, and laboratory results (eg, high-density lipoprotein, triglycerides, and glucose). Blood pressure was measured by the clinic nurses using a manual or electronic sphygmomanometer. Fasting serum high-density lipoprotein, triglycerides, and glucose levels were measured using standard methods in the CHUM Clinical Biochemistry Department. When appropriate, data were collected at (or at the nearest date to) pre-LTx evaluation, transplant admission, 6 mo, and 1, 2, 5, and 10 y post-LTx. Cyclosporin was the principal calcineurin inhibitor until 2005, followed by tacrolimus, whereas azathioprine was the principal antiproliferative agent until 2001, followed by mycophenolate mofetil. The immunosuppressive regimen was tailored according to the serum dosage of each patient. Maintenance therapy for corticosteroids is typically 10 to 15 mg/d.

Outcomes of Interest

Weight and BMI

Weights and waist circumferences were measured in light clothing with shoes off by a nurse or dietitian during clinic visits. BMIs were calculated using the height measured during the evaluation. Patients were categorized according to the World Health Organization’s BMI classification: <18.5 kg/m2 (underweight), 18.5–24.9 kg/m2 (normal range), 25–29.9 kg/m2 (overweight), and ≥30 kg/m2 (obese).8

Recipients were further categorized into 4 groups based on their BMI changes over 2 time periods: (1) from pre-LTx evaluation up to LTx admission and (2) after LTx. The nonobese patients remained in the BMI categories of <30 kg/m2 throughout both periods. New-onset obesity was defined as a BMI <30 kg/m2 from pretransplant evaluation to transplant, which increased above that cutoff after transplant, regardless of the timing of occurrence and subsequent weight fluctuations. Consistently obese patients remained in the obese BMI category throughout both periods. We included in this group obese individuals who lost weight while on the waiting list and had their BMI decreased below 30 kg/m2 at transplant but gained back all lost weight after transplant, as we found those individuals to display similar characteristics to those who remained obese throughout (Table S1, SDC, https://links.lww.com/TP/C464). Patients with BMI ≥30 kg/m2 up to transplant who lost weight and switched to lower BMI categories after transplant formed the obese with post-LTx weight loss group.

PTDM and MS

PTDM ascertainment was based on one or several of the following criteria9 present at least 3 mo following LTx and recorded at least once: formal diagnosis or follow-up by an endocrinologist, presence of glycated hemoglobin levels ≥6.5%, and prescription of insulin or oral hypoglycemic agents. MS was ascertained at pretransplant evaluation, at the time of transplant, and after transplant using harmonized criteria (Table 1).10 MS was considered to be present if an individual had 3 or more criteria.

TABLE 1. - Criteria for metabolic syndrome
Criteria
Elevated fasting glucose Fasting plasma glucose ≥5.6 mmol/L or use of hypoglycemic agents
Elevated waist circumference a Waist circumference: men, >102 cm; women, >88 cm
Elevated triglycerides ≥1.7 mmol/L or use of lipid-lowering agents for high blood triglycerides
Low levels of HDL-c Men: <1.0 mmol/L; women: <1.3 mmol/L or drug treatment for reduced HDL-c
Elevated blood pressure ≥130/85 mm Hg or use of antihypertensive medication
The criteria were based on a joint statement from worldwide expert groups.
aIn the absence of a consensus regarding thresholds for elevated waist circumference, national cutoff points were used.11,12
HDL-c, high-density lipoprotein cholesterol.

Mortality

Data were censored at the end of the observation period (ie, June 19, 2019) or on loss to follow-up or death, whichever came first. Causes of death were grouped into 6 categories: respiratory failure (eg, primary graft dysfunction, chronic lung allograft dysfunction, bronchial stenosis), infections (eg, pneumonia, sepsis), malignancy, cardiovascular (eg, myocardial infarction, stroke), other causes (eg, multiorgan failure, renal failure), and unknown (no clear cause identifiable).

