Apart from its use in patients with end-stage kidney disease or acute kidney injury, there has recently been interest in the potential use of peritoneal dialysis for other, nonrenal indications. Herein, we review two nonrenal areas that are currently being evaluated: use of liposomal-supported peritoneal dialysis for the removal of endogenous and exogenous toxins and use of peritoneal dialysis to reduce risk of secondary brain injury following ischemic stroke.

© 2022 S. Karger AG, Basel

Introduction

Kidney replacement therapy (KRT) is most commonly used in either acute or end-stage kidney disease (ESKD). The major KRT modalities are hemodialysis (HD), peritoneal dialysis (PD), or continuous modalities in hospitalized patients [1]. PD involves the instillation of dialysate into the peritoneum, which is used as a semipermeable membrane across which exchange of solutes, waste, and excess fluid between blood and dialysate occurs [1]. Worldwide, HD is the predominant form of KRT, and it is also often used for nondialysis indications (such as drug toxicity). However, there are situations in which PD may be preferred over HD (such as in hemodynamic instability, ease of access). As a result, there has been renewed interest in PD for both renal and nonrenal indications [2]. This article will not review all topics for which PD has been evaluated (such as use of PD for psoriasis, heart failure, pancreatitis, hypothermia, etc.); rather, we will focus on two distinct entities: liposomal-supported peritoneal dialysis (LSPD) and use of PD in the setting of acute stroke.

LSPD for Endogenous and Exogenous Toxins

Liposomes are nanometric, spherical structures consisting of a phospholipid bilayer with an aqueous, hollow center. Liposomes were first developed for targeted and sustained drug delivery, attainable by loading the aqueous center with medications [3, 4]. More recently, the role of liposomes has been expanded for use as scavengers of endo- and exotoxins. These scavenger liposomes have an empty aqueous center; by adjusting the pH of the center and creating a transmembrane gradient, they act as a sink for molecules of interest. The phospholipid bilayer is typically made with biocompatible materials, such as dipalmitoylphosphatidylcholine or soy phospholipids [4]. Initially, scavenger liposomes were administered parenterally to trap endotoxins; this is limited, however, by difficulty removing the liposomes from the bloodstream and triggering of complement activation-related pseudo-allergic reaction (CARPA) [4]. In contrast, administration of liposomes intraperitoneally (i.e., LSPD) may offer an elegant solution to the complications from parenterally administered liposomes. The liposomes are easily removed from the peritoneal cavity and, by increasing the size of the liposomes to 850 nm, they can be sequestered intraperitoneally for longer periods of time. Furthermore, the small size of peritoneal membrane pores (ranging ∼0.5–5 nm) prevents exposure of complement C3 (>10 nm in size) to liposomes, reducing risk of CARPA [4, 5].

Here, we will conduct a brief overview of the different studies that have evaluated the efficacy of LSPD, both in vitro and in vivo, in the sequestration of both endogenous and exogenous toxins. A summary of these studies is included in Table 1. While an excellent review of these studies was conducted by Hart et al. [5] in 2020, here, we have added a new human clinical study to their review.

Table 1.

Summary of studies evaluating use of LSPD to sequester endogenous and exogenous toxins

Use of LSPD for Endogenous Toxin Sequestration

Clinically, liposomes have been evaluated to remove lipophilic and weakly basic substances, such as ammonia. In patients with liver failure or in-born errors of metabolisms, accumulation of ammonia can cause hepatic encephalopathy and cerebral edema. This is typically treated with a reduced urea diet, medications, and occasionally HD or continuous kidney replacement therapies. In certain situations, as in neonates, HD may be challenging due to limited venous access, and LSPD may offer a better solution [4, 5].

