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Volume: 18 Issue: 3 June 2020

FULL TEXT

ARTICLE
Changes in Body Mass Index and Outcomes After Kidney Transplant: A Single-Center, Retrospective, Observational Study

Objectives: We aimed to describe changes in body mass index after kidney transplant and to assess how these changes influence long-term outcomes.

Materials and Methods: Data were collected from kidney transplant recipients seen at our center between January 2007 and July 2016. Changes in body mass index over the posttransplant period were modeled using a generalized estimating equation, with changes calculated for each patient from pretransplant to 6 months posttransplant. Calculations were then categorized into 3 body mass index groups: stable (change of ±1.5 kg/m2 or less), reduced (reduction of > 1.5 kg/m2), and increased (increase of > 1.5 kg/m2). Outcomes among groups were compared.

Results: Among 1344 total patients, the geometric mean pretransplant body mass index was 27.3 kg/m2. This declined significantly (P < .001) to a geometric mean of 25.6 kg/m2 at 1 month posttransplant, before increasing and stabilizing to pretransplant levels by 36 months (geometric mean body mass index of 27.2 kg/m2; P = .522). Of 822 patients with body mass index measurements at 6 months, 303 had reduced, 388 had stable, and 131 had increased levels relative to pretransplant levels. On multivariate analyses, 12-month creatinine levels were significantly higher in the reduced cohort, with adjusted levels of 160.6 versus 135.0 μmol/L for the stable cohort. However, no significant associations were detected between 6-month body mass index changes and patient survival, graft survival, incidences of posttransplant diabetes and cancer, and a range of other clinical and histologic outcomes (all P > .05).

Conclusions: Our data demonstrated that body mass index was significantly reduced in the first month after kidney transplant before increasing to pretransplant levels during years 3 to 5. Furthermore, patients who retained decreased levels at 6 months had impaired graft function in long-term follow-up. These obser­vations conflict with the existing literature and warrant further investigations.


Key words : Posttransplant outcomes, Renal transplant, Weight loss

Introduction

Posttransplant weight gain is a well-known occurrence in both obese and nonobese transplant recipients.1-4 This occurrence has been documented in all forms of organ transplant,5-7 and several studies have reported an average increase in weight of 5 to 10 kg in the first year after kidney transplant.2,4,8-10 Weight gain may differ by geographic region, with an average increase in the first year after kidney transplant of 2.7 kg documented in France versus 10.3 kg in the United States,2,11 which likely reflects the environmental confounders that affect weight gain among different cohorts. Posttransplant weight gain is a significant risk, as it has been associated with inferior graft and patient survival,3 and is thought to contribute to cardiometabolic risk profiles, including hypertension,3 diabetes,3 and dyslipidemia12,13 and ultimately increased risk for cardiovascular-related death.14,15

Reasons for weight gain after kidney transplant are multifactorial and likely influenced by individual, environmental, and clinical factors. Immunosup­pressive agents, such as corticosteroids, have been shown to stimulate appetite; induce glucose intolerance, hyperlipidemia, and hypertension; and impair vitamin D metabolism.2,4,16,17 However, immunosuppression with steroid-free agents has failed to significantly reduce this risk, with patients still experiencing weight gain.10,18 Additional influences on weight gain may relate to kidney transplant recipients with excellent graft function no longer having dietary restrictions, which had been advised to patients with advanced kidney disease or failure.19,20

Although the effects of recipient or donor body mass index (BMI) on posttransplant outcomes have been detailed in the literature,21,22 the degree of “risk” conferred by increased or decreased BMI after kidney transplant among recipients is poorly understood. Furthermore, the prevailing literature on this topic is outdated (pre-2001) and is published from centers in the United States. Given the changes in transplant care that have occurred in the past decade and the well-documented differences in clinical outcomes among kidney transplant recipients between Europe and the United States23 (including degree of weight gain seen11), we believe a contemporary analysis in a European transplant cohort is warranted.

Therefore, the aim of this study was to explore the evolution of weight change after kidney transplant and its link to clinical outcomes to help transplant clinicians make evidence-based decisions in relation to weight among kidney transplant recipients.

Materials and Methods

This study received institutional approval from the Queen Elizabeth Hospital (Birmingham, UK) and was registered as an audit (audit identifier CARMS-12578). Furthermore, the protocol conformed to the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent to participate was obtained from each patient. The datasets used and/or analyzed in this study are available from the corresponding author on reasonable request.

