Kidney transplant outcomes in obese pediatric patients

Abstract

The increasing prevalence of pediatric obesity has raised numerous questions about its health implications, particularly regarding renal transplant outcomes. These complications often hinder medical interventions in these children. While kidney transplants are often viewed from an organocentric perspective, the overall health of the patient is critical to the success of the procedure. Current discussions make it clear that childhood obesity poses significant problems not only for graft survival, but also for long-term overall health. Childhood obesity can lead to many metabolic disorders such as diabetes and hypertension. These conditions can significantly affect a child's suitability for a transplant or make the process more difficult. A child's weight can affect the pharmacokinetics of drugs used to prevent organ rejection. Obesity impacts the individual and sets in motion a cascade of effects that can jeopardize transplant success and recovery, so understanding is needed. Research on graft survival rates is both optimistic and concerning. Clinical studies show that obese children often have an increased risk of post-transplant complications, which affects transplant longevity. The likelihood of rejection may increase due to the metabolic status of an obese child. Due to the allocation of healthcare resources for the treatment of obesity-related diseases, availability for the transplant itself may be limited. Many children maintain an adequate quality of life after a kidney transplant, but excessive weight can significantly affect their health and chances of survival. The main target is looking for highly successful strategies to give all children who need a transplant a better future, regardless of their weight.

Key Words: Chronic kidney disease; Renal transplantation; Kidney transplant; Pediatric patients; Obesity; Bariatric surgery; Renal replacement therapies; Diabetes; Nutrition; Nutritional therapy

Core Tip: Childhood obesity can lead to various metabolic diseases, including diabetes and high blood pressure. These factors can significantly affect a child's suitability for transplantation or make the procedure more difficult. Obesity in pediatric patients at the time of kidney transplantation is associated with loss of the transplant and serious negative consequences that significantly affect their quality of life. An accurate analysis of the modifiable factors associated with obesity and kidney transplantation is central to providing appropriate support for children with end-stage renal disease needing for renal replacement therapy.

INTRODUCTION

Over the past few decades, the prevalence of obesity has risen in the paediatric population, especially in the lower and middle socioeconomic classes. The global prevalence in children and young adults has increased from 2% in 1990 to 8% in 2022, encompassing 160 million people[1]. It is estimated that there will be almost 260 million children with obesity worldwide by 2030[2]. Obesity is a known cause of cardiovascular, metabolic, and psychosocial complications. These complications can lead to progression from chronic kidney disease (CKD) to end-stage renal disease (ESRD), including the need for renal-replacement therapy (RRT)[3]. In addition, obesity can have a negative impact on patients with ESRD, especially paediatric patients who may have difficulty being considered for kidney transplant, losing valuable time in their lives[4]. It is widely recognized that kidney transplantation is the optimal form of RRT for CKD as it offers significantly better quality of life and survival[5]. This editorial is a ready-made synthesis of the outcomes of renal transplantation in obese pediatric patients by additionally integrating the recent study by Stanicki et al[6] with the existing literature while attempting to identify current knowledge gaps. We will focus on the retrospective cohort study by Stanicki et al[6], describing the impact of body mass index (BMI) classification on graft and patient survival and the health complications associated with obesity in paediatric kidney transplant patients. In addition, we will explore the major obstacles paediatric ESRD patients suffer due to their obesity and the possible steps needed to prepare them for a kidney transplantation.

THE COMPLEX RELATIONSHIP BETWEEN KIDNEY TRANSPLANTATION AND OBESITY

Inflammation plays a key role in various diseases, including CKD. ESKD patients are characterized by chronic severe inflammation, arterial stiffness and increased cardiovascular risk. This manifestation led to early vascular aging, which favors the development of cardiovascular disease and influences the progression of kidney disease[7]. Other models of chronic inflammation, such as obesity, may have a cumulative effect and contribute to poorer graft survival in obese patients. Indeed, increased red blood cell distribution width and increased mean platelet volume appear to be associated with higher mortality in CKD and transplant recipients, underscoring the impact of obesity-related inflammation[6]. The definition of obesity by the American Academy of Pediatrics is stratified by BMI and percentile for age and ranges from overweight (BMI between the 85th percentile to below the 95^th percentile or 25-29.9 kg/m²) to class 3 obesity (BMI equal to or above 140% of the 95^th percentile for age or ≥ 40 kg/m²). In this context, BMI has been used as a criterion for relative or absolute contraindication in both the paediatric and adult populations[8].

