The prevalence of obesity has risen dramatically across the globe, with an alarming rise also in the developing world (1). The United States is facing an obesity epidemic that encompasses almost a third of all adults (2), whereas the prevalence of childhood obesity has tripled in the past 30 years (3). The obesity epidemic also extends to patients with end-stage organ failure because at least 60% of renal transplant recipients in the United States are overweight or obese at the time of transplantation (4). Comparable trends have been reported for liver and cardiac transplantations (5, 6). The number of obese living and deceased donors is also likely to increase in parallel to the growing number of obese individuals.
Consequences of Obesity on Immune Responses
Obesity and Inflammation
Obesity is linked to inflammation and modified immune responses (Fig. 1), potentially impacting allorecognition and alloimmunity.
Obesity can be conceptualized as a chronic inflammatory state in which adipocytes initiate a proinflammatory program of cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and chemokine (c-c motif) ligand 2 (7). These cytokines attract, in turn, immune competent cells such as macrophages into metabolic tissues (8). The resulting chronic inflammation accelerates gradually, is linked to a reduced metabolic rate, and does not resolve (9).
Increased intestinal permeabilities for endotoxins during periods of overfeeding have been brought forward by some as an explanation for the continuously active inflammatory response linked to obesity (10, 11). Others have proposed nutrients themselves as inflammatory triggers because free fatty acids and saturated free fatty acids have been found to elicit inflammatory signaling through toll-like receptor 4 activation in various cell types including adipocytes (12, 13). In excess, those mechanisms may exploit a dose-dependent loss of specificity (“spillover”) and thus engage classical pathogen- and danger-sensing pathways (9). Nutritional excess has also been linked to increased levels of stress proteins measured by activation of the unfolded protein response (UPR) of endoplasmic reticulum (14). Links between UPR activation and inflammation may be initiated through c-jun N-terminal kinase and inhibitor of κ kinase signaling pathways (15).
Obesity is also associated to insulin resistance impacting both patient and graft survivals. The kinases c-jun N-terminal kinase and inhibitor of κ kinase have been identified as major upstream contributors of proinflammatory cytokine production in the context of metabolic inflammation (16). Interestingly, these kinases can target insulin receptor substrate 1, thus inhibiting the insulin receptor signaling cascade (17). Moreover, infiltrating macrophages and changes of the gut microbiome, both linked to obesity, may mediate insulin resistance (18, 19).
Adipose Tissue and Adipocytokines
Adipose tissue has long been considered as an inert energy storage. More recently, the concept of obesity as an intricate network linking nutrition, metabolism, and immunity has emerged. In addition to their production of proinflammatory cytokines in response to metabolic inflammatory triggers, adipocytes have also the capacity to produce several adipocytokines that impact energy homeostasis, neuroendocrine functions, immunity, and inflammation. Adiponectin and leptin are the most abundantly produced adipocytokines (20). Of note, adipose tissue has been found to be a major source of IL-6 during lipopolysaccharide-induced inflammation illustrating a prominent role for metabolic tissue during systemic inflammatory states such as infection, systemic inflammatory response syndrome, or sepsis (21), (Fig. 2).
Adiponectin is an adipocytokine with mainly antiinflammatory capacities. Serum levels of adiponectin are decreased in individuals with visceral obesity, nonalcoholic fatty liver disease, atherosclerosis, and type 2 diabetes mellitus (22). Of note, cardiac transplants in adiponectin-deficient mice were more rapidly rejected (23), a finding that is in line with a less vigorous T-cell response in the presence of adiponectin (24). Moreover, myocardial infarct size, TNF expression, and myocardial apoptosis rate after ischemia-reperfusion injury were more pronounced in adiponectin-deficient mice (25).
Mechanistically, adiponectin induces the production of antiinflammatory cytokines such as IL-10 and promotes the production of IL-1 receptor antagonist through monocytes, macrophages, and dendritic cells (24). Adiponectin has also been shown to inhibit toll-like receptor-induced nuclear factor κ-light -chain-enhancer of activated B cells activation (26) and the production of proinflammatory cytokines such as interferon-γ and TNF in macrophages (24, 27). Moreover, B cell development was suppressed by adiponectin through the induction of prostaglandin synthesis (28).
In contrast to adiponectin, leptin has predominantly proinflammatory cytokine functions and shares structural characteristics with IL-6, IL-12, and granulocyte-stimulating factor as a member of the family of long-chain helical cytokines (29). Leptin seems to play a critical role in controlling appetite and energy intake through neuroendocrine mechanisms. Mice with a mutation in the gene encoding leptin (ob/ob mice) have been used as models of obesity (30). Of note, ob/ob mice have also shown defects in angiogenesis (31) and hematopoiesis (32), both impacting innate and adaptive immunity with relevance for organ transplantation (33, 34). At the same time, serum levels of leptin are increased in diet-induced obese rats and seem to correlate to the overall adipose mass (30).