In vitro studies showed that liposomes with an acidic center effectively sequester ammonia; this effect was maintained in the setting of human ascitic fluid from liver failure patients [5, 6]. In vivo studies in rat cirrhosis models showed that, compared to standard PD, LSPD led to a 20-fold higher dialysate ammonia concentration, with associated reduction in plasma ammonia levels and reduced cerebral edema [7]. Unintentional removal of common metabolites (e.g., K or Mg) was not increased in vivo with LSPD compared to standard PD [4-6]. Liposomes were more effective in vivo when they were pre-treated with citric acid as an “osmotic shock” to reduce the pH to 2, followed by pH neutralization prior to clinical use [5-8]. Preclinical studies conducted in mini-pigs to evaluate safety and pharmacokinetics showed that after 10 days of exposure to both medium and high doses of liposomes, there was no evidence of CARPA, little systemic exposure to phospholipid, low plasma citrate levels, and minimal dipalmitoylphosphatidylcholine absorption. In vivo LSPD studies in hyper-ammonemic swine showed similar results to rat studies, with a significant reduction in plasma ammonia levels and intraperitoneal sequestration [8].

It is important to note that in vitro, liposomal sequestration of ammonia was not significantly reduced in the presence of medications commonly used in liver failure patients, except for propranolol, ofloxacin, and norfloxacin. Ofloxacin and norfloxacin are competitively sequestered by liposomes, and the presence of these medications reduced ammonia sequestration by 27–32%. Incubation with propranolol led to only 6% sequestration of ammonia at 5 h. Yet, there was only 13% sequestration of propranolol, indicating that the reduction in liposomal sequestration of ammonia is likely a function of membrane destabilization by propranolol, rather than competitive uptake [4-6]. It should be noted, however, that these medications were tested at a concentration of 1 mM, approximately 200 times their plasma levels when used therapeutically. The effect of more modest drug doses has yet to be ascertained.

More recently, clinical studies have evaluated the use of liposomes for ammonia sequestration in human patients with decompensated cirrhosis and ascites. In a recent oral abstract, Uschner et al. [9] presented findings from a small, clinical 1b study evaluating the safety and efficacy of the study drug VS-01, a transmembrane pH-gradient liposome, in reducing serum ammonia levels and reducing risk of hepatic encephalopathy. VS-01 was instilled intraperitoneally in an ascending manner as a single dose of either 15, 30, 45 mL/kg (part A) or 4 repeated doses (34–42 mL/kg, part B), dwelled for 2–3 h, and then withdrawn by paracentesis [9]. Outcomes included safety assessments, ammonia levels, psychometric changes, and metabolomic analysis [9]. They report that there were no significant safety changes and that it reduced serum ammonia while increasing peritoneal ammonia levels and improved psychometric changes [9]. However, the data and results from this study are yet to be published outside of their oral abstract. While the design is not technically true PD, their methods expand upon prior published data and utilize the same mechanism inherent to PD. Potentially, this technique could be expanded beyond just single dwells to full PD.

Use of LSPD has also been examined for the removal of protein-bound uremic toxins (PBUTs). PBUTs are usually secreted by the proximal tubule, though this ability is reduced with worsening kidney function, leading to uremic symptoms [10]. In ESKD, because these toxins are heavily protein bound, they are not efficiently cleared by PD or HD as there is only a small free fraction available to be dialyzed [11]. Specifically, p-cresyl sulfate and indoxyl sulfate (IS) are PBUTs that are documented to be associated with increased mortality, infection, cardiovascular events, and worsening kidney function [11]. In HD, clearance of PBUTs can be increased by using a dialyzer with a higher mass transfer-area coefficient of urea (KoA) and increasing the dialysate flow rate [11]. Enhancing clearance of PBUTs with PD is more challenging because the membrane area is fixed and dialysate volumes are small; yet, the addition of a sorbent to the dialysate has been suggested to improve clearance. Based on this, Shi et al. [11] compared LSPD to both albumin-based dialysate and standard PD for removal of PBUTs (p-cresyl sulfate, IS, 3-IAA). In vitro and in vivo rat studies showed that both albumin-based PD and LSPD had significantly higher uptake of PBUTs compared to standard PD. Albumin-based PD was slightly more efficacious than LSPD for removal of IS in vivo, but it is substantially more expensive than is LSPD. Further work has been done regarding modifications of liposomes to enhance the free fraction of PBUTs, such as the addition of linoleic acid to liposomes (which compete with the PBUT to bind albumin) or creation of cationic-supported liposomes (which use electrostatic forces to improve binding of PBUTs) [5].

