Do low GDP neutral pH solutions prevent or retard peritoneal membrane alterations in long-term peritoneal dialysis?

Abstract

Several studies have been published in the last decade on the effects of low glucose degradation product (GDP) neutral pH (L-GDP/N-pH) dialysis solutions on peritoneal morphology and function during the long-term PD treatment. Compared to conventional solutions, the impact of these solutions on the morphological and functional alterations of the peritoneal membrane is discussed, including those of effluent proteins that reflect the status of peritoneal tissues. Long-term PD with conventional solutions is associated with the loss of mesothelium, submesothelial and interstitial fibrosis, vasculopathy, and deposition of advanced glycosylation end products (AGEs). L-GDP/N-pH solutions mitigate these alterations, although vasculopathy and AGE deposition are still present. Increased vascular density was found in some studies. Small solute transport increases with PD duration on conventional solutions. Initially, higher values are present on L-GDP/N-pH treatment, but these may be reversible and remain stable with PD duration. Consequently, ultrafiltration (UF) is lower initially but remains stable thereafter. At 5 years, UF and small pore fluid transport are higher, while free water transport decreased only slightly during follow-up. Cancer antigen 125 was initially higher on L-GDP/N-pH solutions, suggesting better mesothelial preservation but decreased during follow-up. Therefore, L-GDP/N-pH solutions may not prevent but reduce and retard the peritoneal alterations induced by continuous exposure to glucose-based dialysis fluids.

Keywords

AGE deposition fibrosis long-term peritoneal dialysis low GDP neutral pH solutions mesothelium solute transport ultrafiltration vasculopathy

Introduction

Five-year patient survival in incident PD patients in Europe is similar to that of those on hemodialysis (HD), if not better in intention-to-treat analyses.¹ Yet the dropout rate to HD remains high. After 5 years, only 10% of incident PD patients remain on PD, while this is 25% for HD.¹ Besides death and transplantation, catheter complications and peritonitis are the main reasons for PD discontinuation during the initial years,² but thereafter, impaired ultrafiltration (UF) becomes progressively important.³ The UF decline points to the development of peritoneal membrane changes during prolonged treatment. These morphological and functional membrane alterations have been reviewed in detail.⁴ The continuous exposure of the peritoneal tissues to the dialysis solutions is the major culprit of peritoneal remodeling because conventional fluids are composed of extremely high concentrations of glucose, have a low pH, and contain lactate as a buffer substance. Furthermore, they contain glucose degradation products (GDPs) generated during the solution sterilization procedure. A review on GDPs summarized the in vitro data, indicating that glucose with GDPs accelerates the formation of advanced glycosylation end products (AGEs) at a faster rate than glucose alone.⁵ Toxic effects of the low pH are probably limited to in vitro and experimental studies because in PD patients, the initial intraperitoneal pH rapidly increases due to dilution with the residual volume after drainage of the previous exchange.⁶ However, in some, this initial low pH may manifest as initial pain on infusion of the dialysate.

Around the turn of the millennium, many new PD solutions have been developed that contain glucose as the osmotic agent in the usual concentrations but have reduced GDP content. They all have a higher or normal pH and some have totally or partially replaced lactate with bicarbonate. These dialysis fluids are called low GDP neutral pH (L-GDP/N-pH) solutions. They still have an unaltered glucose content. Less inflow pain with L-GDP/N-pH solutions was established shortly after their introduction.⁷ A number of other effects have been summarized in a review, published a decade ago.⁸ Strikingly, all studies with a short follow-up duration of maximally 2 years reported higher or increased effluent concentrations of cancer antigen 125 (CA 125), relative to conventional solutions, regardless of the composition of the investigated biocompatible solution. Although the explanation is not fully understood, better preservation of mesothelial cells is one possibility. In contrast, the results of short-term studies with L-GDP/N-pH solutions on fluid and solute transport are equivocal. This is not unexpected, because marked peritoneal remodeling usually takes a number of years to become clinically evident. A number of studies concerning peritoneal alterations in long-term PD patients treated with L-GDP/N-pH dialysis solutions have been published recently. These will be discussed in the following sections using a case history as starting point.