Statistical Analysis

Univariate analyses included the chi-square or Fisher exact test and the Kruskal-Wallis test. Logistic regression models were fitted to determine the risk factors for post-LTx new-onset obesity compared with nonobese recipients. Overall survival was analyzed using Kaplan-Meier curves and the log-rank test as a statistical contrast. Time origin was set at transplant to compare survival between recipients according to their BMI category at transplant. The risk of PTDM, MS, and death among recipients who developed new-onset obesity was assessed conditional on 2-y survival. This timepoint was selected based on our data showing that 64% of recipients had developed obesity by that time. Cox proportional hazards models were used to determine the risk factors for post-LTx PTDM and MS. Models were adjusted for covariates based on their relationships with the outcomes of interest. The model assumptions of the log-linearity and proportional hazards were checked and found not to be violated. According to the median study period, 2 transplant eras were defined as December 1999 to September 2009 and October 2009 to December 2018. Significance was set at P < 0.05, and analyses were performed using SPSS, version 25 (IBM Corp, Armonk, NY).

RESULTS

Characteristics of the Study Population

Figure 1 details the study flowchart. Based on our criteria, 564 patients were included in the analysis. Table 2 outlines the sample characteristics stratified by their BMI trajectories from pre-LTx evaluation to post-LTx. The cohort was made up of slightly more men than women with a median age of 53 y (interquartile range: 37–59). Nonobese recipients were younger than all other groups, owing to more patients with cystic fibrosis (CF) in this category. Two thirds of recipients were transplanted in the most recent transplant era, reflecting the increasing number of transplants performed in the last years. Rates of pretransplant hypertension, dyslipidemia, and MS varied significantly between groups, whereby obese candidates displayed greater rates. Notably, nonnegligible proportions of patients who developed new-onset obesity already had high blood pressure and dyslipidemia before transplant. As expected, BMI differed significantly between groups throughout the observation period.

TABLE 2. - Sample characteristics stratified by BMI trajectories from pretransplant evaluation to posttransplant
Variables Nonobese (n = 412) New-onset obese (n = 80) Consistently obese (n = 41) Obese with post-LTx weight loss (n = 31) P
Gender
Men 225 (54) 46 (58) 26 (63) 23 (74) 0.147
Women 187 (45) 34 (43) 15 (37) 8 (26)
Age at transplant, y 50 (30–58) 55 (47–61) 56 (52–62) 59 (54–62) <0.001
Primary lung diseases <0.001
COPD 122 (30) 48 (60) 15 (37) 2 (6)
CF/bronchiectasis a 175 (42) 10 (13) 2 (5) 0 (0)
Pulmonary fibrosis 93 (23) 15 (19) 21 (51) 26 (84)
Others 22 (5) 7 (9) 3 (7) 3 (10)
Bilateral transplant 362 (88) 63 (79) 35 (85) 28 (90) 0.153
Waiting time, mo 14.3 (8.7–21.7) 14.9 (9.5–22.0) 13.8 (8.8–20.4) 11.8 (6.3–24.0) 0.795
Era of transplant 0.519
December 1999–September 2009 147 (36) 35 (44) 14 (34) 10 (32)
October 2009–December 2019 265 (64) 45 (56) 27 (66) 21 (68)
Pretransplant diabetes 113 (27) 15 (19) 5 (12) 8 (26) 0.085
Pretransplant high blood pressure 67 (16) 28 (35) 9 (22) 13 (42) <0.001
Pretransplant dyslipidemia 65 (16) 22 (28) 14 (34) 16 (52) <0.001
Pretransplant MS 35 (8) 7 (9) (n = 37) 9 (24) (n = 28) 11 (39) <0.001
BMI, kg/m2
Pre-LTx evaluation 21.3 (18.7–24.2) 26.8 (23.1–28.2) 31.7 (31.0–33.4) 32.0 (30.8–34.0) <0.001
At admission for transplant 21.1 (19.2–23.8) 26.4 (23.7–27.8) 29.0 (27.8–30.4) 28.7 (27.3–31.0) <0.001
Post-LTx
 6 mo 21.5 (19.4–24.0) 27.2 (25.0–28.8) 28.5 (27.0–30.5) 26.0 (25.4–27.1) <0.001
 1 y (n = 369) 22.7 (20.1–25.3) (n = 79) 29.3 (27.2–31.0) (n = 40) 30.8 (29.6–32.5) (n = 23) 26.8 (26.0–28.9) <0.001
 2 y (n = 315) 23.5 (21.0–26.0) (n = 74) 30.6 (28.6–32.3) (n = 35) 32.2 (31.6–34.8) (n = 16) 27.9 (26.2–30.1) <0.001
 5 y (n = 229) 20.7 (19.0–22.8) (n = 61) 30.7 (28.1–33.3) (n = 24) 34.0 (30.8–36.1) (n = 9) 29.2 (26.9–30.9) <0.001
 10 y (n = 113) 22.0 (19.3–25.5) (n = 30) 30.0 (27.6–31.6) (n = 11) 33.1 (27.3–34.5) (n = 2) 30.0 (23.6–36.5*) <0.001
The variables had complete data, unless otherwise indicated. Continuous variables were expressed as medians (IQR or *min-max), and categorical variables were expressed as n (%).
P values in bold are statistically significant.
aSixteen (out of 187; 9%) were non-CF patients with bronchiectasis.
BMI, body mass index; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; IQR, interquartile range; IQR, interquartile range; LTx, lung transplant; MS, metabolic syndrome.

