Both undernutrition and overnutrition can affect the quality of life and survival of patients with pulmonary disease (1 2,3
Patients with lung disease may be underweight, normal weight, or overweight. The cause of weight loss in pulmonary disease is multifactorial and includes altered metabolism (4 5 6
Immunosuppressive therapy after transplantation has been shown to alter skeletal muscle metabolism (7 8 9 10
Thus the evaluation of FFM and body fat in pre-LTR and post-LTR patients can aid in adapting nutrition support, for example, nutrition support in malnutrition and food restriction in obesity. Objective, versus subjective, body-composition measurements can provide valuable information on FFM and body fat mass changes before and after LTR. Recent advances in body composition include the development of easy, noninvasive, and inexpensive bedside techniques, for example, bioelectrical impedance analysis (BIA) for the determination of FFM (11 12 13 2 ), for example, determines if lower FFM with age is the result of shorter height in older subjects or the result of changes in body composition.
Currently there are no studies that evaluate weight changes, and none have reported longitudinal changes in FFM and body fat in LTR patients. The purpose of this longitudinal study was to determine the changes in weight, FFM, and body fat before and up to 4 years post-LTR.
METHODS
Subjects
Between June l993 and January 2001, 61 LTRs were performed at the Geneva University Hospital. This retrospective evaluation includes 297 measurements in 37 LTR patients. Patients were excluded if they died the first year after transplant (n=18), were children (n=3), or had insufficient body composition data (n=3). Body composition was measured at 1 to 6 months pre-LTR and 1, 3, 6, 9, 12, 18, 24, 36, and 48 months post-LTR. Pre-LTR body composition measurements were missing in three patients. Thirty-seven healthy volunteers, matched for age (±2 years) and height (±2 cm), were used as controls.
Immunosuppressive medications prescribed after LTR included induction therapy with antilymphocyte antibodies before 1998 and use of specific antibodies against interleukin-2 receptors after l998. Other immunosuppressors were cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, and steroids (initially 0.5 mg/kg/day, decreased to 0.2–0.3 mg/kg/day since l997, and tapered to 5–10 mg/day beyond the sixth month).
The LTR follow-up protocol was established in l993 and adapted on a yearly basis by the LTR team. Body composition measurements are part of the battery of objective measurements that constitute the protocol of LTR. Patients, by consenting to an LTR, agree to a certain number of tests, including body-composition measurements. Informed consent was obtained from subjects before being placed on the LTR waiting list.
Anthropometric Measurements and Bioelectrical Impedance Analysis
Body height was measured to the nearest 0.5 cm, and body weight was measured to the nearest 0.1 kg on a balance beam scale. Body composition was determined by 50 kHz BIA (Bio-Z, Spengler, Paris, France), as previously described (14 15,16
FFM was calculated using a previously validated multiple regression BIA equation (16 EQUATION
Cross-validation of BIA with dual-energy x-ray absorptiometry (DXA) was excellent:r =0.986, standard error of the estimate (SEE)=1.72 kg, and technical error 1.74 kg. This same BIA equation was also validated in elderly subjects (17 12
FFMI and BFMI (kg/m2 ) facilitate body composition interpretation by normalizing for differences in height. Ranges of FFMI and BFMI were derived from polynomial regression equations for each of the body mass index (BMI) cutoffs (20, 25, and 30 kg/m2 ) from our healthy subjects (n=5,635) (18 2 ), normal weight (20–25 kg/m2 ), overweight (25–30 kg/m2 ), and obesity (>30 kg/m2 ). The respective FFMI and BFMI categories are low, normal, high, and very high.
FFMI was considered:
Low if less than 17.4 kg/m2 (men) and 15.0 kg/m2 (women)
Normal if 17.5 to19.7 kg/m2 (men) and 15.1 to 16.6 kg/m2 (women)
High if greater than 19.8 (men) and 16.7 kg/m2 (women)
BFMI was considered:
Low if less than 2.4 kg/m2 (men) and 4.8 kg/m2 (women)
Normal if 2.5 to 5.1 kg/m2 (men) and 4.9 to 8.2 kg/m2 (women)
High if 5.2 to 8.1 kg/m2 (men) and 8.3 to 11.7 kg/m2 (women)
Very high if greater than 8.2 kg/m2 (men) and 11.8 kg/m2 (women).
Statistical Analysis
Descriptive statistics were calculated for height, weight, percentage of ideal body weight, BMI, and body composition parameters and are expressed as mean ± standard deviation (x±SD). Unpaired t tests were used to test differences between volunteers and patients, and between pre-LTR and selected post-LTR measurements (1 year, 2 years, 3 years, and 4 years). Simple linear regressions were calculated between weight change and FFM change and body fat change using the StatView 5.0 statistical program (SAS Institute, Cary, NC). Statistical significance was set at P =0.05 or less for all tests.