Case history

A 57-year-old female developed kidney failure due to mesangioproliferative glomerulopathy in 1991. She received three kidney transplants in total. The first and second allografts failed due to chronic antibody-mediated rejection, the third one was removed due to thrombotic microangiopathy secondary to chronic hepatitis C. Maintenance immunosuppression included cyclosporin. After the loss of the second and third grafts, she was treated with PD in 2008, altogether for 11 years. Except one mild exit site infection, the patient did well on PD without acute complications or peritonitis. In 2017, Dianeal® was replaced by Physioneal® and icodextrin. Peritoneal function was assessed every 2 years with a 3.86% glucose peeritoneal equilibration test (PET), determination of D/P Na⁺ after 1 h, and measurement of effluent CA 125 after 4 h. Results are presented in Table 1. D/P creatinine started to increase from 2013 onward, accompanied by lower UF and less sodium sieving. Progressive UF insufficiency was present from 2015. No decrease was found for CA 125. A laparotomy for surgical replacement was performed in August 2019 because of an injury of the external part of the catheter in close proximity to the exit site. The intraoperative findings included a stiff mesentery, mural peritoneal invasions, and a serous effusion around the catheter, necessitating its withdrawal. Postoperative CT scan showed localized peritoneal thickening in less than 20% of peritoneal tissue, accompanied by calcifications in 20%, mild bowel tethering, a pelvic fluid collection, and increased density of abdominal fat (Figure 1(a)). A peritoneal biopsy confirmed thickening of the submesothelial layer, microvasculopathy, and calcifications (Figure 1(b)). A diagnosis of localized encapsulating peritoneal sclerosis (EPS) was made, the patient was transferred to HD and treated with prednisone and tamoxifen.

Table 1.

Changes in parameters of peritoneal water and solute transport assessed by 3.86% glucose PET over the time on peritoneal dialysis.

Date	D/P creat	D/P Na⁺	Ultrafiltration (mL)	CA 125 (kU/L)
January 2009	0.82	0.88	800	No data
November 2011	0.75	0.84	800	14.5
November 2013	0.77	0.89	600	19.2
January 2015	0.81	0.89	330	14.8
October 2016	0.83	0.89	430	14.1
May 2018	0.83	0.91	200	22.0

D/P creat: dialysate/plasma creatinine concentration at 240 min; D/P Na⁺: dialysate /plasma sodium concentration at 60 min; NUF: net ultrafiltration after a 4 h dwell; CA 125: cancer antigen 125 concentration in the effluent after 4 h dwell.

Figure 1.

(a) Abdominal CT scan showing irregularly thickened peritoneum with coarse calcifications medial to the caudal portion of the iliopsoas muscle on the left. Discrete fat stranding of mesenterial fat, calcifications in the iliac vessels, and free fluid are present. No signs of bowel obstruction are visible. (b) Hematoxylin-stained peritoneal biopsy showing some mesothelial cells (upper left), submesothelial fibrosclerosis, interstitial fibrosis, calcification on the top and microvasculopathy on the right.

Peritoneal morphology

Until recently, information on the normal structure of peritoneal tissues was based on scarce observations in a small number of individuals. A detailed description of quantitative peritoneal histomorphometry in a large number of children and adults was published in 2016.⁹ The density of blood capillaries in adults increased with age, while the endothelial thickness decreased. No effect of age was found for other vascular properties, submesothelial thickness, and lymphatic density.

An inherent problem with the interpretation of morphologic studies in long-term PD patients is their cross-sectional nature. Longitudinal analyses are usually absent except for one study in which 24 incident pediatric patients (prior to PD) and PD patients underwent a follow-up peritoneal biopsy after a median duration of 13 months.¹⁰ Data on follow-up biopsies in long-term adult patients are not available. Six studies on the development of peritoneal alterations in adult patients are summarized in Table 2. Taken together, the morphological analyses show the progressive development of peritoneal remodeling with the duration of PD using conventional dialysis solutions.

Table 2.

Morphologic peritoneal abnormalities in long-term PD patients on conventional dialysis solutions.^a

Year^ref	Number of patients	PD duration (years)	Mesothelial changes	Interstitial fibrosis	Vascular changes	AGE deposition
1999¹³	25	Incident, n = 7	Not recorded	– ↑With duration – Myofibroblasts	– Vascular density↑ in EPS – Wall/total ↑ max in EPS	Not recorded
		≥2 years, n = 7
		EPS, n = 11
1999¹⁶	14	≤4 years, n = 3	Not recorded	– ± to ++ – + to ++	– Sclerosis – to ++ – Sclerosis + to ++	± to +
1999¹⁶	14	>4 years, n = 11	Not recorded	– ± to ++ – + to ++	– Sclerosis – to ++ – Sclerosis + to ++	+ to ++
2003¹¹	130	≤2 years, n = 58	Absent in 49%	– ↑Submesothelial fibrosis ≥4 years	– Vasculopathy < 2 years 29% – Vasculopathy 2–4 years 62% – Vasculopathy >4 years >70% – Vascular density↑ only in membrane failure	Not recorded
		≤4 years, n = 24
		>4, n = 48
2006¹⁴	41	≤5 years, n = 15	Not recorded	Not recorded.	– Vascular density unchanged, but EPS excluded	Not recorded
2006¹⁴	41	> 5 years, n = 26	Not recorded	Not recorded.	– Vascular density unchanged, but EPS excluded	Not recorded
2014¹²	110	≤4 years, n = 92	Denudation in 5%^b	25%^b	– Vasculopathy 2%^b – Vasculopathy 6–9%^b	Not recorded
2014¹²	110	>4 years, n = 14	Denudation in 15%^b	35 to >50%^b	– Vasculopathy 2%^b – Vasculopathy 6–9%^b	Not recorded
2020¹⁵	60	>1 to >7 years	Not recorded	n.r.	– Vascular density of immature capillaries ↑, related to small solute transport and AGE deposition	Related to PD duration