F1
FIGURE 1.:
Flowchart of study population.

New-onset Obesity and Risk Factors

In the study population, 14% (n = 80) developed post-LTx new-onset obesity, whereas 7% (n = 41) remained consistently obese throughout the pre- and post-LTx period, and 5% were obese at transplant but transitioned to lower BMI categories after transplantation. Eleven percent of patients with new-onset obesity were in the obese BMI category at 6 mo post-LTx. This rate increased to 64% by 2 y. In recipients who developed new-onset obesity, 70% remained in the obese category at the end of the follow-up period.

Recipients with chronic obstrucoctive pulmonary disease (COPD) as primary lung disease were more prevalent in the new-onset obesity category, whereas pulmonary fibrosis was the predominant diagnosis in the 2 other obese categories. These observations were further corroborated by the logistic regression analysis (Table 3), whereby individuals with COPD (Odds ratio [OR]: 6.93, 95% CI [2.30-20.85]; P = 0.001) and other diagnoses (OR: 4.28, 95% CI [1.22-14.98]; P = 0.023) had increased odds of new-onset obesity when compared with patients with CF/bronchiectasis as the reference group.

TABLE 3. - Risk factors for post–lung transplant new-onset obesity
Variables OR (95% CI) P
Age at transplant, years 0.97 (0.93-1.00) 0.045
Sex
Men Ref
Women 1.07 (0.60-1.90) 0.824
Primary lung disease
CF/bronchiectasis Ref
COPD 6.93 (2.30-20.85) 0.001
Pulmonary fibrosis 1.90 (0.59-6.12) 0.281
Others 4.28 (1.22-14.98) 0.023
BMI categories at time of transplant
Underweight 0.16 (0.02-1.19) 0.073
Normal weight Ref
Overweight 9.01 (4.86-16.69) <0.001
A logistic regression model was used to determine the risk factors for post-LTx new-onset obesity (n = 80) compared with nonobese recipients (n = 412). The interaction between primary lung disease and BMI categories at transplant was assessed and found to be nonsignificant. P values in bold are statistically significant.
BMI, body mass index; CF, cystic fibrosis; CI, confidence interval; COPD, chronic obstructive pulmonary disease; LTx, lung transplant; OR, odds ratio; Ref, reference.

Nearly two thirds of recipients with new-onset obesity were overweight at pretransplant evaluation or at transplant. Such proportions were lower in the nonobese group, whereby 16% and 21% of patients were overweight at pre-LTx evaluation and at transplant, respectively. The regression model confirmed that overweight patients at the time of transplantation were 9 times more likely to develop new-onset obesity (OR: 9.01, 95% CI 4.86-16.69; P < 0.001) than normal-weight patients, an association that was also found when patients were overweight at pre-LTx evaluation (odds ratio: 7.02, 95% CI 3.79-13.00; P < 0.001).