As mentioned in the study by Stanicki et al[6], transplant centers have different attitudes depending on their experience with this policy, primarily because the data available for decision making in paediatrics is largely based on studies of adults. Indeed, obesity is a known risk factor in adults, but more studies are needed to assess its value in the paediatric population. The study by Stanicki et al[6] examined the association between paediatric obesity and kidney transplant outcomes, as well as the dual risks of obesity and malnutrition. Their findings are consistent with previous research and show that short-term outcomes in obese paediatric class 1 recipients are comparable to those of healthy weight peers. Furthermore, in both underweight and overweight class 2 patients, the long-term graft survival rate is significantly lower[6]. However, as already mentioned by Stanicki et al[6], the study design does not allow a causal relationship to be established between BMI and transplant outcomes, as unmeasured confounding factors may play a role. These findings on kidney transplant outcomes are partially consistent with previous studies (Table 1). For example, Kaur et al[9] found in their study that while being overweight leads to poorer outcomes in recipients, being underweight appears to protect against negative outcomes. Similar results were already reported by Hanevold et al[10] in which the obesity of the study group appeared to influence the survival of patients and transplants. On the other hand, Pieloch et al[11] in adults and Engen et al[12] in children showed that patients who underwent successful kidney transplantation did not present similar results. In support of these findings, a recent meta-analysis by Yaseri et al[13], with more than 15 articles and 50498 patients included, showed that obese children have higher post-transplant risk of short- and long-term mortality and a higher risk of acute graft vs host disease.

Table 1 The table summarizes the renal transplantation outcomes in obese pediatric patients.