Use of LSPD for Exogenous Toxin Sequestration

LSPD has also been evaluated for removal of exogenous toxins, such as medication overdoses or alcohols. Management of drug overdoses typically involves supportive measures, an antidote if available, and in certain circumstances, HD [4, 5, 12]. If the intoxicant is highly protein bound or has a large volume of distribution (Vd), HD is not usually effective. Currently, standard PD has no role in the treatment of toxicities; however as proposed by Chapman et al. [12], liposomes may have a role in management as certain intoxicants (such as amitriptyline or verapamil) are lipophilic, protein-bound substances that can reversibly associate with the lipid bilayers of the liposomes [4, 12]. These molecules can then transfer across the phospholipid bilayer and be sequestered following protonation by the acidic core. Early rat studies by Forster et al. [4] demonstrated that administration of intravenous liposomes sequestered verapamil and shortened the time to improved hemodynamics. Due to associated side effects and the physical difficulty of removing intravenous liposomes, LSPD was also trialed for verapamil removal. Compared to standard PD, LSPD showed an 80-fold removal in verapamil after 11 h of treatment, as well as significantly improved hemodynamics after only 3 h of treatment. LSPD also was able to sequester amitriptyline, propranolol, haloperidol, and phenobarbital [4, 5]. Two other animal studies also showed significantly higher uptake of amitriptyline with LSPD than standard PD [5, 12].

Liposome-supported enzymatic PD (LSEPD) is a variant of LSPD that has been evaluated in acute alcohol intoxication. LSEPD involves loading liposomes with enzymes, such as alcohol oxidase and catalase [5, 13]. In vitro models with LSEPD showed significantly reduced ethanol levels and increased acetaldehyde levels compared to control. This effect was increased with the addition of hydrogen peroxide (H2O2) as alcohol oxidase requires an O2 source for ethanol degradation [13]. In vivo rat models of alcohol poisoning showed that the ethanol metabolite acetaldehyde increased intraperitoneally with LSPED, but there was no significant decrease in plasma ethanol levels between control animals and those treated with LSEPD [13].

Thus, LSPD offers an exciting area for PD in the future, as these preliminary studies suggest a possibility for PD clearance of exogenous and endogenous toxins, including highly protein-bound substances, which previously were challenging to remove with PD. A summary of studies evaluating LSPD for the removal of endogenous and exogenous toxins is presented in Table 1.

PD for Stroke

In the central nervous system, L-glutamate is an excitatory neurotransmitter that is involved in a number of physiologic reactions [14, 15]. Glutamate is stored in vesicles in synapses and its release and binding to neighboring synapses is tightly regulated, causing the extracellular concentration to be quite low (<2 μmol/L). In contrast, outside the brain, the plasma concentration of glutamate is much higher, 40–100 μmol/L [15]. The blood-brain barrier prevents influx of glutamate from the plasma into the brain, but efflux of glutamate to the peripheral circulation does occur when the brain glutamate level exceeds that of the peripheral circulation [15]. This movement of glutamate down its concentration gradient and out of the brain is the basis for treating intracerebral glutamate toxicity; by lowering the peripheral glutamate concentration, excess glutamate in the brain will follow down the concentration gradient and be removed from the brain [15].

In the setting of acute ischemia, a cascade of events causes a large release of glutamate into the extracellular space, leading to excitotoxicity from overactivation of neurons, release of reactive oxygen species, and activation of caspases that cause neuronal death [15]. It has been shown that a high level of glutamate in blood and cerebrospinal fluid during the first 24 h after a stroke correlates with worse outcomes. Therefore, many efforts have been made to reduce glutamate levels [15]. One therapy involves use of blood glutamate scavengers. These drugs, such as oxaloacetate transaminases, bind and reduce levels of peripheral glutamate, encouraging diffusion of glutamate out of the brain. Scavengers have shown some improved neurologic outcomes in rat models but have systemic toxicities [14]. Extracorporeal methods to remove peripheral glutamate, such as HD, may offer a solution but are often limited by clinical instability, potential need for anticoagulation, and risk of worsening ischemic damage [14].