Of relevance for adaptive alloimmune responses are marked increases in the proliferation of CD4+ T cells in response to allogeneic peripheral blood mononuclear cells in the presence of leptin (34). This effect was more pronounced in naive CD4+ CD45RA+ T cells, and the resulting response showed a bias toward a Th1 cytokine profile (34). Moreover, leptin also provides survival signals to thymocytes and protects from starvation-induced lymphoid atrophy (35). In addition to their impact on adaptive immune responses, leptin also impacts innate immune responses by promoting the phagocytic capacity of monocytes/macrophages and their production of leukotriene B4, cyclooxygenase 2, and nitric oxide (36, 37). Chemotaxis and production of reactive oxygen species in neutrophils are furthermore stimulated by leptin. Moreover, leptin-dependent pathways have been linked to the differentiation, proliferation, and cytotoxicity of natural killer cells (38, 39).
Metabolic Inflammation and Tissue-Specific Consequences of Obesity
Metabolic inflammation has been linked to organ-specific deleterious effects potentially impacting graft quality in addition to accelerating graft deterioration in obese transplant recipients.
Systemically applied leptin resulted in glomerular staining for type 4 collagen in rat kidneys, more pronounced glomerulosclerosis with increased mesangial matrix, and proteinuria (40). Clinically, proteinuria and obesity-related glomerulopathy (focal segmental glomerulosclerosis and glomerulomegaly) have been linked to an increased expression of vascular endothelial growth factor and TNF-α, suggesting that inflammatory factors may be involved in the pathogenesis of obesity-related glomerulopathy (41).
In the liver, Kupffer cells undergo an obesity-associated inflammatory activation (42). Animal models of obesity have linked the expression of inflammatory cytokines in the liver with the development of steatohepatitis (43). Moreover, pathways of insulin resistance have also been shown to be active in fatty livers, leading to hepatic gluconeogenesis and hyperglycemia (44). Subsequent to a high-fat diet, proinflammatory cytokines including IL-1β and interferon-γ are released in the pancreas, initiating glucose intolerance (45–47).
Adipocytokines and mechanisms of metabolic inflammation may also play an important role in the pathophysiology of atherosclerosis, a major condition limiting patient and graft survivals after organ transplantation. Adiponectin-deficient mice demonstrated more advanced neointimal proliferation subsequent to vascular injury (48), and clinical reports have demonstrated that hypoadiponectinemia is linked to coronary artery calcification and ischemic heart disease (49, 50). Moreover, UPR is chronically activated in endothelial cells and residual macrophages of atherosclerotic lesions (51). Conversely, leptin-deficient Treg cells have been more efficient in suppressing atherosclerotic lesions (52).
Taken together, recent advances in the field of obesity-associated metabolic inflammation have provided crucial insights into the pathophysiology of obesity and its associated comorbid conditions. Although chronic inflammatory responses subsequent to obesity remain as an evolving and intriguing concept at this time, consequences on alloimmune responses, organ quality, and immunogenicity are expected to gain interest and will require future in-depth analysis.
Clinical Consequences of Obesity
A body mass index (BMI) higher than 30 has been identified as the most significant risk factor for wound infections in renal transplant recipients (53). Others also reported on significantly prolonged operating times and length of stay (54) in addition to a higher incidence of early (<30 days) graft loss primarily caused by vascular complications in the graft such as renal artery thrombosis (55).
Data from the United States Renal Data System (USRDS) showed a significant correlation between a BMI higher than 36 and delayed graft function (56). Some, but not all, studies confirmed this finding for kidney and (57–59) kidney-pancreas transplantation (60–62). When comparing the engraftment of kidneys from the same donor, significantly more recipients with delayed graft function were obese (63).
Obesity has been linked to higher rates of acute rejections in a large registry analysis for renal transplantations (64). Most studies, however, have been unable to support this correlation (55, 56, 59, 65). Of note, obesity may increase the threshold for biopsies and thus lead to an underrepresentation of the correlation between obesity and acute rejections.
USRDS data have shown a U-shape association between long-term graft survival and BMI, with both, lowest (<18) and highest (>28), BMI categories being associated with a significantly higher risk of death-censored graft loss (56). Some smaller studies recently confirmed these results for candidates with a BMI higher than 35 (64, 66).
The impact of obesity on patient and graft survivals in renal transplant recipients is, at least in part, mediated by cardiovascular risk factors, preventing a delineation of the differential effects of comorbid conditions and obesity per se. Cardiovascular disease is the leading cause of death in renal transplant recipients (67), and clinical studies have associated increased mortality rates in obese renal transplant recipients, with highly elevated rates of cardiovascular events in obese patients (68, 69). When patients with abnormal coronary angiograms were excluded from transplantation in a single-center experience (65), patient survival did not differ between obese and nonobese patients.
Other comorbid conditions limiting survival in renal transplant recipients that are exacerbated by obesity include posttransplantation diabetes mellitus (70, 71), dyslipidemia (72), and hypertension (73, 74). Advancing glomerulosclerosis caused by an increased production of proinflammatory cytokines, renal lipotoxicity, hemodynamic effects of increased renin-angiotensin activity, and glomerular hyperfiltration based on differences in donor and recipient body size have also been proposed as mechanisms for poorer graft survival in obese recipients (75–77).