	Ref.	Population	Control	Results
Kidney transplant in obese pediatric patients	Stanicki et al[6]. Retrospective study	Recipients (23081) aged < 18 years	None	Class 3 obese recipients had lower 1-year graft survival (88.7%) compared to healthy-weight recipients (93.1%, P = 0.012). Underweight recipients had lower 10-year patient survival (81.3%, P < 0.05) than healthy-weight recipients. Class 2 and 3 obese recipients had the lowest 5-year graft survival (67.8% and 68.3%, P = 0.013) and Class 2 obesity had the lowest 10-year graft survival (40.7%). Cox regression identified increases in BMI category as an independent predictor of graft failure [(HR) = 1.091, P < 0.001] and mortality (HR = 1.079, P = 0.008). Obese patients experienced longer cold ischemia times (11.6 and 13.1 hours vs 10.2 hours, P < 0.001). Class 3 obesity had the highest proportion of Black recipients (26.2% vs 17.9%, P < 0.001)
	Saygılı et al[29]. Cross-sectional, single-center study	Recipients (52) aged from 13.8 to 18.4 years	None	Nineteen patients (36.5%) were obese or overweight, 43 (83%) had hypertension or controlled hypertension, 23 (44%) had dyslipidemia, and 9 (17%) had hyperglycemia. Ten patients (19.2%) were diagnosed with metabolic syndrome. Twenty-eight patients (54%) had left ventricular hypertrophy. The prevalence of left ventricular hypertrophy was higher in patients with metabolic syndrome than in those without metabolic syndrome (90% vs 45%, P = 0.014), whereas estimated glomerular filtration rate did not differ between the 2 groups
	Kaur et al[9] (2018). Retrospective study	Recipients (18261) aged from 2 to 21 years	Normal weight population (11209 of 18261)	Obesity was associated with greater odds of delayed graft function (OR 1.3 95%CI: 1.13-1.49, P < 0.001), acute rejection (OR: 1.23 95%CI: 1.06-1.43, P < 0.01), and prolonged hospitalization (OR: 1.35 95%CI: 1.17-1.54, P < 0.001) as well as greater hazard of graft failure (HR: 1.13 95%CI: 1.05-1.22, P = 0.001) and mortality (HR: 1.19 95%CI: 1.05-1.35, P < 0.01). The overweight cohort had an increased risk of graft failure (HR: 1.08 95%CI: 1.001-1.16, P = 0.048) and increased odds of delayed graft function (OR: 1.2 95%CI: 1.04-1.38, P = 0.01) and acute rejection (OR: 1.18 95%CI: 1.01-1.38, P = 0.04)
	Sgambat et al[30] (2018). Longitudinal study	Recipients (42) aged from 3 to 20 years	Healthy children (24)	The longitudinal strain of transplant group was worse than controls at all time points (P < 0.001). Hemodialysis was independently associated with 21% worse longitudinal strain during the pre-transplant period (P = 0.04). After transplantation, obesity, MS, and systolic hypertension predicted increased odds of left ventricular hypertrophy (P < 0.04). Worse longitudinal strain was independently associated with obesity, MS, hypertension, and the combination of MS with elevated low density lipoprotein cholesterol (P < 0.04), whereas higher estimated glomerular filtration rate conferred a protective effect (P < 0.001)
	Ladhani et al[31] (2017). Retrospective study	Recipients (750) aged from 8 to 18 years	Normal weight population (129 of 750)	102 (16.2%) experienced acute rejection within the first 6 months of transplantation, 235 (31.3%) lost their allograft and 53 (7.1%) died. Compared to children with normal BMI, the adjusted HR for graft loss in children who were underweight, overweight or diagnosed as obese were 105 (95%CI: 0.70-1.60), 1.03 (95%CI: 0.71-1.49) and 1.61 (95%CI: 1.05-2.47), respectively. There was no statistically significant association between BMI and acute rejection (underweight: HR 1.07, 95%CI: 0.54-2.09; overweight: HR: 1.42, 95%CI: 0.86-2.34; obese: HR: 1.83, 95%CI: 0.95-3.51) or patient survival (underweight: HR: 1.18, 95%CI: 0.54-2.58, overweight: HR: 0.85, 95%CI: 0.38-1.92; obese: HR: 0.80, 95%CI: 0.25-2.61
	Hanevold et al[10]. Retrospective study	Recipients (6658) aged from 2 to 17 years	Normal weight population (6009 of 6658)	Obese children were significantly younger and shorter and had been on dialysis for a longer time than nonobese children. There was no significant difference in the overall patient and allograft survival between the 2 groups. However, obese children aged 6 to 12 years had higher risk for death than nonobese patients (adjusted relative risk: 3.65 for living donor; adjusted relative risk: 2.94 for cadaver), and death was more likely as a result of cardiopulmonary disease (27% in obese vs 17% in nonobese). Overall, graft loss as a result of thrombosis was more common in obese as compared with nonobese (19% vs 10%)
	Mitsnefes et al[32]. Retrospective study	Recipients (76) aged from 1.9 to 22.5 years	None	3 groups: (1) BMI > or = 95th; (2) BMI < 95th but became obese at 1 year after Tx; and (3) BMI < 95th percentile at time of Tx and 1 year later. Patients with BMI > or = 95th percentile doubled at 1 year after Tx when compared with pre-Tx data: 10 (13%) vs 22 (29%), respectively. Fifteen (20%) patients developed obesity and 10 (13%) patients had BMI between the 85th and 95th percentile at 1 year post Tx. Group 1 had significantly lower mean GFR [46.1+/-15.0 mL/min per 1.73 m(2)] than group 2 (57.7+/-24.5 mL/min per 1.73 m(2), P < 0.05) and group 3 (60.4+/-21.5 mL/min per 1.73 m(2), P < 0.01)

BMI: Body mass index; HR: Hazard ratio; OR: Odds ratio; MS: Metabolic syndrome; TX: Transplant; GFR: Glomerular filtration rate.