AGE: advanced glycosylation end products; EPS: encapsulating peritoneal sclerosis.

^a Studies are cited according to the year of publication.

^b Expressed as volume percentage.

Six studies on peritoneal morphology during PD with exposure to L-GDP/N-pH solutions have been published, two of which are in children.^10,17 The latter analyses were done in the same large population and comprised a comparison with nondialyzed children with CKD stage 5 and a follow-up biopsy in 12% of all biopsies. One-third of the patients received PD for more than 2 years and 16% for more than 4 years. Mesothelial thickness was especially decreased in children treated for more than 4 years and peritoneal blood vessel density was higher in children on PD compared to those with CKD5 but without evident progression. Remarkably, the lumen/vessel diameter (L/V) ratio was not different between CKD5 and PD, irrespective of its duration. Previous peritonitis was only associated with increased submesothelial thickness and vascular density compared to controls in patients with a PD duration of at least 4 years.¹⁷

Comparisons between L-GDP/N-pH and conventional solutions were made in adult dialysis populations.^18

–21 These are summarized in Table 3. It can be concluded that all studies in patients treated with L-GDP/N-pH solutions showed better preservation of mesothelial cell integrity, less peritoneal submesothelial thickness, and a reduction of the severity of vasculopathy and AGE deposition, compared with those on conventional fluids. Increased vascular density was present in some but not in all analyses. However, it should be noticed that submesothelial fibrosis, vasculopathy, and AGE deposition still occurred despite the lower GDP content of PD solutions used.

Table 3.

Morphologic differences between long-term treatment with conventional and low ↑GDP neutral pH dialysis solutions.^a

	Conventional		L-GDP/N-pH
Year^ref	Number of patients	PD duration (years)	Number of patients	PD duration (years)	Differences
2013¹⁸	12	5 ± 0.5	12	4 ± 0.5	Submesothelial fibrosis ↓
					Lumen/vessel diameter ↑
					AGE ↓, but still present
2015²⁰	19	0 to >5	29	0 to >5	Submesothelial fibrosis =
2015²⁰	19	0 to >5	29	0 to >5	Lumen/vessel diameter ↑
2016¹⁹	23	2 ± 1.5	23	2 ± 1.3	Mesothelium↑
					Submesothelial fibrosis↓
					Vasculopathy↓
					EMT =
2019^21b	54	7 (6–11)	73	2–6	Submesothelial fibrosis ↓^c
					Lumen/vessel diameter ↑
					AGE ↓, but still present

L-GDP-N-pH: pow GDP neutral pH; EMT: endothelial-to-mesenchymal transition.

^a Studies are cited according to the year of publication. Means ± SD is given, or medians (range).

^b Patients from the literature²⁰ are included.

^c All differences were also present when only patients with a PD duration from 4 years to 10 years were analyzed separately.

Time course of peritoneal solute and fluid transport

In contrast to morphological studies, longitudinal follow-up of peritoneal solute transport parameters is possible when standardized dialysis dwells and dialysate tonicity are used. Most attention has traditionally been given to small solutes like creatinine and urea. Their transfer from the microcirculation to the dialysate is mainly by diffusion through small interendothelial pores and therefore by the number of perfused peritoneal microvessels, often summarized as the effective peritoneal surface area.²² Three longitudinal studies have been published on the time course of small solute transport during PD with conventional dialysis solutions, as summarized in Table 4.^3,23,24 They all showed an increase of D/P creatinine or its mass transfer area coefficient (MTAC) after a follow-up of 2–3 years, pointing to an enlargement of the effective peritoneal surface area. This enlargement also influences the absorption of dialysate glucose into the circulation, leading to a rapid disappearance of the crystalloid osmotic gradient. No evidence exists that the diffusion of small solutes is directly influenced by the mesothelial layer or by fibrotic interstitial changes.

