Weight Gain After Simultaneous Kidney and Pancreas Transplantation

Abstract

Background. 

Excessive weight (EW) gain is common after solid organ transplantation, but there is little information concerning obesity after pancreas transplantation. The study goal was to characterize EW gain after kidney-pancreas (KP) transplantation.

Methods. 

This was a retrospective single-center review of 100 KP recipients transplanted between September 2007 and June 2015.

Results. 

The median percent weight gain for all recipients at 1 year posttransplant was 10% (interquartile range, 2.7%–19.3%) of baseline weight. EW gain, defined as greater than or equal to a 19% 1-year increase in weight, included all recipients (n = 26) above the upper limit of interquartile range for weight gain at 1 year. In multivariate analysis, recipient age <40 years, the use of tacrolimus/mammalian target of rapamycin immunosuppression, and an acute rejection event were independent risk factors for EW gain. At a mean follow-up of 43±23 months, there was no difference in patient or graft survival between the EW and non-EW cohorts. Although mean hemoglobin A1c levels between groups were equivalent, the EW versus non-EW cohort displayed a significant increase in mean insulin levels and a trend towards higher C-peptide levels. Criteria for posttransplant metabolic syndrome was met in 34.6% of EW versus 17.6% of non-EW cohorts (P = 0.07).

Conclusions. 

At intermediate-term follow-up, EW gain after KP transplantation was not associated with an increased risk of death or graft loss, although there was a trend toward a greater risk of posttransplant metabolic syndrome. There may be a metabolic consequence of successful pancreas transplantation that results in EW gain in a proportion of recipients, leading to an increased risk of long-term cardiovascular complications.

INTRODUCTION

Excessive weight (EW) gain has been reported after both kidney and liver transplantation, but there is scant information concerning the risk of obesity after pancreas transplantation.^1-6 Potential complications associated with posttransplantation obesity include graft loss, development of the metabolic syndrome, and an increased risk of cardiovascular death. Recognized risk factors for posttransplantation weight gain include both younger recipient age and immunosuppressive medications.^3,6,7 In particular, the use of corticosteroids has been implicated in weight gain.^8,9

As commonly performed, the portal vein of the transplanted pancreas drains insulin directly into the peripheral circulation, resulting in peripheral insulin levels that are higher than that of an endogenous pancreas that has hepatic extraction first. Peripheral hyperinsulinemia has direct effects not only on glucose but also on fatty acid metabolism and can promote weight gain. For that reason, we were interested in the association between peripheral hyperinsulinemia and weight gain. Specifically, we hypothesized that elevated insulin levels may result in EW gain and progression to posttransplant metabolic syndrome (PTMS).

The aim of this retrospective single-center study was to characterize EW gain after kidney-pancreas (KP) transplantation. Specifically, we sought to determine both the incidence and characterize pretransplant risk factors for excessive posttransplant gain. Furthermore, we wanted to examine the relationship between peripheral hyperinsulinemia and weight gain. Finally, we hoped to determine whether there was an association between EW gain and the development of PTMS and early cardiovascular death.

MATERIALS AND METHODS

Patient Population

This was a retrospective single-center review of consecutive primary KP recipients transplanted between September 2007 and June 2015 from the Houston Methodist J.C. Walter Transplant Center in Houston, Texas. Patients with either type 1 or type 2 insulin-dependent diabetes with end-stage renal disease were considered as candidates for KP transplantation. Patients with type 2 diabetes considered for KP transplantation were nonobese (defined as a body mass index [BMI] of <30 kg/m²), with an elevated C-peptide level and daily insulin requirements of <0.7 units/kg/day. All recipients were followed for a minimum of 1 year. Recipients with graft failure before 1 year were excluded from analysis. The Houston Methodist Hospital Institutional Review Board approved this study.

Surgical Procedure

Both kidney and pancreas grafts were placed in an intra-abdominal position. The kidney was anastomosed to the left external iliac vessels with a lich ureteroneocystostomy over a double j stent. The pancreas was anastomosed to the right iliac vessels with systemic venous drainage and enteric exocrine drainage.