BIAS AND ETHICAL CONSIDERATION FOR OBESE PAEDIATRIC PATIENTS

Currently, BMI is considered a controversial measure of obesity, as it does not consider many confounding factors (muscle mass, gender, puberty, etc.). Some ethical considerations have been made regarding the use of BMI as a criterion for eligibility for kidney transplantation. One of the basic principles of medical ethics is to do no harm. According to most clinical guidelines, obesity is not considered an absolute contraindication to transplantation but merely presents a technical difficulty and increases the risk of complications. As mentioned above, BMI has been used by some transplant centers as a criterion for relative or absolute contraindication, increasing the waiting time for transplantation and increasing the risk associated with dialysis. In fact, Stanicki et al[6] consider transplant centers that define obesity as an absolute contraindication to be too conservative and call for a more individualized approach. The dynamics of childhood obesity should not be simplified, and socioeconomic, cultural, genetic and environmental factors that play an important role in weight control should be taken into account[2]. Childhood obesity rates are particularly high in communities of lower socioeconomic status, where food insecurity is a risk factor for the development of obesity[2]. Segev et al[14] studied more than 120000 people in the United States who were on the waiting list and found that the likelihood of receiving a transplant was inversely correlated with the degree of obesity. The authors speculated that obese patients are considered less lucrative due to the increased hospitalization time and penalties transplant centers face for unfavourable outcomes. Also gender disparity has been evaluated. For example, in the work by Gill et al[15] obese women had poorer access to kidney transplantation compared to obese men with greater waiting times. The authors pointed out that BMI is a potentially modifiable factor in gender disparity in access to transplantation. The need for weight loss prior to admission for transplantation prompts the question of to what extent it can effectively mitigate harm. However, organs from both living and deceased donors are scarce, which makes understandable the need for careful consideration to ensure the best possible use of these organs by selecting the patients most likely to achieve a successful outcome. Therefore, denying access to transplantation based on incomplete evidence may lead to greater injustice. It is critical that health authorities and policymakers promote initiatives that target systemic inequities to further eliminate inequities and improve access to kidney transplantation. Equitable policies mean equitable allocation of organs and therefore fairer and more effective transplantation.

LIFESTYLE CHANGES AND PHARMACOLOGICAL/SURGICAL THERAPY

Obesity is a major challenge for almost all children, especially when a medical intervention such as a kidney transplant is required. It is of utmost importance to treat this serious condition prior to such a demanding surgical procedure like transplantation. We must carefully consider that obesity can complicate surgical outcomes and the healing process. For this purpose, effective kidney transplant for a child requires appropriate weight management, good preparation, and a successful surgical procedure (Figure 1). Obesity management should begin with intensive lifestyle therapy that includes dietary counselling, physical activity, and shared decision making with the patient and family, followed by modification of all weight-promoting medications[16]. A knowledgeable dietitian who specializes in paediatric nutrition can develop individualized meal plans, which include a diverse selection of fruits, vegetables, healthy grains, and lean proteins, which allow all children to make healthier choices through education. Families should also contribute to improve portion management and minimize consumption of sugary drinks and snacks. In addition, weight control should become a collective and cooperative goal for the entire family, rather than an individual struggle, as the child participates in the preparation of nutritious meals, encouraging parents for healthier choices. In this context, parents and healthcare providers are critical to this process through their unwavering support and encouragement. Psychological and psychiatric therapy should be considered both before and during transplantation, as obesity correlates with an increased risk of depression[17], which in turn can contribute to inadequate adherence to therapy and increases the risk of graft rejection and graft failure[18].

Figure 1 Step-by-step guide for obesity management in kidney transplant patients. BMI: Body mass index.

When non-pharmacologic measures are not sufficient anti-obesity medications should be considered. However, there are few medications approved for paediatric patients. Therefore, caution must be exercised when prescribing off-label medications to this population[19]. Currently, the Food and Drug Administration has approved GLP-1 agonists exclusively for children with type 2 diabetes aged 10 years and older. These molecules could be considered as a treatment option for childhood obesity due to their relative efficacy and safety. Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are approved for the treatment of type 2 diabetes in adults, have also been shown to facilitate weight loss[20]. The use of SGLT2 inhibitors is not approved for patients under 18 years of age and are currently being tested in children aged 10 to 17 years with type 2 diabetes but the results are still preliminary[21,22].