RESULTS
Twelve of the 37 patients demonstrated a single LTR (Table 1 ). The patients, aged 18 to 63 years, were between 10 months and 8 years post-LTR. Five patients died at 1 to 5.5 years after LTR. Anthropometric and BIA data of patients and healthy age- and height-matched volunteers are shown in Table 2 . Patients showed lower weight, BMI, and percentage of ideal body weight at the pre-LTR evaluation than volunteers. The BIA-determined resistance was significantly higher in patients than volunteers. Higher resistance values indicate lower FFM.
Table 1: Diagnosis leading to lung transplantation and time since transplantation
Table 2: Anthropometric characteristics of healthy volunteers and patients at the time of the pretransplant evaluation
Body Composition Before and After Transplantation
Table 3 shows the body weight and body composition measurements during follow-up. Weight, FFM, and FFMI were significantly lower in LTR men and women than controls during year 1, and FFM and FFMI were significantly higher than pre-LTR measurements beginning at year 1 and remained higher thereafter. Weight, FFMI, and BFMI increased progressively throughout the 4 years of follow-up in women and until 2 years in men and remained stable thereafter (Table 3 ). BFMI was nonsignificantly lower during the first 9 months of follow-up (except for lower BFMI at 1 and 3 months in men) and nonsignificantly higher thereafter. The percentage of body fat increased progressively until 2 years in men and 18 months in women and remained stable thereafter (Table 3 ).
Table 3: Body composition characteristics of healthy controls and patients with varying length of posttransplant follow-up
Thus, the increase in weight after LTR was the result of an increase in FFM and body fat. Weight, FFM, FFMI, and BFMI in men, and weight, FFM, and FFMI in women were lowest at l month post-LTR, whereas BFMI and percentage of body fat in women were lowest before LTR (Table 3 ).
Weight, Fat-Free Mass, and Body Fat Changes After Transplantation
Mean weight changes were +16.6%, +3.2%, −0.2%, and −3.2% and FFM +14.0%, +2.5%, −0.3%, and −1.0% during years 1, 2, 3, and 4, respectively. During year 1, all patients gained weight (+0.5–+22.2 kg), and 28 of 30 patients gained FFM (+1.7–+ 12.5 kg); one patient demonstrated no change and one lost −1.4 kg. During the second year, three of 27 patients developed obliterative bronchiolitis. These patients presented with a loss of −5.1, 0, and −5.1 kg compared with a gain of 2.7, 1.3, and 1.4 kg of weight, FFM, and body fat, respectively, in obliterative bronchiolitis-negative patients. Similarly, during the third year, 5 of 24 patients were positive and presented with a loss of −4.7, −0.8, and −3.8 kg compared with stable weight, FFM, and body fat in obliterative bronchiolitis-negative patients. During year 4, seven patients were positive for obliterative bronchiolitis, and these patients continued to lose weight, FFM, and body fat (−4.1, −1.3, and −2.8 kg, respectively) compared with a weight and body fat mass loss (−1.3 kg) and stable FFM in obliterative bronchiolitis-negative patients.
Figure 1 shows the percentage of weight, FFM, and body fat mass change during the 4-year follow-up period, compared with pre-LTR measurements in patients without and with obliterative bronchiolitis. Compared with pre-LTR measurements, the percentage of weight, FFM, and body fat were highest at 3 years post-LTR in patients without obliterative bronchiolitis. In patients with obliterative bronchiolitis, mean weight, FFM, and body fat decreased 2 years after LTR and was only 104% to 105% of pre-LTR values at 4 years post-LTR, compared with 114% to 116% for weight and FFM and 125% for body fat in obliterative bronchiolitis-negative patients.
Figure 1: Percentage of body weight change (top ), fat-free mass (FFM) change (middle ), and body fat (bottom ) between pretransplant (PR) and 1 to 48 months posttransplant evaluation in patients without obliterative bronchiolitis syndrome (BOS) (left ) and those who develop BOS after 24 months of follow-up (right ). The pretransplant measurement was the baseline measurement (100%). The horizontal lines of the box plots represent the 25th, 50th (median), and 75th percentile and the error bars the 10th and 90th percentiles. The increase in percent of weight, FFM, and body fat is lower in patients with BOS than those without BOS.
Proportion of Fat-Free Mass and Body Fat Mass Change to Body Weight Change
Figure 2 shows the respective changes in FFM and BF in comparison with body weight changes. The FFM increased by 0.39, 0.25, 0.21, and 0.48 kg for each kilogram of weight change during years 1, 2, 3, and 4, respectively. The FFM change was higher (39% of weight) during year 1 than during year 2 (25%) or year 3 (21%). From these results it can be concluded that an increase in weight resulted in an FFM increase, whereas weight loss was accompanied by an FFM loss.
