Novel Hypothesis for the “Obesity Paradox” in ESKD Subjects on Dialysis

In the general population, obesity is a well-established risk factor for development of cardiovascular disease, diabetes mellitus, and other comorbidities to include CKD. By contrast, there are some studies suggesting a seemingly counterintuitive survival benefit of obesity in individuals with ESKD on dialysis, a phenomenon referred to as the “obesity paradox.”¹ Theories to explain this paradox suggest greater fat and muscle mass in obese subjects with ESKD serves as a buffer against the metabolic demands of chronic illness, reduces the risk of malnutrition, provides protection against cardiovascular complications, and decreases the risk of cachexia while on maintenance dialysis.¹

Regarding cardiovascular protection, obese dialysis patients with heart failure have higher systolic BPs compared with nonobese subjects with similar capillary wedge pressures and cardiac indices. A more favorable hemodynamic response to volume overload in individuals with a higher body mass index and rates of ultrafiltration may serve to minimize the likelihood of intradialytic hypotension and attenuate the degree of sympathetic nerve and renin-angiotensin-aldosterone system activation, all of which are linked to poor outcomes in heart failure and patients with CKD. Higher lipoprotein concentrations typically present in obese subjects may neutralize the harmful effects of circulating endotoxins by binding to lipopolysaccharides which are the primary component of bacterial endotoxins, which could again explain why obese individuals do better on dialysis. Therefore, the obesity paradox in dialysis patients is likely due to a combination of factors as there is no one current universally accepted theory or strong evidence as to how obesity affords health protective effects in this population.

Despite these theories, it is important to note that the obesity paradox is controversial, and it is not even mentioned in the recent Kidney Health Guidance Workgroup on Obesity and Kidney Diseases.² One component of the controversy is that it is well-established that obesity is a health risk. There are data clearly indicating that weight loss in subjects with ESKD on dialysis waiting for a kidney transplant who later receive the transplant has favorable outcomes. What is not known and is of considerable interest is whether ESKD subjects on hemodialysis treated with weight loss strategies in preparation for kidney transplant but never receive the procedure have better or worse outcomes compared with those who remain obese. This is an area for future exploration. We acknowledge that the obesity paradox in ESKD subjects on dialysis is multifactorial, and there is no current universally accepted theory or strong evidence as to the existence of the obesity paradox and/or if obesity affords health protective effects in this population.

In this perspective, we explore the hypothesis that obesity may offer a protective effect against the adverse health consequences of microplastic and nanoplastic (MNPs) exposure in patients with ESKD undergoing dialysis. MNPs are defined as particles (microplastics<5 mm; nanoplastics <1 μm) which are byproducts of plastic degradation. Humans are exposed to MNPs from a variety of sources to include the air, plastic food containers, trash, synthetic textiles, and personal care products. In addition, these particles have been identified throughout the human body, penetrating into every organ including the kidneys, brain, heart, and placenta.³ Importantly, and relevant to this discussion, many of the MNPs are lipophilic and have been shown to accumulate in adipose tissues.⁴ Studies in rodents have shown the accumulation of MNPs in the epididymal and inguinal white adipose tissue after only 14 days of exposure. The accumulation of MNPs in the kidney has been linked to deleterious effects to include thickening of the glomerular basement membrane causing decreased barrier function and endothelial cell damage exacerbated by oxidative stress induced by particle exposure.³ Despite these adverse effects on kidney function, data in humans and rodents indicate that the kidney is one of the organs critical for reducing the body burden of MNPs. Subjects with ESKD are therefore at a distinct disadvantage related to their inability to clear MNPs from the body. Furthermore, subjects with ESKD on dialysis are further exposed to MNPs through the components of the dialysis circuit.^5,6 Increased exposure to MNPs coupled with the impaired ability to remove them from the body through kidney mechanisms could result in higher exposure to MNPs in this population. To the extent these compounds cause kidney injury, exposure may hasten the loss of residual kidney function which adversely effects outcomes in dialysis populations. In addition, accumulation of MNPs has been suggested to play an etiologic role in the risk of sudden death in patients on dialysis.⁷

Although there is variability in the literature, resolution of uremic symptoms after initiation of hemodialysis leads to an increased fat mass.⁸ This change is expected since many patients on hemodialysis do not engage in activity predicted to increase muscle mass such as resistance training. Importantly, once on maintenance hemodialysis, those who loose fat mass have higher mortality when compared with those who continue to gain fat mass. We put forth the idea obese individuals on hemodialysis have better outcomes than lean individuals because the excess adipose tissue acts as a “sink” to allow accumulation of MNPs and mitigate toxicity that would otherwise occur through deposition in various organ systems (Figure 1). To the extent MNP sequestration in adipose tissue is protective, we propose that loss of fat mass may allow MNPs to redistribute within the body going to other lipophilic tissues leading to toxicity.^9,10 In the setting of weight loss, fat cells shrink as stored triglycerides are broken down and released as energy. Any substances sequestered in the fat, such as MNPs, and constituents of MNPs to include heavy metals, or endocrine disrupting chemicals, could be mobilized to other lipophilic tissues in the body. Weight loss is associated with increased release of stored lipophilic hexachlorobenzene and other chlorinated hydrocarbons from adipose tissues, and it is hypothesized that the same could be true for lipophilic MNPs. The idea that weight loss might release sequestered MNPs into the bloodstream or other parts of the body, potentially leading to toxicity, is speculative but theoretically plausible based on what we know about how substances are stored and released from fat cells.

Figure 1.

Hemodialysis patients are susceptible to a high body burden through release of MNPs from the dialysis circuit and reduced excretion secondary to loss of kidney function. It is speculated that increased fat mass may serve as a reservoir for sequestration of MNPs preventing untoward accumulation in visceral organs. Weight loss has the potential to release these substances into the circulation where they can then be deposited into various organ systems potentially causing long term toxicity. MNP, microplastic and nanoplastic.

Much like asbestos and lead, addressing the health risk(s) of MNPs is important to the future of healthcare. Research furthering our understanding of how MNPs interact with ESKD dialysis subjects will be critical in knowing if dialysis procedures and/or constituents of the dialysis tubing need to be augmented to improve outcomes.

In conclusion, MNPs present a new challenge in medicine because of correlative data on their effect on human health. Despite over 20 years of research, we still know relatively little regarding the human health effects of MNPs despite strong evidence of the nearly ubiquitous nature of MNPs and human exposure. For these reasons, further research into the role of MNPs in ESKD individuals on dialysis and the obesity paradox as well as the role of MNPs in human health are increasingly imperative as we progress as a society reliant on plastic products.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C264.

Funding

None.

Author Contributions

Conceptualization: Deborah J. Clegg.

Writing – original draft: Christopher Baker, Deborah J. Clegg.

Writing – review & editing: Christopher Baker, Deborah J. Clegg, Biff F. Palmer.