Table 4.

Longitudinal follow-up studies on peritoneal transport during PD with conventional dialysis solutions.

Year^ref	Number of patients	Follow-up (years)	Single or multicenter	Test solution (glucose conc)	Key findings
1994²³	56	≥3	Single	Various	– Small solutes ↑ after 3 years – Ultrafiltration capacity ↓ after 3 years
2004²⁴	209	≥3, n = 129	Single	2.27%	– Small solutes ↑ continuously – Ultrafiltration ↓ after 2 years, more rapidly after 4 years – Osmotic conductance to glucose ↓ ≥4years
2004²⁴	209	≥4, n = 80	Single	2.27%
2014³	63	≥3, n = 33	Single	3.86%	– Small solutes ↑ after 3 years – Ultrafiltration ↓ after 3 years – Free water transport ↓ after 3 years – Small pore fluid transport ↓↓ after 4 years
2014³	63	≥4, n = 30	Single	3.86%

Transcapillary ultrafiltration (TCUF) is the main determinant of net UF, that is, the difference between the drained and the instilled dialysate volume. TCUF of water with dissolved solutes occurs by interendothelial pores, small pore fluid transport (SPFT), which is largely dependent on the hydrostatic pressure gradient.²⁵ In addition, water without solutes leaves the circulation by the intraendothelial water channel aquaporin-1 (AQP-1).^26,27 This free water transport (FWT) is dependent on the crystalloid osmotic pressure gradient. FWT explains the decrease of the dialysate sodium concentration by dilution, the so-called sodium sieving,²⁸ which can be used in clinical practice for assessment of FWT.²⁹ Calculating the sodium clearance allows simultaneous assessment of SPFT.³⁰

The first longitudinal study on the time course of fluid transport published in 1994 showed a progressive decline of net UF after 3 years on PD.²³ This was related to an increase of the D/P or MTAC creatinine, suggesting a rapid disappearance of the crystalloid osmotic gradient. Shortly thereafter, similar results were published in prospective studies from Japan³¹ and the UK; the latter in a large number of incident PD patients.³² The longitudinal studies on peritoneal transport are summarized in Table 4. The inverse relationship between net UF and D/P creatinine is different in long-term patients because the decrease in net UF was more than one would anticipated bases on an increase in D/P creatinine alone.²⁴ This phenomenon has been interpreted as an impaired osmotic conductance to glucose but may in retrospect also have been caused by a reduction in FWT. A separate prospective longitudinal analysis of the time course of SPFT and FWT confirmed this assumption because both decreased after 3–4 years on PD.³

All studies cited above were performed with conventional dialysis solutions. Based on the results of the first randomized trial done in prevalent PD patients, no important differences in fluid and small solute transport were found between the patients treated with L-GDP/N-pH and those with conventional solutions.³³ This first study was followed by a number of others, summarized in a study from central Europe,³⁴ which either showed no differences in the transport of small solutes and net UF or somewhat lower net UF values in patients treated with L-GDP/N-pH solutions during short-term follow-up. The multicenter randomized clinical trial balANZ in almost 200 incident PD patients with a follow-up of 2 years showed stability of D/P creatinine and net UF in those randomized to the L-GDP/N-pH solution, while D/P creatinine increased and net UF decreased in the controls.³⁵

A more pathophysiologic approach with special emphasis on the initial 3 months of treatment in incident CAPD patients and a crossover design after 6 weeks allowed further insights into the early effects of a dialysis regimen, consisting of a combination of one icodextrin-based solution for the long dwell combined with one amino acid-based and two L-GDP/N-pH glucose-based solutions (NEPP).³⁶ The NEPP treatment was associated with higher values of D/P creatinine compared to the controls and higher effluent levels of dialysate CA 125, interleukin-6 (IL-6), and vascular endothelial growth factor. The results of plasma concentrations of GDPs were variable,³⁷ while C-reactive protein concentrations showed no consistent results.³⁸ Although unlikely, a contribution of the amino acid exchange to the observed differences cannot be excluded with certainty.³⁹ Recently, two large studies were published on changes in peritoneal transport during long-term follow-up for more than 4 years.^40,41 The results of these and the balANZ study are summarized in Table 5. The initially lower UF reported in the study from The Netherlands⁴¹ confirmed the results of the NEPP study³⁶ and those of a previous study from Canada.⁴² This effect lasted up to 3 years. Thereafter, the MTAC creatinine increased 2.7 mL/min/year and glucose absorption 4.6% per year in the conventional group, which coincided with a marked decrease in sodium sieving and FWT. Both parameters remained stable in the L-GDP/N-pH group. SPFT showed a gradual decrease during the first 4 years in both groups. Peritonitis induced a decrease of TCUF after 2 years in the conventional group, which was absent in the patients on L-GDP/N-pH solutions. No effect of peritonitis on other transport parameters was found in the two patient groups.

