New Fluids for Peritoneal Dialysis : why do we need them and what is it about?

Abstract

Peritoneal dialysis (PD) fluids generate concentration and osmotic gradients across the peritoneal membrane to remove uremic toxins and to achieve ultrafiltration. The use of current-era dialysis fluids also drives peritoneal and systemic pro-inflammatory, pro-fibrotic and pro-angiogenic processes that could be linked to patient outcomes. As the most frequent causes of PD technique failure are mortality, infections, insufficient solute clearance and ultrafiltration failure, it is important to reflect on the effects and modifiable power of the PD fluids’ compositions.

This paper discusses the peritoneal and systemic effects of glucose-based PD fluids and the evidence on the use of icodextrin and amino-acid based alternatives. Recent innovations in PD fluids try to overcome the peritoneal and systemic toxicities of current formulations by using an alternative osmotic agent and/or by counteracting the metabolic effects of the carbohydrate load by the PD fluid.

Introduction

Peritoneal dialysis (PD) fluids generate a concentration gradient across the peritoneal membrane allowing diffusion of uremic toxins from the patient’s circulation towards the peritoneal cavity. Diffusion is a bi-directional process, hence, small molecules within the PD fluid will also be absorbed by the patient during a PD dwell. The osmotic gradient exerted by the PD fluid on the other hand allows water flux across the peritoneal membrane. The application of the physical principles of diffusion and osmosis by a PD fluid dwelling in the peritoneal cavity allows to manage clearance and volume status of the patient during PD.

PD offers similar overall survival compared to center-hemodialysis with a trend towards a survival advantage for patients treated with PD in the first years after dialysis start[1][2]. Nevertheless, overall patient survival remains poor with survival probability of only 47% at 5 years after dialysis initiation[1]. Among patients surviving, PD technique failure is not uncommon with 1- and 2-year death-censored PD technique failure rates of 23% and 35% respectively in a contemporary European cohort[3]. Common causes of death-censored PD technique failure over time are infections, insufficient clearance and/or ultrafiltration problems[3].

This article describes the composition of PD fluids and their peritoneal and systemic effects. Although the primary goal of PD fluids is to serve solute removal and ultrafiltration, dialysis fluids also play a role in peritoneal membrane integrity, and systemic absorption of PD fluids influence systemic metabolic pathways. We discuss how novel developments in PD fluids overcome the downsides of current-era PD fluids and how PD fluids innovations aim to optimize the composite outcome of solute clearance, ultrafiltration, peritoneal membrane changes over time on PD and systemic effects by the PD fluid (Figure 1).

Figure 1.Peritoneal dialysis fluids serve solute removal and ultrafiltration. PD fluids also affect peritoneal membrane integrity and systemic absorption of PD fuids solutes influence systemic metabolic pathways. PD fluids innovations aim to optimize the composite outcome of solute clearance, ultrafiltration, peritoneal membrane changes over time on PD and systemic effects by the PD fluid.

First-generation peritoneal dialysis fluids

First-generation PD fluids, also called conventional PD fluids, contain electrolytes, a buffer, and glucose as the primary osmotic agent (Table I). The glucose content of these solutions is 10-50 times higher than the plasma glucose concentration. The heat sterilization process of the PD fluids leads to the production of glucose degradation products (GDPs), despite being performed at low pH. Conventional PD fluids are thus characterized by low a pH, a high glucose and a high GDP content.

A landmark study published in 2002 showed significant histopathologic damage of the peritoneal membrane over time with the use of these conventional PD fluids. After prolonged exposure to low pH, high glucose and high GDP fluids, follow-up histopathological assessments of the patients’ peritoneal membrane demonstrated mesothelial cell loss, submesothelial thickening, angiogenesis, and peritoneal vasculopathy[4]. In the early 2000’s, it was also recognized that peritoneal solute transport increases with time on treatment in a proportion of patients treated with PD and that this increase was associated to a higher peritoneal exposure to hypertonic glucose[5]. Although change in solute transport status over time is associated to glucose exposure, the functional and histopathological changes within the peritoneal membrane induced using low pH, high glucose and high GDP PD fluids guided the “biocompatibility hypothesis of PD fluids”. The hypothesis of biocompatibility suggests that morphological and functional peritoneal damage might be caused by conventional PD fluids - low pH, high glucose and high GDPs content PD fluids - and that these changes might be attenuated by second generation, so called biocompatible fluids.

Second-generation peritoneal dialysis fluids

To decrease the toxicity of low-pH, high glucose and high GDP PD fluids on the peritoneal membrane, multi-chambered bags were developed allowing glucose to be sterilized separately at very low pH, generating less GDPs. Before use, the glucose compartment is mixed with the other compartment(s) of the PD fluid containing electrolytes and a buffer. After mixing the different chambers of the PD fluid bag, a neutral pH PD fluid is obtained containing less GDPs compared to the first-generation PD fluids. Second-generation PD fluids are thus defined by their neutral pH and lower GDP content and are so-called biocompatible solutions (Table I).

Table I.Composition of currently commercially available PD fluids.

	Plasma reference (adult)	First-generation G%-based fluid	Second-generation G%-based fluid	Amino-acid solution	Icodextrin
		"Low pH, high GDP solutions"	”Neutral pH, low GDP solutions"
Electrolytes (mmol/L)
Sodium	136-145	132	132-134	132	133
Calcium	1.12-1.32	1.25/1.75	1.25-1.75	1.25	1.75
Magnesium	0.65-1.05	0.25/0.75	0.25/0.5	0.25	0.25
Chloride	98-107	95/102	95-104	105	96
Potassium	3.5-5.1	0	0	0	0
Buffer (mmol/L)
Acetate	0
Lactate	0.5-2	40/35	10-15/35/0	40	40
Bicarbonate	22-28		25/0/34
pH	7.4	5.5	7.0-7.4	6.7	5.5
Osmotic agent (g/dL) (osmolality)
Glucose	0.05 - 0.1	1.36/2.27/3.86	1.36-1.5/2.27-2.5/3.86-4.25
	280-300	347/398/486	± 350/397/490
Amino acid	0.05 - 0.1			1.1
	280-300			365
Icodextrin					7.5
					284

Preclinical in vitro and in vivo studies using second-generation PD fluids showed promising histopathological effects with reduced mesothelial damage induced by the biocompatible fluid, less epithelial-to-mesenchymal transition (EMT), less deposition of GDPs, decreased sub-mesothelial fibrosis and angiogenesis and less progression of vasculopathy with better preservation of the endothelial glycocalyx[6][7][8][9]. Also, observational data from clinical practice in Japan suggest that biocompatible PD fluid use contributes to decreased encapsulated peritoneal sclerosis

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