Obesity as a risk factor in renal transplant patients

Introduction

Obesity, defined as a body‐mass index (BMI)>30 kg/m², is a widespread disorder that currently affects as many as 20% of the adult population in industrialized countries [1]. Increased body weight is a well‐established risk factor for a variety of conditions including hypertension and type 2 diabetes [2]. Recently, the importance of obesity was also underscored by the fact that the American Heart Association now considers obesity a major risk factor for ischaemic heart disease [3]. Furthermore, surgical procedures in obese individuals are associated with an increased risk both for intraoperative complications and wound‐related problems [4].

Renal transplantation is currently considered the treatment of choice for most patients with end‐stage renal failure. However, availability of organs is limited and therefore, selection of patients who are likely to have a positive outcome remains an important issue. Based on previous studies and local experience, some centres currently consider obesity as a significant risk factor for renal transplantation, and are unwilling to consider obese patients for transplantation [5]. However, this policy is not accepted in most centres.

In this article we review the current literature regarding the relationship between obesity and outcome of renal transplant patients. We identified studies that specifically addressed the influence of obesity on kidney allograft recipients from Medline, reference lists of papers, and through personal communications. Data were analysed with regard to patient morbidity, mortality, graft survival, and kidney function.

Characteristics of the identified studies

Our literature search revealed nine studies which met our inclusion criteria. The characteristics of these studies are summarized in Table 1. The follow‐up ranged from 24 to 120 months and included a total of 2791 kidney transplant patients. The effect of obesity on patient outcome in terms of selected end‐points is discussed in the following sections.

Definition and prevalence of obesity

The definitions of obesity and normal weight varied among the studies, as the criteria for the definition of obesity have changed over recent years. Thus, while seven articles [5–11] used the current WHO definition of obesity as a BMI >30 kg/m² [1], three defined obesity as >120% of ideal body weight [12–14]. Definitions of normal weight ranged from a BMI <25 kg/m² [5,6,9] to <27.5 kg/m² [7] or to <120% of ideal body weight [12–14]. The prevalence of obesity ranged from 10% [7] to 19% [14] with a marked exception of only 2% in a study by Orofino et al. [12]. In one study [13], obesity was reported to be almost three times as frequent in women than in men (27 vs 9%). From these studies it appears that the prevalence of obesity in the renal transplant population is comparable to that currently found in the general population [1].

Patient mortality

In most studies there was a distinct trend towards increased overall mortality in obese patients compared to the non‐obese subjects. Over 5 years, mortality in obese patients ranged from 23 to 45% vs 10 to 11% in non‐obese patients [8,11] and in one study [5], this difference was still statistically significant after 10 years (60 vs 40%). In these studies, increased mortality was mainly caused by an increase in cardiac events, which was reported to be twice as high in obese patients [8,11]. No difference in 5‐year patient survival was observed by Orofino et al. [10], but this study only included 13 patients with a BMI >30 kg/m². In shorter‐term studies, Halme et al. [6] described a 1‐year patient survival rate of 65% in obese vs 75% in non‐obese patients in the non‐cyclosporin era, but found no difference (90 vs 93%) after the introduction of cyclosporin. Nevertheless, it appears fair to conclude that in general, obesity is associated with a significant reduction in long‐term survival in patients undergoing renal transplantation. A large proportion of this increased risk appears attributable to cardiovascular complications, possibly related to obesity.

Post‐transplant complications

The most frequent reported complications are summarized in Table 2. Obesity has been well‐recognized as a risk factor for all kinds of operations [4]. It is therefore not surprising that six [5,7–9,11,13] out of seven [10] studies showed an increase in post‐transplant complications in obese patients compared to non‐obese patients. Halme et al. [5], reported that obese patients more often had serious post‐operative complications, resulting in graft loss within 30 days of transplantation. Pirsch et al. [7] described more surgical complications (urological, wound) in obese than in non‐obese patients, but found no difference in medical complications (cardiovascular, pulmonary, neurological) between the groups. According to Modlin et al. [8], obese patients not only experienced significantly more complications per patient (3 vs 2), but also had a higher incidence of post‐transplant diabetes, an observation also reported in the studies by Holley et al. [9] and Gill et al. [11]. While in most studies, complications generally did not affect patient mortality, this was the case in a study by Holley et al. [9], in which significantly more deaths occurred in obese than in non‐obese patients (11 vs 2%) during the initial period of hospitalization. Mean length of hospitalization, as a surrogate marker for post‐transplant complications, was reported in five studies, but only one of them showed a significant increase in duration [9]. Together, these findings suggest that obese patients are more likely to have surgical and post‐surgical complications and increased perioperative morbidity than non‐obese patients.