Table 5.

Longitudinal follow-up studies on peritoneal transport in incident PD patients comparing conventional with low GDP neutral pH dialysis solutions.

Year^ref	Single/ multicenter	Test solution (glucose conc)	Conventional		L-GDP/N-pH		Key findings with L-GDP/N-pH, compared to conventional
Year^ref	Single/ multicenter	Test solution (glucose conc)	Number of patients	Follow-up (years)	Number of patients	Follow-up (years)	Key findings with L-GDP/N-pH, compared to conventional
2012³⁵	Multi/RCT	2.27%	82	2	85	2	Initial D/P_creat ↑, ultrafiltration =
2012³⁵	Multi/RCT	2.27%	82	2	85	2	Follow-up D/P_creat =, ultrafiltration =
2018⁴⁰	Multi/long	2.27%	295	Median 3	71	Median 2	Initial D/P_creat ↓, ↑ for 2 years, thereafter =;
2018⁴⁰	Multi/long	2.27%	295	Median 3	71	Median 2	no ultrafiltration data
2020⁴¹	Single/long	3.86%	135	Median 2 IQR 1-4	116	Median 2 IQR 1-6	Initial MTAC_creat ↑, ultrafiltration↓
							Follow-up MTAC_creat =, ultrafiltration =, but ↑ at 4 years
							Sodium sieving and free water transport = to ↓
							small pore fluid transport: gradual small ↓

L-GDP/N-pH: low GDP neutral pH; IQR: interquartile range; MTAC: mass transfer area coefficient.

Taken together, long-term PD with conventional dialysis solutions leads to an increase of the effective peritoneal surface area and impaired UF. The latter is partly due to a decrease in FWT, caused by a rapid disappearance of the glucose-induced crystalloid osmotic pressure gradient, but also by a reduction of SPFT, possibly due to a decreased hydrostatic pressure gradient as a consequence of vasculopathy.⁴³ Peritonitis episodes may modify some of the effects of exposure.^40,41,44 In contrast, the long-term changes in small solute transport and FWT were minor with L-GDP/N-pH solutions and independent of peritonitis, although SPFT still declined with time. It is speculative if the latter is caused by vascular deposition of AGEs, leading to narrowing of vascular lumina. The initially higher small solute transport rates were not reported in all studies, possibly due to heterogeneity of the population investigated. Initially, higher solute transport rates observed with L-GDP/N-pH solutions have been postulated to be due to higher production rates of vasoactive mediators due to less inhibition of peritoneal cell functions, as has been shown in vitro.⁴⁵

Peritoneal effluent biomarkers

Peritoneal effluent after drainage of the dialysis solution contains proteins and peptides that may reflect the health and integrity of peritoneal tissues. Longitudinal data are available for CA 125, IL-6, and plasminogen activator inhibitor type 1 (PAI-1). All three can be measured as proteins in effluent and as the expression of their transcripts in effluent cells.⁴⁶ The current knowledge on all three has been reviewed recently.⁴⁷ Associations between the above-mentioned markers and peritoneal transport are discussed below, and associations with peritoneal morphology are not available.

Dialysate CA 125 originates from mesothelial cells and its dialysate appearance rate is related to its gene (MUC 16) expression in effluent cells. Peritonitis causes a moderate transient increase lasting over days.⁴⁸ Effluent CA 125 decreases with PD duration,⁴⁹ which corresponds to the mesothelial denudation described in morphological analyses.^11,12 Treatment with L-GDP/N-pH dialysis solutions is associated with higher effluent CA 125 levels than with conventional ones during a maximal follow-up of 2 years.^50
–52 However, unpublished observations (Coester AM. PhD Thesis, University of Amsterdam, 2010) suggest that CA 125 also shows a decrease with dialysis duration using L-GDP/N-pH fluids only.