Immunosuppression Protocol

As per institutional protocol, all recipients received a 5-day course of rabbit anti-human thymocyte globulin for a cumulative dose of 7.5 mg/kg. Tacrolimus was initiated when the serum creatinine fell at least 25% from baseline. Tacrolimus doses were targeted to a trough level of 8–10 ng/mL until 3 months posttransplant, when the range was lowered to 6–8 ng/mL. Mycophenolate mofetil was initiated on the day of surgery at a dose of 500 mg twice daily and then increased to 1000 mg twice daily at completion of all antithymocyte globulin dosages (d 6 posttransplant). Methylprednisolone (250 mg) was given on the day of transplantation and then tapered to 30 mg of prednisone by day 3 posttransplantation. Corticosteroids were discontinued by 7 days posttransplantation for recipients considered to be at low-risk of acute rejection (non–African American recipients receiving a first transplant and with a peak pretransplant panel reactive antibody <20%). All other KP recipients were gradually tapered to a maintenance dose of 5–10 mg/day of prednisone by 1-month posttransplantation. Beginning in December 2009, the majority of recipients were converted at 1-month posttransplantation, from full-dose tacrolimus and mycophenolate mofetil to a mammalian target of rapamycin (mTOR) inhibitor, either sirolimus or everolimus (target trough level of 4–6 ng/mL) and reduced-dose tacrolimus (target trough level of 2–4 ng/mL) immunosuppressive regimen.

EW Gain Definition

For this report, we arbitrarily defined EW gain as the upper limit of the interquartile range (IQR) of weight gain dispersion for the cohort at 1 year. As the IQR is the middle 50% of recipient weight gain, we thus defined the EW gain cohort as the upper quartile of recipient weight gain. Based on this value, the remaining recipients were defined as the non-EW group.

Metabolic Values

Serum fasting glucose, C-peptide, insulin, and hemoglobin A1c (HgbA1c) levels were measured on all recipients at 1, 3, 6, 9, 12 months, then 6 months thereafter, as part of a standard clinical protocol at our center for pancreas graft surveillance.

PTMS, based on the World Health Organization definition¹⁰ and utilized by Charlton et al⁷ in a study of weight gain after liver transplantation, required at least 3 of the following factors: obesity (BMI >30 kg/m²), serum triglyceride level >150 mg/dL, or treatment for hyperlipidemia, high-density lipoprotein level <39 mg/dL in men and <50 mg/dL in women, hypertension (systolic blood pressure ≥140 mm Hg or treatment for hypertension), and fasting plasma glucose of 100 mg/dL or greater, or oral glucose-lowering therapy.

Statistical Analysis

Baseline data are reported as medians (range) for continuous variables and as frequencies and percentages for categorical variables. Differences between groups were compared using chi-square or Fisher exact test (where appropriate) and logistic regression. Odds ratio with 95% confidence intervals (CI) were reported. Multiple logistic regression models were fitted using the Bayesian model averaging method to identify the significant risk factors associated with EW gain.¹¹ Change over time in body weight and continuous lab parameters were analyzed within each group using linear mixed models with repeated time factor set at baseline and months 1, 3, 6, 9, 12, 36, 48, and 60. Post hoc marginal pairwise comparisons were performed to obtain the adjusted means (95% CIs) of change over time of each continuous variable from baseline to 12 and 60 months. All the analyses were performed on Stata version 15.1 (StataCorp LLC, College Station, TX). A P of <0.05 was considered statistically significant.

RESULTS

Of 114 consecutive KP transplants performed at this center between September 2007 and June 2015, 100 recipients were included in this analysis. Fourteen recipients were excluded because of either graft thrombosis (n = 6), or death with function (n = 3) resulting in graft loss before 1 year posttransplant; 5 recipients were excluded because of incomplete follow-up data. Demographic and metabolic factors of the study group are shown in Table 1. Of note, at the time of transplantation, the median BMI of the entire cohort was <25 kg/m². Thirty-six percent of recipients were transitioned to an mTOR at 1-month posttransplantation, and 40% of recipients were prednisone-free. Whereas the median pretransplant C-peptide level was 0.1 ng/mL, there were 7 recipients with a level >2.9 ng/mL (range, 3.0–13.8 ng/mL), whom we defined as having type 2 diabetes. Five of those recipients displayed a pretransplant BMI of <25 kg/m², whereas 2 were overweight (BMI, 25.9 and 26.7 kg/m²).