Figure 2: Correlations between changes in weight and ▴ FFM, and weight and ▪ body fat (BF) during year 1 (top left ), year 2 (top right ), year 3 (bottom left ), and year 4 of follow-up (bottom right ). The respective FFM and BF changes are expressed in relation to body weight changes. The FFM change was higher (39% of weight) during year 1 than during year 2 (25%) or year 3 (21%).
Underweight and Overweight Versus Low Fat-Free Mass Index and Very High Body-Fat Mass Index
At 1-month post-LTR, 33.3% of men and 42.5% of women were underweight (BMI <18.5 kg/m2 ), compared with 76.2% of men and 85.7% of women with low FFMI (Fig. 3 ). At year 1, 26% and 57% demonstrated low FFMI, but only 5.3% and 21.5% of men and women, respectively, were underweight. Twenty-eight percent of men and 38% of women showed a low FFMI at year 2.
Figure 3: Prevalence (%) of low, normal, and high fat-free mass index (FFMI) in male (top ) and female (bottom ) volunteers and patients at pretransplant and posttransplant (1–48 months) follow-up evaluation.
At 1-month LTR, 4.8% of men and none of the women were obese (BMI >30 kg/m2 ), but 10% and 7.1% of men and women, respectively, were in the very high (obese) BFMI range. The prevalence of very high BFMI increased considerably from 18 to 24 months (8%–38%) and 24 to 36 months (7%–33%) in men and women, respectively. In comparison, 14.3% of men and 15.4% of women were obese at year 2. Thus, BMI underestimated the prevalence of FFM depletion and very high BFMI and was inadequate to evaluate nutritional status in LTR patients. Weight gains noted after LTR were responsible for an increase in obesity rates.
DISCUSSION
Protein calorie malnutrition and obesity is often severe in respiratory insufficiency patients before and after lung LTR. Currently there are no studies that evaluate weight changes, and none have reported longitudinal changes in FFM and body fat in LTR patients. The purpose of this longitudinal study was to determine the changes in weight, FFM, and body fat mass before and up to 4 years post-LTR.
Underweight and Overweight
Both low and high BMI have been reported to be significant risk factors for nonsurvival after transplantation (19 2 and above 27 kg/m2 , respectively, compared with 40% and 20% of Canadian LTR patients (20 8 2
Weight Changes
The weight loss noted between pre-LTR and 1-month post-LTR measurements were probably the result of inadequate calories and protein intake and hypermetabolism (21
The weight increased by 16.6% (translating into 9.4 and 9.0 kg) in men and women, respectively, during year 1. Smaller increases were noted during year 2 (+3.2% or 4.6 kg in men and 2.9 kg in women). Thereafter, weight gains and losses were noted in patients.
Fluctuations of ±2 kg were clinically insignificant. A weight loss of 2 to 4 kg was noted in several patients who were in good health and who believed that losing some of the (excess) weight would improve their overall well-being. Three of the 5 patients who died showed significant weight loss (>4 kg) during the 12 months preceding death. However, only one patient with obliterative bronchiolitis died during the 4-year study period. Two patients with significant weight loss required retransplantation. Thus, it is important to evaluate changes in weight and determine whether the weight loss is voluntary or the result of changes in overall health status, graft rejection, or organ failure.
The dietitian saw the patients at each time point in which a body composition measurement is reported in this study. The dietitian consultation served to discuss body composition results and to adapt the diet, depending on weight, FFM, and body fat gain or loss. Despite this, FFM change was negative during the first 3 months, and only small gains in weight and FFM were seen at 6 months. It is likely that the small FFM gains are the result of the limited physical activity level during the first 3 months after LTR.
Fat-Free Mass and Body-Fat Mass Changes
Table 3 and Figure 1 show significant weight and FFM increases after LTR. A diagnosis of obliterative bronchiolitis after LTR was associated with loss of body weight, FFM, and body fat in this study. During years 2, 3, and 4, three, five, and seven patients, respectively, were diagnosed with obliterative bronchiolitis. These patients consistently showed weight, FFM, and body fat loss compared with weight, FFM, and body fat mass gain during years 2 and 3 and small decreases in weight and body fat (−1.3 kg) and stable FFM during year 4 in obliterative bronchiolitis-negative patients. Thus, weight, FFM, and body fat loss are associated with obliterative bronchiolitis and indicate poor outcome.