The dialysate concentrations of IL-6 are often higher than in the circulation due to local production by peritoneal cells. However, no upregulation of its gene could be detected in peritoneal cells, while no relationship was present between gene expression and effluent concentrations.^42,43 The combination of this finding, together with the high intraindividual variability of effluent IL-6 which averages 28%,⁵³ suggests that local intraperitoneal factors are important determinants of its concentration. Transport from the circulation will also contribute. Therefore, the relationships reported in cross-sectional studies between small solute transport and dialysate IL-6 are all biased by mathematical coupling.⁵⁴ This is present because peritoneal transport affects both dialysate small solute and effluent IL-6 concentrations. An increasing trend for IL-6 has been reported during the first 2 years of the treatment.^53,55,56 The results of using L-GDP/N-pH solution in the first month of PD on effluent IL-6 are not uniform. Higher levels were reported in the NEPP study,³⁶ but no difference was present in the Global Fluid Study.⁴⁰ Therefore, no evidence is currently available that effluent IL-6 is influenced by the amount of GDPs in the dialysis solution.

PAI-1 is the most promising effluent biomarker. Its appearance rate is related to the expression of the SERPINE 1 gene in effluent cells.^42,43 PAI-1 is involved in various fibrosing processes by inhibition of fibrinolysis. Transport from the circulation accounts for about one-fourth of the effluent concentration, the reminder is locally produced. Among others, PAI-1 production is stimulated by high glucose concentrations.⁵⁷ The SERPINE 1 gene expression by effluent cells was mildly increased in PD patients after 2 years.⁴² Effluent PAI-1 in PD patients on a L-GDP/N-pH dialysis solution was related to FWT and showed an increase with dialysis duration, irrespective of whether conventional or L-GDP/N-pH dialysis fluids were used.^42,58 Furthermore, dialysate PAI-1 is a predictor of EPS.⁵⁹

L-GDP/N-pH solutions and EPS

EPS is a rare but very serious complication of long-term PD. The discrepancy between the incidence of severe fibrosis and EPS is the reason that a second hit, for example, a peritonitis episode, has been suggested for the development of the clinical picture of EPS with bowel obstruction.⁶⁰ The importance of a second hit is illustrated in the development of EPS in two patients on L-GDP/N-pH solutions, one already after 1 year on PD after severe peritonitis, the other following abdominal surgery.⁶¹ Yet it is impossible to identify the second hit in all EPS patients. The condition is macroscopically characterized by thick fibrous bands and extensive adhesions. Light microscopy shows extensive interstitial sclerosing type fibrosis often with myofibroblasts¹³ and an abundance of collagen fibers.⁶² Relationships have been found between myofibroblasts, the deposition of collagen IV, and vascular density.¹³ UF failure is almost always present, especially due to impaired FWT,^62,63 despite normal AQP-1 expression.⁶² This marked decrease in FWT, which is also observed in long-term PD on conventional solutions, is probably caused by the development of interstitial fibrosis.⁶⁴ The pathophysiological mechanism is still speculative. However, the reduction in submesothelial fibrosis during the treatment with L-GDP/N-pH solutions, which was found in almost all morphological studies and the stability of FWT in the patients on L-GDP/N-pH therapy, suggest a cause/effect relationship. This has been confirmed by clinical observations. The center of one of the authors (RTK) abandoned conventional dialysis solutions completely in 2004. This had a marked effect on EPS incidence, which was 3.5 per 1000 patient-years,⁶⁵ to almost zero⁶⁶ with the exception of one patient with Alport syndrome, which is a collagen IV disease.⁶⁷ Since then, almost all dialysis centers in The Netherlands switched to L-GDP/N-pH solutions. In time, this was associated with a marked reduction of EPS.⁶⁸ Similar associations have been reported from Japan⁶⁹ and Germany.⁷⁰ Therefore, it can be concluded that the main advantage of PD with L-GDP/N-pH dialysis solutions may be the reduction and delay of functional and morphologic alterations, but not complete obliteration, that can occur in long-term PD, possibly preventing EPS.

Lessons from the case history and concluding remarks

The patient developed some decrease in sodium sieving during follow-up and a slight decrease of effluent CA 125 on conventional solutions. However, the sensitivity of CA 125 to predict EPS is only 63%.⁵⁹ The switch to L-GDP/N-pH solutions after 8 years of PD on conventional fluids had no effect on peritoneal fluid and solute transport but was associated with some increase in CA 125, while some mesothelial cells were still present. Lubrication of peritoneal tissues is the most important function of the mesothelium, preventing the formation of adhesions. This may explain why the patient had no symptoms of bowel obstruction, despite the other microscopic findings. The L-GDP/N-pH solutions were not associated with regression of fibrosis and vasculopathy in this patient but the switch to these possibly prevented important morbidity. These findings are in accordance with results of an RCT,⁷¹ a systematic review and meta-analysis⁷² and a Cochrane analysis,⁷³ that all failed to show an effect of L-GDP/N-pH solutions on mortality and technique survival. But none of these included a detailed analysis of the effects on peritoneal morphology and the time course of peritoneal function with regard to UF and small solute transport, including biomarkers in peritoneal effluent. It can be concluded from the current analysis that indicating L-GDP/N-pH dialysis solutions as biocompatible solutions is incorrect, because they still induce peritoneal alterations although less severe and after prolonged treatment. Such delay can be very important for individual patients. In the absence of side effects, the use of L-GDP/N-pH solutions may be preferable over conventional dialysis fluids, but for both solution types, reducing the peritoneal exposure to high glucose concentrations is important.