New-onset Obesity, PTDM, and MS

Given that abdominal obesity is associated with an increased risk of diabetes and MS in the nontransplant population,13 we examined whether post-LTx obesity, particularly new-onset obesity, was associated with the risk of developing PTDM and MS after transplant. Among our cohort of 564 recipients, 141 (25%) had pretransplant diabetes, and among patients who did not have pretransplant diabetes, 224 developed PTDM (53%) for an overall prevalence of post-LTx diabetes of 65%. Rates of PTDM ranged from 46% to 64% in the 4 BMI trajectories but did not differ between the groups (P = 0.392). In our cohort, 71% of recipients (n = 398) had 3 or more MS criteria after transplantation. Prevalence rates differed significantly between groups, with most recipients with new-onset obesity (94%, n = 75), consistent obesity (98%, n = 40), and obesity with weight loss (81%, n = 25) having MS compared with 63% (n = 258) of nonobese recipients (P < 0.001).

We performed Cox regression analysis to assess whether new-onset obesity was associated with the subsequent risk of developing PTDM and MS conditional on being alive at 2 y post-LTx. Table 4 shows the results of the univariate and multivariable regression analysis. New-onset obesity was inversely associated with the risk of developing PTDM when compared with nonobese recipients in univariate analysis, but the association disappeared after adjusting for age, sex, and underlying disease. In contrast, new-onset and consistent obesity were both associated with an increased risk of MS both in the univariate and multivariable models when compared with nonobese patients. Other factors associated with a greater risk of MS included older age (≥55) and CF as underlying lung disease.

TABLE 4. - Risk factors for posttransplant new-onset diabetes after transplantation and MS
Variables Univariate Multivariate
HR (95% CI) P HR (95% CI) P
PTDM
Sex
 Men Ref Ref
 Women 1.30 (0.96-1.74) 0.085 1.26 (0.93-1.70) 0.141
Age, y
 <30 Ref Ref
 31–55 0.64 (0.43-0.95) 0.028 0.76 (0.46-1.25) 0.274
 ≥55 1.17 (0.77-1.77) 0.460 1.55 (0.84-2.87) 0.162
Primary lung disease
 COPD Ref Ref
 CF 1.35 (0.95-1.93) 0.096 1.56 (0.93-2.64) 0.095
 ILD 1.49 (1.01-2.18) 0.043 1.33 (0.89-1.99) 0.166
 Others 1.21 (0.63-2.30) 0.565 1.46 (0.73-2.91) 0.290
BMI trajectories
 Nonobese Ref Ref
 New-onset obesity 0.65 (0.43-0.99) 0.043 0.79 (0.51-1.24) 0.301
 Consistent obesity 1.30 (0.80-2.10) 0.296 1.43 (0.87-2.37) 0.160
 Obesity with weight loss 1.98 (0.87-4.52) 0.105 1.78 (0.75-4.21) 0.193
MS
Sex
 Men Ref Ref
 Women 0.97 (0.78-1.21) 0.794 1.02 (0.77-1.35) 0.909
Age, y
 <30 Ref Ref
 31–55 0.96 (0.71-1.28) 0.760 0.97 (0.63-1.49) 0.898
 ≥55 1.87 (1.38-2.53) <0.001 2.00 (1.15-3.48) 0.015
Underlying disease
 COPD Ref Ref
 CF 0.96 (0.74-1.25) 0.756 1.65 (1.01-2.71) 0.047
 ILD 1.44 (1.06-1.94) 0.018 1.54 (0.98-2.41) 0.062
 Others 0.78 (0.45-1.36) 0.385 1.13 (0.55-2.33) 0.736
BMI trajectories
 Nonobese Ref Ref
 New-onset obesity 1.27 (0.96-1.66) 0.092 1.70 (1.17-2.46) 0.005
 Consistent obesity 1.73 (1.20-2.50) 0.003 1.70 (1.04-2.76) 0.033
 Obesity with weight loss 1.63 (0.92-2.89) 0.095 2.10 (0.90-4.86) 0.085
Diabetes (LTx) 1.12 (0.88-1.43) 0.346 1.24 (0.89-1.74) 0.203
High blood pressure (LTx) 1.08 (0.81-1.44) 0.610 0.93 (0.67-1.29) 0.666
Dyslipidemia (LTx) 1.42 (1.11-1.82) 0.006 1.29 (0.90-1.84) 0.165
Univariate and multivariable Cox regression analysis of risk factors for PTDM and MS. The time of origin was set at 2 y posttransplantation, and 441 patients were still alive at that timepoint. The number of events was 179 (PTDM) and 319 (MS). P values in bold are statistically significant.
BMI, body mass index; CF, cystic fibrosis; CI, confidence interval; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; ILD, interstitial lung disease; LTx, lung transplant; MS, metabolic syndrome; PTDM, posttransplant diabetes mellitus; Ref, reference.