The weight increases during year 1 were responsible for normalization of FFM. The use of FFMI permits comparison of subjects with differing age and height. Figure 3 shows that 76.2% of men and 85.7% of women were FFM depleted (low FFMI) at 1-month post-LTR, whereas two-thirds of FFM-depleted men and 56% of FFM-depleted women normalized their FFM by year 2. Thus, a significant proportion of patients reached age- and height-expected quantities of FFM by year 2. There was no difference in the prevalence of low FFMI and high BFMI between obliterative bronchiolitis-positive and bronchiolitis-negative patients. The increases in weight led not only to beneficial effects of normalizing FFM but also to an increased risk of obesity after LTR. Body fat mass increases were less than half of increases reported in liver transplant patients (10
Our study contradicts liver and heart posttransplant studies that do not show increases in FFM, except in the presence of exercise. Hussaini et al. (10 22 23
Refeeding after energy deprivation has been shown to increase FFM in anorexia nervosa (24 25 26 25 25 25 27
Effects of Physical Activity on Body Composition
The discrepancies in FFM changes between our data and studies reported in heart and liver patients may be the result of a greater proportion of LTR patients being underweight before LTR (33.3% and 42.5% demonstrated a BMI <18.5 kg/m2 and 76.2% and 85.7% of men and women, respectively, were FFM depleted, Figure 3 ) and of significant increases in physical activity after LTR. Our end-stage respiratory disease patients were extremely inactive in the pre-LTR period. Subjective observations indicate that activity level began to normalize 3 to 6 months after LTR and stabilized at 30 to 60 min of walking per day in most subjects. Two subjects reported significantly greater activity levels (3–5 hr of walking and mountain biking per day). We also noted subjectively that those patients who were least physically active gained the most body fat. Van den Ham et al. (28
Effects of Steroid Therapy
Steroid treatment may also affect body composition by inducing alterations in substrate oxidation. Horber et al. (29
Metabolic Alterations After Organ Transplantation
Metabolic responses after lung, liver, and renal transplantation may also account for some of the differences in FFM gain after transplantation. Plank et al. (22 22 30 31
Proportion of Fat-Free Mass and Body Fat Mass Change to Body Weight Change
Forbes (32 Fig. 3 ) between FFM and weight changes in our subjects showed a change of 0.39 and 0.25 kg FFM per kilogram of weight change during year 1 and year 2, respectively. Thus, the FFM increases after LTR were in the expected ranges of change noted during recovery from energy deprivation. FFM to weight gain changes were higher in the early versus later recovery period, whereas higher rates of body fat to weight change were noted during years 2 and 3, compared with year 1. The higher FFM change to weight change ratio noted during year 4 may be the result of differences in the ratio, depending on whether weight and FFM changes were gain or loss. Further research is necessary to determine the magnitude and profile of the FFM to weight gain or loss changes in healthy and ill subjects.
Limitations of Study
The BIA methods used may be criticized, but they have been optimized for this study, namely, water and electrolyte abnormalities are known to influence body composition measurements, including BIA measurements. Mild nonvisible hydration abnormalities (overhydration) may have been present in some patients, and the FFM may have been overestimated. However, we have simultaneous data by BIA and DXA for 184 of the 297 measurements included in this study and found that the mean bias for FFM between DXA and BIA was −0.4±1.5 kg, range −3.9 to 3.4 kg, r =0.987, and SEE=1.5 kg. Thus, there is good agreement between BIA and DXA in our data. We believe that our BIA results are valid, and that the greater increases in FFM seen in lung patients compared with liver patients were not the result of methodologic errors. DXA was not used in this study because of too much missing data at various times during the 4-year study period, which would have severely limited the number of subjects at various follow-up time points.
Because of the use of single frequency BIA, no attempt was made to evaluate total body water and its tissue distribution and changes in pre- and posttransplant patients. Such information is of interest and should be included in future research protocols.
CONCLUSION
LTR results in increases in weight, FFM, and body fat. Two-thirds of the patients reached normal or high levels of FFM by year 2. A weight increase resulted in an FFM increase, whereas weight loss was accompanied by an FFM loss. The FFM increases noted after LTR indicate that despite posttransplant infections and grafts rejection, LTR permits FFM recovery. A diagnosis of obliterative bronchiolitis after LTR was associated with loss of body weight, FFM, and body fat. Body composition assessment is useful for the evaluation of nutritional status, especially in patients in whom clinical prognosis depends on adequate FFM and adequate but not excessive body fat reserves. Nutritional therapy should aim to minimize weight and FFM loss during the pre-LTR period and encourage early weight gain and increased physical activity after LTR.
Acknowledgments.
The authors thank Pascale Chevrolat and Laurie Karsegard for technical assistance.
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