Study population
Our analysis included all adult patients (18 years of age and older) who received a living-donor or deceased-donor kidney transplant between January 2007 and July 2016 at our center (excluding recipients of multiple organs). Living transplant donors included living related and living unrelated. We used BMI as our marker of change in weight, as it is the accepted measure for defining anthropometric height/weight characteristics in adults.24

Outcome measures
Our primary outcome measures were patient survival and death-censored graft survival. Secondary outcome measures included clinical outcomes comprising graft function (creatinine levels at 12 months after kidney transplant), incidence of medical complications (eg, posttransplant diabetes mellitus, cancer, cardiac events, cerebrovascular events, cytomegalovirus viremia, urology com­plications, septicemia, and transplant artery stenosis) and histopathologic findings. Because changes in BMI were measured over the 6-month period posttransplant, follow-up for these outcomes commenced at this time. Patients with outcome complications before 6 months were excluded from the analysis of that outcome.

Immunosuppression protocol
All patients received the same immunosuppression as discussed in the SYMPHONY protocol, while the amount of tacrolimus received was reduced.25 Patients received induction immunosuppression with basiliximab and methylprednisolone. Maintenance immunosuppression was tacrolimus (12-hour trough level of 5-8 ng/L) and mycophenolate mofetil (2 g tapering to 1 g daily at 6 months).

To identify any dysfunction in the transplanted graft, biopsies were taken and scored according to the Banff criteria.10 Treatment for patients included corticosteroids for acute rejection, with T-cell depletion if there was steroid-resistant rejection. Patients with antibody-mediated rejection were treated with plasmapheresis with or without intravenous immunoglobulin.

Statistical analyses
We first modeled changes in BMI in the posttransplant period using a generalized estimating equation model. The timing of the measurement was set as the independent variable, and a first-order autoregressive structure correlation structure was used to account for correlations between repeated measures of BMI on the same patient. Because the BMI measurements followed a skewed distribution, the values were log10-transformed, prior to analysis, to normalize the distribution and improve model fit. The coefficients from the resulting model were then anti-logged and converted into estimated geometric means with 95% confidence intervals (95% CI).

To assess the effects of weight changes on posttransplant outcomes, we first calculated the change in BMI 6 months after transplant by subtracting the BMI at transplant from the BMIat 6 months (ie, negative values represented a reduction in BMI). Patients were then stratified into 1 of 3 groups, based on these values: stable BMI (a change within ±1.5 kg/m2), reduced BMI (reduction of > 1.5 kg/m2), and increased BMI (increase of > 1.5 kg/m2). We then compared a range of factors across these 3 BMI groups, using Kruskal-Wallis tests for continuous variables and chi-square tests for nominal variables.

Different outcome measures were then compared across the BMI change groups, with Cox regression models for time to event outcomes and binary logistic regression models for dichotomous outcomes. Creatinine levels were found to follow a skewed distribution; therefore, values were log10-transformed to normalize the distribution before they were analyzed using general linear models, with number of biopsies compared using Kruskal-Wallis tests. Multivariate analyses were then performed for each outcome to account for the effect of confounding factors. Before this analysis, continuous factors were divided into categories, based on the tertiles of the distribution, to improve model fit. All factors were then considered for inclusion in the model, with a backward stepwise approach used to select those that were independently predictive of patient outcome. When significant differences between the BMI groups were detected on multivariate analysis, adjusted outcomes for each group were calculated. This was achieved by multiplying each coefficient by the proportion of patients in the associated category and evaluating the resulting model for each of the 3 BMI groups. This gave the expected outcome for the “average” patient in the cohort, hence removing the impact of confounding factors.

All statistical analyses were performed using IBM SPSS version 22 (SPSS: An IBM Company, IBM Corporation, Armonk, NY, USA), with P < .05 deemed to be indicative of statistical significance throughout.

Results

Trends in body mass index
During the study period, data were available for 1387 transplant recipients, in which 1344 patients (97%) had a recorded pretransplant BMI measurement. These patients had a geometric mean pretransplant BMI of 27.3 kg/m2 (95% CI, 27.0-27.5), which was found to fall significantly by 1 month after transplant to 25.6 kg/m2 (95% CI, 25.3-25.9; P < .001). Average BMI was found to increase progressively over the subsequent months (Figure 1 and Table 1) before stabilizing to approximately the pretransplant levels, reaching a geometric mean of 27.2 kg/m2 by 36 months posttransplant (95% CI, 26.8-27.5; P = .522 vs pretransplant).

Baseline demographics by change in body mass index
Of total patients, 822 (59%) had BMI measurements recorded both before and 6 months after transplant. Of those with missing data, most (n = 417) had returned to their referring center after transplant and thus did not attend local follow-up for BMI to be recorded. A further 27 patients lost their graft and 16 died within 6 months of transplant and so were excluded. Of the remainder, 85 patients did not have their BMI recorded at the 6-month appointment and 30 patients had less than 6 months of follow-up.