New-onset Obesity and Survival

The overall median follow-up time was 4.7 y (range 0.3–19.5). During the follow-up period, 217 patients (38%) died, and the overall median survival was 9.8 y (95% CI 8.9-10.6). Figure 2 shows the survival curves of recipients stratified according to their BMI category at transplant. Although median survival time was longer in normal/overweight patients (10.2 y [95% CI 9.3-11.1]) than in underweight (8.4 y [95% CI 6.4-10.4]) and obese patients (6.4 y [95% CI 2.2-10.6]), group differences did not reach significance (P = 0.09). To assess the impact of post-LTx new-onset obesity on survival, we focused our analyses on normal/overweight patients, as we found that most of new-onset obese recipients were in this category at transplant. Patients were divided into 3 groups: those who developed obesity, those who became underweight, and those who remained within the normal/overweight category after transplant. Survival conditional on being alive at 2 y post-LTx was subsequently determined. As shown in Figure 3, recipients who developed obesity (7.8 y [95% CI 6.1-9.4]) and those who moved to the underweight category (6.9 y [95% CI 0.0-16.7]) had shorter median conditional survival than recipients who stayed within the normal/overweight category (10.1 y [95% CI 8.6-11.6]; P = 0.005). Median survival of recipients with new-onset obesity did not differ from that of consistently obese recipients who survived at least 2 y post-LTx (9.9 y [95% CI 3.5-16.2]; P = 0.52).

F2
FIGURE 2.:
Survival curves of lung transplant recipients based on body mass index category at transplant. Between-group comparisons were made using the log-rank test. Numbers indicate the surviving recipients at each timepoint.
F3
FIGURE 3.:
Conditional survival curves of normal/overweight lung transplant recipients who were alive at 2 y posttransplant and stratified according to body mass index evolution after transplant. Between-group comparisons were made using the log-rank test. Numbers indicate the surviving recipients at each timepoint.

The causes of mortality are listed in Table 5. The most common cause of death was infection (31%), followed by respiratory failure (21%). Survival distributions did not differ between the causes of death (log-rank test, P = 0.272). Mortality rates did not vary significantly between the groups and the categories of causes of death (P = 0.08).

TABLE 5. - Causes of posttransplant mortality by body mass index trajectories
Causes of death Overall (n = 217) Nonobese (n = 159) New-onset obese (n = 30) Consistently obese (n = 15) Obese with post-LTx weight loss (n = 13)
Respiratory failure 46 (21) 35 (22) 9 (30) 1 (7) 1 (8)
Infections 67 (31) 49 (31) 5 (17) 5 (33) 8 (62)
Cardiovascular 16 (7) 15 (9) 0 (0) 1 (7) 0 (0)
Malignancy 20 (9) 10 (6) 7 (23) 2 (13) 1 (8)
Other causes 38 (18) 28 (18) 5 (17) 4 (27) 1 (8)
Unknown 30 (14) 22 (14) 4 (13) 2 (13) 2 (15)
The categories are detailed in the Methods section. Data are presented as n (%).
LTx, lung transplant.