Bariatric surgery may be considered if all the other therapies failed. Indeed, children with a BMI greater than 40 kg/m² or 140% of the 95^th percentile and those with a BMI greater than 35 kg/m² or 120% of the 95^th percentile who also have obesity-related comorbidity are unlikely to benefit from lifestyle modification or drug treatment and should therefore be considered for bariatric surgery[23]. In this population, the implications of obesity and the benefits of bariatric surgery are particularly pronounced. Integrating bariatric surgery into the pre-transplant management of obese paediatric patients could be a strategic approach to enhance their overall health and transplant outcomes[24]. For example, sleeve gastrectomy prior to transplantation has been shown to improve access to the transplant waiting list[25]. Patients can achieve a 60%-80% decrease in surplus weight within 18-24 months[26]. Moreover, bariatric surgery can enhance renal function in patients with CKD who are not yet on RRTs and has been shown to reduce graft failure and death after transplantation. Focusing on an active and balanced lifestyle can greatly aid weight loss and instill lasting habits that will benefit the child after surgery. A child's journey is different, but with proper support and ample resources, they can venture down the path to a healthier future.

FUTURE RESEARCH DIRECTIONS

Given the growing prevalence of obesity, a more tailored patient centered approach is needed to improve the long-term health and survival of obese children in need of kidney transplantation.

Current evidence is insufficient to establish a standardized criterion for eligibility for transplantation. Prospective studies should aim to include larger pediatric cohorts and new body composition assessment tools beyond BMI to evaluate the true metabolic risks associated with obesity and other mechanisms that may contribute to transplant outcomes.

Additionally, there is a need to extend the safety and efficacy of proven pharmacologic agents for obesity in adults to the pediatric transplant population[27]. Moreover, longitudinal studies are also needed to asses long-term effects on graft survivability, quality of life, and psychosocial outcomes. Simultaneously, a call for ethical and health policy focused research should requested. Socioeconomic and demographic disparities should not continue to influence health care accessibility, not only for children with obesity, but for all children[28]. The results of current literature and the future research should be used to develop specific guidelines for kidney transplant eligibility in obese paediatric patients.

CONCLUSION

Recent data on the prevalence of obesity show an increasing incidence among the paediatric population, including the one in need for renal transplantation. In their study, Stanicki et al[6] explored the complex relationship between obesity and paediatric kidney transplant recipients. The recent wave of study assessing transplantation outcomes associated with weight management seems to be the natural answer to the disparities and complications that obese patients face on the journey to transplantation. However, current evidence is insufficient to support the use of well defined BMI cutoffs as a criterion for excluding children from kidney transplant eligibility and the need for systemic interventions is clear. The unequal impact of obesity on children from a socioeconomically disadvantaged and minority populations background call for renewed inclusion criteria. Moreover, the work of Stanicki et al[6], as well as other studies, showed that simply relying on BMI is no longer the most accurate method to assess obesity. Furthermore, obesity is a well established risk factor for adverse outcomes in kidney transplantation and many pre and post transplant strategies have been proposed to manage outcomes in order to expand the pool of eligible donors/recipients. We should consider adopting a more tailored approach that considers a patient's overall health. Physicians must educate families on the potential risks of excessive weight gain for their children both pre and post transplantation. Obesity requires a fair procedure for the allocation of organs. In the absence of strictly regulated and clear evidence-based guidelines on this topic, access to transplantation can be influenced by implicit and explicit biases. Obese patients, regardless of their background, may be categorized as “poor” transplant candidates because they believe that their condition is completely under their control due to voluntary choices. Children have limited control over their circumstances and typically lack the ability to make critical decisions while facing the same challenges that adults face due to their obesity. Transplant centers should consider providing additional support to “vulnerable" children who are more susceptible to healthcare inequities. Using obesity as a justification for denying a potentially life-improving procedure can penalize a child. Decisions must be based on the best interests of the child, balancing risks and benefits. Although severe obesity may increase the risks after transplantation, current evidence is still limited. Providing families with clear, evidence-based information means keeping the child’s future in mind. Obesity should not be treated as an absolute contraindication and there should be third party monitoring to achieve an unbiased allocation of organs.

In conclusion, more studies, especially prospective studies with more detailed clinical data, on the long-term outcomes are needed to completely assess the complex “weight” that obesity has on the quality of live and survival rates of paediatric kidney transplant recipients.