As in renal transplantation, surgical complications such as wound infections and wound dehiscence, in addition to length of stay and costs are also increased in most clinical reports in liver transplantation (78, 79). Using the United Network for Organ Sharing database, patient survival after orthotopic liver transplantation had been compromised in recipients with a BMI higher than 40 or lower than 18.5, with increased infectious complications being the most frequent complication (80). This clinical correlation, however, is not supported by all studies (79, 81–83). Notably, a study that adjusted BMI for ascites has been unable to link BMI and poorer patient or graft survival (84).
Cardiac transplant recipients with a BMI higher than 35 demonstrated poorer long-term survival with higher rates of rejection, transplant coronary artery disease, and infections, in addition to increased incidences of renal complications and diabetes mellitus (6, 85). Some retrospective analyses, however, have been unable to link obesity to compromised cardiac transplantation outcome (86).
Obesity is an independent risk factor for death after lung transplantation, contributing to up to 12% of deaths in the first year after transplantation (87). The observation that higher mortality of obese lung transplant recipients seems to be governed by survival in the first year after transplantation was also stated in a more recent study (88).
Thrombosis of the pancreas allograft has been observed as a major complication in obese recipients in addition to general surgical complications and infections (60, 89, 90). Technically, more challenging aspects of the pancreas transplantation procedure in obese recipients may in part be responsible for these findings (91).
Do Obese Patients Benefit From Transplantation?
USRDS data on patients with a BMI higher than 30 demonstrated a mortality rate for patients on the waiting list of 6.6/100 patient-years compared with 3.3/100 patient-years in deceased-donor transplant recipients and 1.9 deaths per 100 patient-years in living-donor renal transplantation, thus establishing a survival benefit of renal transplantation for obese candidates (92). Of note, a benefit of deceased-donor transplantation was not found for morbidly obese patients (BMI >41). Benefits for transplantation in obese recipients were also reported for liver and cardiac transplantations (85, 93).
Of note, obese patients seem to wait significantly longer for organ transplants. For those awaiting renal, liver, or cardiac transplantation, waiting times increased in parallel to obesity (85, 86, 94, 95). Moreover, the probability of accepting an organ for an obese recipient decreased in parallel to a rising BMI (85, 86, 95).
Thus, clinical data probing the effects of obesity on transplantation outcome and immune responses are not univocal. Further studies will be necessary to delineate the impact of obesity per se as compared with comorbidities associated with obesity. Particularly noteworthy are clinical studies pointing toward more pronounced immune responses and data showing prolonged waiting times for obese patients.
Pretransplantation and Posttransplantation Weight Loss
Dietary restrictions or bariatric surgery may improve transplantation access and outcomes.
A nonrandomized trial of weight loss with orlistat and lifestyle modification (nutrition education, diet, and exercise) showed significant weight loss and weight-loss maintenance in obese patients with chronic kidney disease and may have enabled some of the patients to undergo renal transplantation (96). Orlistat was also well tolerated and safe in overweight and obese liver transplant recipients, although efficacy was not evaluated (97).
Bariatric surgery may be superior to nonsurgical therapy in achieving sustained weight loss in morbidly obese patients (98, 99). Bariatric surgery (predominantly gastric bypass) in patients with end-stage renal disease before or after kidney transplantation was linked to a slightly increased 30-day mortality and, possibly, less median excess body weight loss compared with a general population (100). A single-center experience in renal transplantation, on the other hand, reported on a sustained weight loss without perioperative mortality (101). In a retrospective analysis of morbidly obese patients with end-stage renal disease, comorbid conditions and BMI improved in all patients after bariatric surgery, and most patients were subsequently waitlisted (102). In theory, reduced serum levels of leptin (103–105), ameliorated peripheral insulin resistance (106), and altered levels of gut hormones (107) observed after bariatric surgery may all contribute in improving transplantation outcome.
Bariatric surgery and, especially, gastric bypass surgery may compromise the absorption and metabolism of immunosuppressive drugs as a consequence of a reduced surface area and an elevated gastric pH (108). After bariatric surgery, dose requirements of cyclosporine had increased significantly (109), while lower area under the curve–to–dose ratios have been reported for sirolimus, tacrolimus, and mycophenolate mofetil, suggesting that higher doses are needed to provide similar exposure (101).
The worldwide epidemic of obesity represents a pressing clinical challenge for organ transplantation. Immediate postoperative morbidity and mortality and long-term patient and graft survivals of transplant recipients are impacted by obesity and related comorbidities. In transplantation studies, obesity has mainly been assessed by BMI, although waist-to-hip ratio may more adequately represent the immunologically active visceral adipose tissue.
With the ever-increasing scarcity of donor organs, it will get more important to assess organ quality and immunogenicity. Obesity has been shown to impact organ quality; however, transplantation-specific data assessing the correlation between donor obesity and transplantation outcome remain scarce at this time.
More recently, obesity has been conceptualized as a chronic inflammatory process. Achieving mechanistic insights into links between metabolic changes, immune response, and transplantation outcome will be critical in refining patient selection and treatment. Exciting basic science and clinical data suggest that obesity will have an impact on alloimmune responses. Those data will require confirmation in future transplantation studies.
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