Footnotes

Acknowledgments

None.

Authorship

All authors agree with the sequence of authors.

Informed consent to participate

All authors provide consent.

Informed consent to publish

All authors agree with submission in its present form.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

None.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Raymond T Krediet

References

Van de Luijtgaarden

MWM

Jager

Stegelmark

, et al. Trends in dialysis modality choice and related patient survival in the ERA-EDTA Registry over a 20-year period. Nephrol Dial Transplant 2016; 31: 120–128.

Kolesnyk

Dekker

Boeschoten

, et al. Time dependent reasons for PD technique failure and mortality. Perit Dial Int 2010; 30: 170–177.

Coester

Smit

Struijk

, et al. Longitudinal analysis of fluid transport and their determinants in PD patients. Perit Dial Int 2014; 34: 195–203.

Krediet

Struijk

. Peritoneal changes in patients on long-term peritoneal dialysis. Nat Rev Nephrol 2013; 9: 419–429.

Jorres

. Glucose degradation products in peritoneal dialysis: from bench to bedside. Kidney Blood Press Res 2003; 26: 113–117.

Pedersen

Ryttov

Deleuran

, et al. Acetate versus lactate in peritoneal dialysis solutions. Nephron 1985; 39: 55–58.

Mactier

Sprosen

Gokal

, et al. Bicarbonate and bicarbonate/lactate peritoneal dialysis solutions for the treatment of infusion pain. Kidney Int 1998; 53: 1061–1067.

Perl

Nessim

Bargman

. The biocompatability of neutral pH, low-GDP peritoneal dialysis solutions: benefit at bench, bedside, or both? Kidney Int 2011; 79: 814–824.

Schaefer

Bartosova

Macher-Goeppinger

, et al. Quantitative histomorphometry of the healthy peritoneum. Sci Rep 2016; 6: 21344.

10.

Schaefer

Bartosova

Machter-Goeppinger

, et al. Neutral pH and low glucose-degradation product dialysis fluid induce major early alterations of the peritoneal membrane in children on peritoneal dialysis. Kidney Int 2018; 94: 419–429.

11.

Williams

Craig

Topley

, et al. Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 2002; 13: 470–479.

12.

Taranu

Florea

Paduraru

, et al. Morphologic changes in the peritoneal membrane in patients with long-term dialysis. Rom J Morphol Embyol 2014; 55: 927–932.

13.

Mateijsen

van der Wal

Hendriks

PMEM

, et al. Vascular and interstitial changes in the peritoneum of CAPD patients with peritoneal sclerosis. Perit Dial Int 1999; 19: 517–525.

14.

Sherif

Nakayama

Maruyama

, et al. Quantitative assessment of the peritoneal vessel density and vasculopoathy in CAPD patients. Nephrol Dial Transplant 2006; 21: 1675–1681.

15.

Nakano

Mizumassa

Kuroki

, et al. Advanced glycation end products are associated with immature angiogenesis and peritoneal dysfunction in patients on peritoneal dialysis. Perit Dial Int 2020; 40: 67–75.

16.

Honda

Nitta

Horita

, et al. Accumulation of advanced glycation end products in the peritoneal vasculature of continuous ambulatory peritoneal dialysis patients with low ultra-filtration. Nephrol Dial Transplant 1999; 14: 1541–1549.

17.

Bartosova

Schaefer

Vondrak

, et al. Peritoneal dialysis vintage and glucose exposure but not peritonitis episodes drive peritoneal membrane transformation during the first years of PD. Front Physiol 2019; 10: 356.

18.

Kawanieshi

Honda

Tsukada

, et al. Neutral solution low in glucose degradation products is associated with less peritoneal fibrosis in patients receiving peritoneal dialysis. Perit Dial Int 2013; 33: 242–251.

19.

Del Peso

Jimenez-Heffernan

Selgas

, et al. Biocompatible dialysis solutions preserve mesothelial cell and vessel wall integrity. A case-control study in human biosies. Perit Dial Int 2016; 36: 129–134.

20.

Hamada

Honda

Kawanishi

, et al. Morphological characteristics in peritoneum in patients with neutral peritoneal dialysis solution. J Artif Organs 2015; 18: 243–250.