Patients with measurements before and 6 months after transplant were divided into 3 groups based on changes in BMI over this time period. Over this period, 36.9% (n = 303) experienced a reduction in BMI of more than 1.5 kg/m2, 15.9% (n = 131) had an increase in BMI of more than 1.5 kg/m2, and 47.2% (n = 388) had stable BMI (ie, change within ±1.5 kg/m2). Table 2 compares the demographic and transplant characteristics across the 3 groups. Overall, recipients with a BMI increase were significantly younger (P < .001) and had a lower BMI at the time of transplant (P < .001). In addition, they tended to receive organs from younger donors (P < .001), were more likely to have received kidneys from living donors (P < .001), and had a reduced rate of delayed graft function (P = .032).

Recipients with BMI reductions were conversely older and had a higher baseline BMI. They received organs from older donors and were more likely to receive kidneys from deceased donors (all P < .001). Both wait time and cold ischemia time followed a U-shaped association, that is, highest in the reduced and increased BMI groups and lower in the stable BMI group (P < .001). Body mass index change and outcomesOn univariate analysis (Table 3), the change in BMI at 6 months posttransplant was not significantly associated with patient survival (P = .384), graft survival (P = .124), incidence of posttransplant diabetes mellitus (P = .628), or risk of cancer development (P = .419). However, a significant difference in 12-month creatinine level was noted (P < .001), with median levels being higher in the reduced BMI group (144.0 μmol/L) and lower in the increased BMI group (117.5 μmol/L).

We performed multivariate analyses for previously identified baseline differences across the 3 groups according to recipient-, donor-, and transplant-related factors to account for potentially confounding factors. The effect of the BMI change remained nonsignificant for all outcomes, except for renal function (Table 4), with the previously noted difference in 12-month creatinine levels remaining significant on multivariate analysis (P < .001). After adjustment for confounding factors, creatinine levels at 12 months posttransplant were found to be 19% higher in patients who had a reduction in BMI versus those with stable BMI. When we evaluated the model at the midpoint of the confounding factors, we estimated adjusted creatinine levels of 160.6 μmol/L in the reduced BMI group, 135.0 μmol/L in the stable BMI group, and 131.0 μmol/L in the increased BMI increase.

We further conducted a subsidiary analyses of clinical and histologic outcomes, the results of which are presented in Table 5. Overall, in univariate analysis, changes in 6-month BMI were not associated with any risk of cardiac or cerebrovascular events, cytomegalovirus viremia, septicemia, or transplant renal artery stenosis (all P > .05). Furthermore, no association between 6-month BMI change and histologic rejection was seen (all P > .05).

Discussion

To our knowledge, this is the largest study to analyze the relationship between BMI or weight change and outcomes after kidney transplant outside of the United States. Interestingly, BMI was not seen to rise significantly posttransplant among our cohort, with a geometric mean BMI of 26.6, 27.0, and 27.2 kg/m2 at 6 months (P < .001), 1 year (P = .005), and 3 years (P = .522) after transplant compared with 27.3 kg/m2 before transplant. After stratifying cohorts by their change in BMI at 6 months, we noted a higher average creatinine level at 1 year among patients with reduced BMI in multivariate analysis (P < .001), with an adjusted average of 160.6 μmol/L in the reduced BMI cohort compared with 135.0 μmol/L in the stable BMI group. However, there were no significant differences in patient survival, death-censored graft survival, or any posttransplant medical complication.

Our results add to the conflicting previous studies in this area. Although there are several small single-center studies on this topic, analyses that include large cohorts are lacking. The most recent analysis, from Switzerland, assessed 777 kidney transplant recipients from 2008 to 2013.26 Overall weight initially dropped in the first 6 months after transplant by an average of 1.2 kg. Thereafter, posttransplant weight gradually increased, with a mean 1.2 kg weight gain at 3 years after transplant compared with the 6-month value. el-Agroudy and colleagues performed a similar analyses in 650 kidney transplant patients between 1990 and 2001 in Mansoura, Egypt.3 In contrast, their study reported a marked increase in body weight in the first 6 months after kidney transplant, with a trend for slow increases in subsequent years. Furthermore, this study stratified patients by their 6-month BMI into the following cohorts: < 25 kg/m2, 25 to 30 kg/m2, and > 30 kg/m2. In multivariate analysis, the authors reported a significantly increased risk in graft failure and patient death among the obese cohort. In addition, they observed higher incidence of post­transplant diabetes mellitus, hypertension, and ischemic heart disease in the obese cohort. However, there were methodologic differences between our analyses (such as our focus on temporal change in BMI rather than a specific time point).

Interestingly, a recent analysis from Harhay and colleagues27 identified that pretransplant weight loss of > 10% from listing to transplant was associated with prolonged hospital stay, increased risk of graft loss (adjusted hazard ratio of 1.11; 95% CI, 1.06-1.17; P < .001), and mortality (adjusted hazard ratio of 1.18; 95% CI, 1.11-1.25; P < .001) relative to the < 5% weight loss cohort. Although this study measured weight loss before transplant and ours measured changes after transplant, we noted similar findings among our cohorts.