TABLE 1.: Recipient demographic and metabolic factors (n = 100)

Weight Gain

The mean percent weight gain for all recipients at 1 year posttransplant was 10% (IQR, 2.7% to 19.3%) of baseline weight. For this study, we defined EW gain as greater than or equal to a 19% gain in weight at 1-year transplant, as this corresponded to all recipients above the upper-limit IQR of weight gain for the entire cohort at 1 year posttransplantation, as described above. Based on this value, 26% (n = 26) of recipients gained an excessive amount of weight by 1 year posttransplant. As shown in Figure 1, the EW gain (EW) cohort gained 30% of baseline weight at 1 year posttransplantation compared with 7% for the non-EW cohort (n = 71, P < 0.001). Expressed another way, over the first posttransplant year, the mean BMI of all recipients increased by 2.7 kg/m² (95% CI, 2.3–3.0), the mean BMI of the EW cohort increased by 7.0 kg/m² (6.3, 7.8), and the mean BMI of the non-EW cohort increased by 1.2 kg/m² (0.7, 1.6, P < 0.001). Beyond the first year posttransplantation, there was continued BMI increase in both cohorts, with a mean BMI increase of 11.4 kg/m² (8.9, 13.8) in the EW cohort versus 2.2 kg/m² (0.8, 3.6) in the non-EW group from transplant to 5 years posttransplant (P < 0.001).

FIGURE 1.: Pancreas graft function of no EW vs EW recipients over time. Percent weight gain of excessive weight (EW) gain vs non-EW gain (No EW) groups. CI, confidence interval.

Risk Factors for Weight Gain

We next examined a number of demographic and metabolic variables to determine risk factors for EW gain posttransplantation. In univariate analysis, recipient age < 40 years, a C-peptide level > 0.5 ng/mL at the time of transplantation, and a steroid-free immunosuppression regimen were significantly associated with EW gain (Table 2). However, in multivariate analysis, among those variables, only recipient age <40 years remained as a risk factor for EW gain. Additionally, the use of Tac/mTOR immunosuppression and an acute rejection event within the first year posttransplant were also found to be independent risk factors for EW gain (Table 3).

TABLE 2.: Univariate analysis of risk factors for EW gain after transplantation

TABLE 3.: Characteristics associated with excessive weight gain, multiple logistic regression modeling

As noted above, there were 7 recipients that were defined as type 2 diabetics, based on higher C-peptide levels (3.0–13.8 ng/mL) pretransplant. Five of these 7 recipients gained an excessive amount of weight posttransplant. Although not included in the multivariate analysis, it is reasonable to state that type 2 diabetes was a surrogate risk factor for EW gain.

Weight Gain and Immunosuppression

As both the Tac/mTOR immunosuppression protocol and an early acute rejection episode were found to be independent predictors of EW gain, we analyzed the relationship between each immunosuppression regimen, the incidence of acute rejection, and EW gain. As shown in Table 4, the incidence of acute rejection was equivalent across all immunosuppression protocols and between steroid use and steroid-free regimens. Similarly, subdividing the analysis between those with and without EW gain produced the same findings, although the subjects per group were small.

TABLE 4.: The relationship between immunosuppression, acute rejection, and EW gain

Weight Gain and Allograft Function

As shown in Table 5, we next examined the effect of EW gain on pancreatic allograft function at 1 year posttransplantation. Whereas the mean HgbA1c, fasting glucose, and C-peptide levels were similar between groups, the median insulin level of the EW gain cohort was significantly higher than that of the non-EW gain group. Based on this finding, we compared the change in mean HgbA1c, insulin, and C-peptide from month 3 to 5 years posttransplantation. As shown in Figure 2A, whereas there was no difference in mean HgbA1c levels between groups, from month 3 to year 5, the EW group displayed a significant increase in mean insulin levels and a nonsignificant trend towards higher C-peptide levels compared to the non-EW group (Figure 2B and C).

TABLE 5.: Pancreatic allograft function at 1 y

FIGURE 2.: A, Mean hemoglobin A1c (HgbA1c) levels (%) of excessive weight (EW) gain vs non-EW gain (No EW) groups. B, Mean insulin levels (ng/mL) of EW vs non-EW gain (No EW) groups. C, Mean C-peptide levels (ng/mL) of EW vs non-EW gain (No EW) groups. CI, confidence interval.

We also examined the effect of renal function on weight gain by comparing the mean serum creatinine of the EW and non-EW groups at various time points posttransplantation. As shown in Table 6, there was no difference in renal function between groups at any time point studied.