DISCUSSION

This study describes the rate of new-onset obesity after LTx, its risk factors, and whether this status is associated with the risk of PTDM, MS, and mortality. Our findings revealed that 14% of patients developed new-onset obesity after transplant with overweight candidates, and patients with COPD and other diagnoses were at greater risk. New-onset obesity was associated with a higher risk of posttransplant MS but not PTDM and worse survival than nonobese recipients, which partially confirms our hypothesis.

New-onset obesity has been studied in other solid-organ transplants14-16 but not extensively in the context of LTx. Previous studies showed that the prevalence of obesity increased from approximately 5% at transplant to 7% to 16% in the first 3 y after LTx1,17,18; however, studies have not always clearly stated whether obesity was present before transplantation. We found that 13% of candidates had a BMI in the obese category, with 57% maintaining this status after transplantation. When we combined these recipients with recipients who developed new-onset obesity, the prevalence of posttransplant obesity increased to 21%, which is greater than previously reported rates but lower than that found in Canadian adults (24.3%).19 The discrepancy between our results and others may arise from the short follow-up period of some studies that may have underestimated the true obesity prevalence after LTx. By differentiating new-onset obesity, consistent obesity, and obesity with post-LTx transplant weight loss, our study provides novel information on the clinical trajectories of these subsets of patients.

We showed that overweight patients at transplant and recipients with COPD were at a higher risk of developing new-onset obesity. Previously, we found that overweight LTx recipients lost weight in the early posttransplant period but regained weight between 1 and 2 y.1 Although the magnitude of weight gain was below that of underweight and similar to normal-weight patients, it is probably enough to shift overweight patients into the obese category. The finding that COPD patients are at a higher risk of new-onset obesity raises questions regarding metabolic changes after transplantation. A decline in resting energy expenditure (REE) is commonly seen after transplantation, accentuating the imbalance between energy expenditure and intake; however, a closer look at the factors contributing to this lower REE reveals differences related to primary lung disease. In overweight and obese LTx recipients with COPD, decreased REE was attributed to a lower percentage of fat-free mass secondary to reduced physical activity levels.20 In contrast, in CF recipients, a decline in REE occurred despite a gain in fat-free mass.21 It is also interesting to point out that the nontransplant obese population displayed higher REE values,22 suggesting the involvement of transplant- and disease-specific factors. Posttransplant adaptation of energy metabolism is thus a heterogeneous process that is subjected to many factors.

In our cohort, 53% of recipients developed PTDM, but an obesity status was not associated with a greater risk of developing this complication. Obesity, especially abdominal obesity, is known to promote insulin resistance, which leads to impaired glucose metabolism and ultimately to diabetes. Our results suggest that PTDM onset is more likely attributed to the immunosuppressive medications than to obesity. Metabolic disorders are well-recognized side effects of immunosuppressive therapy.23 Both corticosteroids and calcineurin inhibitors are known to induce dyslipidemia and exert hyperglycemic effects by promoting insulin resistance.23 In addition, corticosteroids cause high blood pressure and enhance appetite, especially for high-fat and high-sugar foods, which may result in the accumulation of truncal fat.

When we looked at MS, which encompasses a cluster of risk factors, we found both new-onset and consistent obesity to be associated with the risk of developing MS. High rates of posttransplant MS were found in the liver,24,25 kidney,26 and heart transplant recipients,27 but there has been limited investigation of LTx recipients. A prospective study of 67 recipients reported rates to increase from 3% before transplant to 24% by 1 y posttransplant,28 whereas others showed a prevalence of MS of 18% in 35 lung recipients.29 In comparison, we found that 11% and 71% of patients had 3 or more MS criteria before and after transplantation, respectively. Such disparity in results may be explained by differences in study populations, notably disease distribution, and our longer follow-up time. The time from transplantation is a major determinant of MS development after heart transplantation.30 The fact that 94% and 98% of recipients with new-onset and consistent obesity developed MS (versus 63% of nonobese) leads us to postulate that obesity triggers the onset of MS in individuals who already have compromised metabolic health. MS predisposes to cardiovascular disease and mortality in the nontransplant population,31,32 yet such an association remains to be determined in LTx. The small number of deaths from cardiovascular causes (n = 16) or malignancy (n = 20) prevented us from further exploring the association between obesity status, MS, and specific causes of mortality.