Although kidney transplant recipients are appropriately counseled with regard to the long-term risk of weight gain, it could be argued that the immediate period after stressful kidney transplant may contribute to weight loss rather than weight gain. In addition, corticosteroid exposure (which is at its highest in the early posttransplant period) should contribute to increased appetite; however, this could be countered by gastrointestinal side effects from mycophenolate mofetil, including nausea, vomiting, and/or diarrhea attenuating appetite. These adverse effects have been well detailed within the literature. Postoperative complications or severe illnesses could also impact nutritional status and lead to weight loss as opposed to weight gain, but there were no suggestions of more significant com­plications in the reduced BMI group in our data analyses (either within the first 6 months or thereafter). It has been reported that kidney transplant recipients objectively drop their frailty scores in the immediate few months after kidney transplant compared with at time of transplant, beyond rebounding,28 and our observation of reduced BMI could be a surrogate measure of this physiologic change. Being inactive posttransplant could also lead to a significant reduction in both muscle mass and fat (ie, a reduction in overall weight). However, frailty status is not a routinely checked parameter after kidney transplant; therefore, we did not have the ability to check for any association.

Alternatively, we must consider that the pre­transplant weight measurement may not be a true reflection of the patient’s actual weight. Patients in renal failure may have significant water retention (edema), leading to a false increase in pretransplant weight. Improved kidney function in the post­transplant period may lead to a reduction in this water retention and thus an early reduction in BMI, as we observed. In an observational study by Beckmann and associates, early weight loss in the 6 months posttransplant was seen in the liver transplant cohort only (with a mean reduction of weight of 5 kg), whereas kidney, heart, and lung transplant recipients all had increased weight in the first 6 months posttransplant. The authors attributed such weight loss to the patient’s edema and ascites associated with liver failure pretransplant that resolved in the posttransplant period.26 Unfortunately, we were unable to determine the degree of any potential preexisting water retention/edema among our cohort.

The importance of our data rests in the lifestyle modification advice that we offer our kidney transplant recipients. The KDIGO clinical practice guidelines for the care of kidney transplant recipients has the following recommendation29: “We recom­mend that patients are strongly encouraged to follow a healthy lifestyle, with exercise, proper diet, and weight reduction as needed.” Although this lifestyle intervention advice is relevant over the long-term, we must ensure adequate advice is offered to prevent BMI loss in recipients early after kidney transplant where it is not intended (eg, in those with normal weight at time of transplant). Patients with chronic kidney disease or who are on dialysis therapy often benefit from input from a renal dietitian, but this support can be lost after kidney transplant. Our study reinforces the value of such allied health professional support in the overall care that is offered to patients after kidney transplant. This is important in light of our results showing inferior graft function at 12 months after kidney transplant. Further work is warranted to understand the mechanisms behind this and to understand what drives the loss of BMI for some kidney transplant recipients and how this may relate to inferior graft function.

There are several limitations to our analysis that we must consider when interpreting the results. This study was retrospective and single center in design, and we must acknowledge these limitations. Certainly, there will be covariates and confounders that we cannot adjust for in this analysis that could affect graft function and patient survival. For example, the underlying reason for weight loss after kidney transplant was not ascertained, and this is of critical importance, as BMI loss out of choice as a lifestyle intervention choice will be different from weight changes due to critical illness. Furthermore, BMI is not an ideal measure of body mass and does not differentiate muscle and fat mass. However, it provides us with real-world data that can influence the decision-making process to assess posttransplant body mass changes.

Conclusions

We reported a significant weight reduction among kidney transplant recipients in the months after transplant, with return to pretransplant levels after between 3 and 5 years. This should reassure transplant physicians that weight gain after transplant, which is often reported in the literature, may not be as common in some transplant cohorts. Importantly, we reported inferior graft function among patients with the greatest BMI reduction; thus, greater emphasis on assessing and mitigating this weight loss should be enacted by transplant teams.


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Volume : 18
Issue : 3
Pages : 292 - 299
DOI : 10.6002/ect.2019.0416


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From the 1College of Medical and Dental Sciences, University of Birmingham; the 2Institute of Translational Medicine, Queen Elizabeth Hospital; the 3Department of Nephrology and Transplantation, Queen Elizabeth Hospital; and the 4Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
Acknowledgements: The authors have no conflicts of interest or funding to declare. The results presented in this paper have not been published previously in whole or part, except in abstract form at the ERA-EDTA 2019 and ATC 2019 conferences.
Corresponding author: Adnan Sharif, Department of Nephrology and Transplantation, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2WB, UK
Phone: +44 121 371 5861
E-mail: adnan.sharif@uhb.nhs.uk