Unlike HD, PD does not cause significant hemodynamic shifts: therefore, it may be better tolerated in this critically ill population. Initial studies in otherwise healthy PD patients indicated that during PD, plasma glutamate levels were reduced, correlating with an increase in dialysate levels [16]. In a model of stroke in rats, initiation of PD 2.5 h after acute stroke significantly reduced infarct size (12.1%, p < 0.001), correlating with a reduction in plasma glutamate levels and increased dialysate glutamate [17]. Furthermore, imaging (functional MRI) showed that the functional damage to tissue was partially prevented using PD [17]. In control rats, the benefit of PD on infarct size was not seen when glutamate was added to the dialysate (reducing clearance of plasma glutamate) [17].

One human clinical trial of PD in stroke has been completed [EudraCt Number: 2012-000791-42] [18]. The trial involved 10 patients with ischemic stroke, of which 5 served as control patients, while the other 5 underwent PD [18]. The treatment group received 6 cycles of PD with 2L exchanges, occurring every 4h, during the acute phase of stroke. PD was started on average within 13 h of onset of stroke symptoms. Of the 5 patients in the treatment arm, only 1 patient completed all 6 exchanges [18]. One patient had an error with PD catheter placement and did not receive PD; the other 3 had technical issues with PD and only underwent 1–2 cycles. Following completion of the study, there were no significant differences in infarct volume or neurologic and functional outcomes [18]. The treatment group had a 46% reduction in serum glutamate within 2 h, but this was not significant (though it did meet significance with exclusion of the patient with the misplaced catheter). Glutamate was detected in dialysate after 4 h in all patients in whom PD was run, and levels were 22-fold higher in the patient who completed all 6 cycles [18]. Thus, while technically flawed, this study did demonstrate the dialyzability of glutamate in humans. Further study is clearly needed.

Discussion

As discussed above, PD provides a unique opportunity for both renal and nonrenal related indications, such as LSPD and PD in the setting of stroke. Although less common than HD, there may be some situations where PD is preferred to HD. For example, patients with cirrhosis often have chronic hypotension, and thus LSPD for hyperammonemia would likely be better hemodynamically tolerated than HD [4]. Additionally, in the neonate population with in-born errors of urea metabolism, LSPD may be preferred to HD for ammonia removal due to better ease of access [4]. Finally, in ESKD patients on PD, albumin-PD or LSPD may have an additive benefit to their typical PD regimen by improving PBUT clearance, which are typically poorly removed by standard PD [11]. On the other hand, PD has limitations, such as the need for a surgically placed catheter. Because of this, PD initiation in emergent situations is less feasible. Although LSPD improved hemodynamics in rat models of verapamil overdose, the extrapolation of this to clinical practice would require the placement of PD catheters urgently, in critically ill, hemodynamically unstable patients [4]. Similarly, the trial that evaluated use of PD in ischemic stroke in humans had placement and initiation of PD within an average of 13 h from acute stroke [18]. Currently in the USA, where PD catheters are predominantly placed in an outpatient setting, the requirement for urgent/emergent PD catheter placement for these indications may be prohibitive. However, with newer government incentives to increase use and preference of PD, there may be shift toward its use in emergent situations in the future.

Conclusion

Further exploration into the extrarenal uses of PD as described above has the potential to expand the use of PD beyond kidney failure. Additional studies are eagerly anticipated.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors report no funding sources for this review.

Author Contributions

Dr. Ruth Campbell authored and edited the initial and final drafts of the manuscript. Dr. Isaac Teitelbaum authored and edited the initial and final drafts of the manuscript.

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