Acute rejection and delayed graft function

The impact of obesity on acute rejection was addressed in six studies [5–8,10,12], none of which showed a statistically significant difference between obese and non‐obese patients. The initial renal function rate was often reported to be lower [7,9,10,13,14] in obese than in non‐obese patients, although this was not evident in all studies [8,11]. Pirsch et al. [7], observed a delay in graft function in 27% of the obese but only in 9% of the non‐obese patients. Along similar lines, Blümke et al. [13] reported initial graft function in only 33% of the obese compared to 58% of the non‐obese group. Delayed graft function may in part be attributable to longer revascularization and total operating time, which were noted to be significantly higher in obese patients than in controls [8,11]. From these findings, it is evident that while obesity is not a risk factor for acute allograft rejection, it is often associated with delayed graft function related to surgical or post‐operative complications.

Graft survival

Virtually all investigators reported a lower graft survival in obese compared with non‐obese renal transplant recipients [6–9,11,14]. Halme et al. [6] found a significantly lower 1‐year graft survival in obese patients compared to non‐obese patients (65 vs 75%), and Pfeiffer et al. [14] found a significant difference in graft survival between obese and non‐obese patients both 1 (83 vs 91%) and 3 (75 vs 88%) years after transplantation. The difference between the two groups appeared within the first 6 months after transplantation, suggesting that this difference was due to early transplant loss. In one study [5], in which early graft loss within 30 days after transplantation was significantly higher in obese than in non‐obese patients (17 vs 4%), this was also largely attributable to post‐operative complications. Interestingly, Halme et al. [6] reported arterial thrombosis as a cause of graft loss in four (36%) obese, but in none of the non‐obese patients in their series. Lower allograft survival rate at 5 years were noted both in the study by Holley et al. [9] (66 vs 84%) and Gill et al. [11] (42 vs 66%). Modlin et al. [8] also described a significantly lower graft survival 5 years after transplantation in obese patients, but when patients who died with a functioning graft were censored, allograft survival was similar between the two groups.

From these findings it appears that the overall decrease in long‐term allograft survival in obese recipients is related both to an increased incidence in early graft loss and a long‐term increase in recipient mortality, often with a functioning allograft. Although obesity is a risk factor both for the development of hypertension as well as diabetes, factors well known to play an important role in determining long‐term allograft survival [15], chronic graft dysfunction does not appear to be markedly more common in obese patients than in non‐obese controls.

Weight gain

A marked increase in body weight is often noted both in obese and non‐obese patients undergoing renal transplantation. Merion et al. [12] found a significant weight gain of 9 kg in non‐obese and 14 kg in obese patients 1 year after transplantation, while Gill et al. [11] found a gain of 8.5 kg at 1 year after transplantation in both groups. Similarly, in a study by Pfeiffer et al. [14], the prevalence of obesity increased from 19% at the time of transplantation to 36% 1 year after transplantation, and in a study by Johnson et al. [16], mean body weight increased by 10.9% during the first year and by 15.3% over 5 years. Weight gain was greater in women and in black recipients [16]. While younger patients tended to gain more weight than older patients, weight gain was not related to pre‐existing obesity [16] or the dose of corticosteroids [12,16]. In fact, the dose of corticosteroids administered to obese patients was actually lower when expressed as dose per kilogram body weight [12]. Weight gain was also not related to the number of acute rejection episodes [16]. Both the incidence of post‐transplant diabetes and non‐fatal myocardial infarction tended to be higher in patients who experienced excessive weight gain (>10%) [16].

Given the lipophilic nature of cyclosporin A, Modlin et al. [8] found similar levels of cyclosporin in obese and non‐obese patients, although obese patients received 0.75–2 mg/kg less cyclosporin than non‐obese recipients. This is in accordance with the observation of Orofino et al. [10], who found higher cyclosporin levels in obese patients although the cyclosporin dosages were lower than in non‐obese controls.

Conclusions

Obesity is commonly present in patients undergoing renal transplantation and is significantly associated with a higher overall mortality and reduced allograft survival. Obese patients experience a greater incidence of perioperative complications, often resulting in delayed graft function, early graft loss and, in some cases, delayed discharge from hospital. In contrast, immunological complications of transplantation are apparently not related to body weight. A substantial proportion of transplant patients experience a marked increase in body weight following transplantation and obesity remains a significant cause of diabetes and cardiac complications in this population. According to current recommendations for the general management of obesity [2], a 5–10% reduction in body weight over a 6‐month period with subsequent weight maintenance should be feasible in most patients, and should contribute significantly to reducing the risks related to renal transplantation in obese patients with end‐stage renal failure.

References