TABLE 6.: A comparison of posttransplantation mean serum creatinine values between EW and non-EW cohorts

Recipient and Graft Survival

At a mean follow-up, of 43 ± 23 months, there were no deaths in the EW group versus 3 deaths in the non-EW cohort. Two deaths were due to cardiovascular disease and 1 to cancer. To determine the effect of EW gain on pancreas allograft survival, we compared death-censured graft survival of both groups. As shown in Figure 3, there was no difference in estimated pancreas graft survival between groups at 5 years posttransplantation. Of the 7 graft losses in both groups, 6 were due to acute/chronic rejection and 1 was due to infection. To date, there has been 1 death-censured kidney graft loss among all recipients, occurring in the EW gain cohort, resulting from chronic rejection.

FIGURE 3.: Kaplan-Meir death-censured graft survival of excessive weight (EW) gain vs non-EW gain (No EW) groups.

Posttransplant Metabolic Syndrome

As shown in Table 7 and Figure 4, we next compared the rate of PTMS at most recent follow-up between the EW and non-EW cohorts. At a mean follow-up of 43±23 months posttransplant, 34.6% of the EWG cohort met criteria for PTMS compared with 17.6% of the non-EWG cohort (P = 0.07).

TABLE 7.: Posttransplant metabolic syndrome

FIGURE 4.: Incidence of posttransplant metabolic syndrome (PTMS) at most recent follow-up of excessive weight (EW) vs non-EW (No EW) gain groups.

DISCUSSION

In this single-center review of 100 consecutive KP recipients, we sought to determine the incidence, risk factors, and outcomes of EW gain in the early posttransplant period. At 1 year posttransplantation, the mean percent weight gain for the entire cohort was 10% of the baseline weight. Yet, after dividing those individuals with EW versus non-EW gain, we noted a significant difference in weight gain at both 1 and 5 years posttransplantation. For this report, we arbitrarily defined EW gain as the upper limit of the IQR of weight gain dispersion for the cohort at 1 year. As the IQR is the middle 50% of recipient weight gain, we thus defined the EW gain cohort as the upper 25% of recipient weight gain; this included all subjects who had gained >19% of their baseline weight. Based on this value, we thus identified 2 distinct groups of recipients. Approximately one-quarter of recipients gained a large amount of weight by 1 year and continued to gain weight out to 5 years posttransplantation, whereas the majority of recipients gained a relatively small amount of weight over the same period. Outcomes were the same when the analysis was based on change in BMI, with the EW cohort showing a significantly greater increase in mean BMI at both 1 and 5 years posttransplantation.

We next sought to identify any factors at the time of transplantation that would predict EW gain. In our report, both younger recipient age, the use of a tacrolimus/mTOR immunosuppression protocol, and an early acute rejection episode were all independent risk factors for EW gain.

As this was a retrospective review, our explanation for these results can only be speculative. The finding that younger recipient age was associated with EW gain is in agreement with a number of other studies of weight gain after solid organ transplantation.^3,6 As discussed below, after successful pancreas transplantation, the recipient will release a more appropriate amount of insulin after ingestion of a meal and thus become more efficient at absorbing a carbohydrate load. Assuming the recipient is ingesting the same diet as he did pretransplant, he should thus increase his ingestion of calories, resulting in weight gain. One can only postulate that a percentage of recipients, including a larger number of younger subjects, were less disciplined regarding their diet posttransplantation, liberalizing their carbohydrate intake, resulting in greater weight gain. Based on this finding, we are now organizing a prospective study of newly transplanted patients, to record changes in diet composition along with calorie counts.

Additionally, immunosuppression, in particular, corticosteroids and the use of calcineurin inhibitors have been suggested as causative agents for EW gain,^7-9,12 although a number of studies have shown no relationship between the use of steroids and weight gain posttransplantation.^1,4 The finding that both a Tac/mTOR regimen and an acute rejection episode were independent risk factors EW gain would suggest that this particular maintenance immunosuppression regimen was associated with an elevated incidence of acute rejection. Yet, as shown in Table 4, that was not the case. The likely association is that Tac, mTOR, and high-dose steroids, utilized for treatment of acute rejection, are all associated with insulin resistance. In this report, the EW cohort was shown to have both higher mean peripheral insulin and C-peptide levels. Therefore, one may speculate that the use of these immunosuppressive agents led to insulin resistance resulted in higher peripheral insulin levels, which, as noted before, may lead to EW gain.