Consistent with previous reports, we found worse survival among obese recipients when compared with normal-weight patients4,33-36; however, previous work has rarely addressed the impact of post-LTx BMI evolution on mortality. We showed that an unfavorable BMI evolution among obese (weight gain or maintenance) and normal/overweight (weight gain) recipients resulted in a 2.62-fold greater risk of mortality, without distinguishing between trajectories.4 Our study thus extends knowledge by documenting the survival of normal/overweight recipients according to 3 post-LTx BMI trajectories: loss of BMI (normal/overweight to underweight), maintenance of BMI within the normal/overweight range, and gain of BMI (normal/overweight to obese). We found that normal/overweight recipients who managed to maintain their BMI within that range demonstrated a better survival (conditional on 2-y survival) than normal/overweight recipients who became underweight or obese. In fact, recipients with new-onset obesity had a survival comparable to that of consistently obese recipients. The fact that we reported data on recipients who were still alive after 2 y highlights the long-term detrimental metabolic impact of obesity on post-LTx survival. With time, expansion of adipose tissue may trigger inflammatory responses, which, combined with other metabolic perturbations, like high blood pressure, dyslipidemia, or PTDM, may lead to the gradual deterioration of health.

Even though being underweight was associated with a greater risk of mortality post-LTx, few data exist regarding the impact of weight loss among patients transplanted with a BMI within the normal/overweight range. We found a shorter survival in normal/overweight patients who became underweight. A closer look at the causes of death of this subset of patients revealed that one third of them died from infection-related causes. Interestingly, we also found that obese recipients who experienced rapid weight loss after transplantation demonstrated the shortest survival (data not shown) and that nearly two thirds of them died from an infectious cause. Our findings support previous observations made in a larger cohort36 and thus provide additional evidence linking involuntary weight loss to poor posttransplant outcomes.

This is the first study to describe new-onset obesity and report data on PTDM and MS in a large cohort of LTx recipients. By distinguishing outcomes of recipients with consistent obesity, new-onset obesity, and obesity with posttransplant weight loss, our study provides a new perspective on the spectrum of post-LTx obesity. Our study had inherent limitations, including the retrospective design and the single-center setting, which reflects the local practices and characteristics of recipients seen in our institution. Bias may have been introduced due to missing data, particularly MS assessment. Waist circumference was not available in all patients, and we assumed that central obesity was present when BMI was >30 kg/m2, as recommended by the International Diabetes Foundation.37 Given that most obese patients already display 3 other MS criteria, misclassification of obese patients with MS is unlikely; however, some nonobese patients with a waist circumference above the cutoff points may have been misclassified as not having MS, thereby underestimating the prevalence of MS in our cohort. As for patients who died from respiratory failure, the numbers were too small to distinguish between primary graft dysfunction and all phenotypes of chronic lung allograft dysfunction. Last, we did not have access to complete data on corticosteroid dosages. Given the relationship between corticosteroids, enhanced appetite, and weight gain, it would be interesting to explore associations between weight fluctuations, obesity status, and corticosteroid dose regimens or dose tapering over time.

In conclusion, new-onset obesity is not uncommon in LTx recipients. Attention should be given to overweight individuals and those with COPD and other diagnoses more at risk of developing this condition. As post-LTx survival is steadily improving, a better understanding of the spectrum of post-LTx obesity may lead to more personalized weight control strategies.

ACKNOWLEDGMENTS

We would like to thank Miguel Chagnon, MSc, PStat, who provided advice and guidance for the statistical analyses.

REFERENCES

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