In the surgical procedure described herein, the portal vein of the pancreas graft is anastomosed to the iliac vein of the recipient. Thus, insulin is released directly into the systemic circulation rather than into the portal system, resulting in relatively high peripheral insulin levels. For that reason, we were interested in the association between peripheral hyperinsulinemia, weight gain, and progression to PTMS.

A provocative and controversial hypothesis, referred to as the carbohydrate-insulin model of obesity, proposes that increased insulin production is a principal cause of obesity, whereas inadequate insulin treatment of type I diabetes leads to weight loss. This theory states that hyperinsulinemia promotes deposition of calories in fat cells, increases hunger, and slows the metabolic rate leading to weight gain.¹³ Thus a type I diabetic with advanced end-organ complications such as renal failure likely represents a model of inadequate insulin administration associated with inefficient absorption of ingested carbohydrates. Consequently, post-KP transplantation, with appropriate insulin response to a carbohydrate load, the likely result would be more efficient absorption and metabolism of glucose, resulting in fat deposition and weight gain.

In support of this hypothesis, our results showed that there was, in fact, a correlation between higher mean fasting insulin and C-peptide levels in the EW gain versus non-EW cohorts from month 1 to 5 years posttransplantation. In the context of this retrospective review, it is not possible to conclude that elevated insulin levels were a cause of EW gain or simply a result of insulin resistance as a consequence of an increase in body weight. Nonetheless, the association of EW gain with higher peripheral insulin levels suggests that this is a promising direction for further investigation.

Weight gain after renal transplantation has been associated with a greater risk of death due to infection and cardiovascular disease.^3,14 Thus of great concern in this population of recipients with a history of diabetes, renal disease and, in many cases, advanced complications of cardiovascular disease, was that EW gain might accelerate the progression of cardiovascular disease via the development of PTMS.

In our study, we found no significant difference in patient survival between groups, from year 1 to year 5. Similarly, during the period of this review, based on pancreas graft function and serial HgbA1c levels, there was no evidence that the weight gain resulted in graft loss or a progression to type 2 diabetes. However, the EW gain cohort displayed a greater risk of PTMS, although the difference did not reach statistical significance.

It is important to recognize that a percentage of KP recipients will, at the time of transplantation, be underweight owing to the effects of sarcopenia associated with end-stage renal disease. Sarcopenia, defined as age-related loss of muscle mass, strength, or physical function, is common in the chronic kidney disease (CKD) population and associated with duration of dialysis. CKD is a catabolic state, known to be associated with protein wasting and with multiple metabolic derangements associated with uremia. In addition to impaired muscle regeneration, increased catabolism is common in CKD and attributed to a number of factors including accumulation of uremic toxin, chronic inflammation, insulin resistance, malnutrition, vitamin D deficiency, and oxidative stress.¹⁵ Thus, an increase in weight posttransplantation if indicative of an increase in muscle mass would be a positive finding. Our study, however, did not analyze how much of the increase in weight was due to increase in muscle mass or simply fat deposition. Yet, in this regard, a recent publication from our center found that weight gain after kidney transplantation, analyzed using dual-energy x-ray absorptiometry, air displacement plethysmography, and total body potassium and nitrogen counters, was principally due to adipose tissue accumulation and not muscle mass or fluid accumulation.¹⁶

There are a number of important limitations to this study, principally due to the fact that it is a retrospective review of data. As noted above, we were unable to assess whether the gain in weight posttransplantation was due to an increase in lean body mass or adipose tissue. Additionally, we did not assess the importance of physical activity or socio-economic status of weight gain. We also have no information on the impact of dietary intervention in the early posttransplant period.

In summary, we found that, in common with liver and kidney, pancreas transplantation is associated with weight gain in the first year posttransplantation. Importantly, a significant proportion of recipients will gain a substantial amount of weight over the first several years posttransplantation. Although EW gain was not associated with an increased risk of death or graft loss, we noted higher peripheral insulin levels and a trend toward a greater risk of PTMS. These data suggest that there may be a specific metabolic consequence of successful pancreas transplantation that results in EW gain and that, with longer follow-up, may increase the risk of cardiovascular complications.