21.

Tawada

Hamada

Suzuki

, et al. Effects of long-term treatment with low-GDP, pH-neutral solutions on peritoneal membranes in peritoneal dialysis patients. Clin Exp Nephrol 2019; 23: 689–699.

22.

Krediet

Zemel

Imholz

ALT

, et al. Indices of peritoneal permeability and surface area. Perit Dial Int 1993; 33(Suppl 2): S31–S34.

23.

Selgas

Fernandez-Reyes

Bosque

, et al. Functional longevity of the human peritoneum: how long is continuous peritoneal dialysis possible? Results of a prospective medium long-term study. Am J Kidney Dis 1994; 23: 64–73.

24.

Davies

SJ.

Longitudinal relationship between solute transport and ultrafiltration capacity in peritoneal dialysis patients. Kidney Int 2004; 66: 2437–2445.

25.

Parikova

Smit

Zweers

, et al. Free water transport, small pore transport and the osmotic gradient. Nephrol Dial Transplant 2008; 23: 2350–2355.

26.

Rippe

Stelin

. Simulations of peritoneal solute transport during CAPD. application of two-pore formalism. Kidney Int 1989; 35: 1234–1244.

27.

Verbavatz

J-M

Rippe

, et al. Aquaporin-1 plays an essential role in water permeability and ultrafiltration during peritoneal dialysis. Kidney Int 2006; 63: 1518–1525.

28.

Nolph

Hano

Teschan

. Peritoneal sodium transport during hypertonic peritoneal dialysis. Ann Intern Med 1969; 70: 931–941.

29.

Monquil

MCJ

Imholz

ALT

Struijk

, et al. The contribution of transcellular water transport in net ultrafiltration during CAPD. Perit Dial Int 1995; 15: 42–48.

30.

Parikova

Smit

Struijk

, et al. The contribution of free water transport and small solute transport to the total fluid removal in peritoneal dialysis. Kidney Int 2005; 68: 1849–1856.

31.

Imai

Satoh

Ohtani

, et al. Clinical application of the peritoneal dialysis capacity (PDC) test: serial analysis of peritoneal function in CAPD patients. Kidney Int 1998; 54: 546–553.

32.

Davies

Phillips

Russel

. Peritoneal solute transport predicts survival on CAPD independently of residual renal function. Nephrol Dial Transplant 1998; 13: 962–968.

33.

Tranaeus

. A long-term study of a bicarbonate/lactate-based peritoneal dialysis solution-clinical benefits. Perit Dial Int 2000; 20: 516–523.

34.

Pajek

Kveder

Bren

, et al. Short-term effects of bicarbonate/lactate-buffered and conventional lactate-buffered dialysis solutions on peritoneal ultrafiltration: a comparative crossover study. Nephrol Dial Transplant 2009; 24: 1617–1625.

35.

Johnson

Brown

Clarke

, et al. The effect of low glucose degradation product, neutral pH versus standard peritoneal dialysis solutions on peritoneal membrane function: the balANZ trial. Nephrol Dial Transplant 2012; 27: 4445–4453.

36.

Le Poole

Welten

AGA

ter Wee

, et al. A peritoneal dialysis regimen low in glucose and glucose degradation products results in increased cancer antigen 125 and peritoneal activation. Perit Dial Int 2012; 32: 305–315.

37.

Le Poole

van Ittersum

Valentijn

, et al. “NEPP” peritoneal dialysis regimen has beneficial effects on plasma cell and 3-DG, but not pentosidine, CML, and MGO. Perit Dial Int 2012; 32: 45–54.

38.

Le Poole

Schalkwijk

Teerlink

, et al. Higher plasma levels of von-Willebrand factor and C-reactive protein during a peritoneal dialysis regimen with less glucose and glucose degradation products. Perit Dial Int 2013; 33: 208–212.

39.

Douma

de Waart

Struijk

, et al.

Effect of aminoacid based dialysate on peritoneal blood flow and permeability in stable CAPD patients: a potential role for nitric oxide?

Clin Nephrol 1996; 45: 295–302.

40.

Elphick

Teece

Chess

, et al. Biocompatible solutions and long-term changes in peritoneal solute transport. Clin J Am Soc Nephrol 2018; 13: 1526–1533.

41.

Van Diepen

ATN

Coester

Janmaat

, et al. Comparison of longitudinal membrane function in peritoneal dialysis patients according to dialysis fluid biocompatibility. Kidney Int Rep 2020; 5: 2183–2194.

42.

Fang

Mullan

Shah

, et al. Comparison between bicarbonate/lactate and standard lactate dialysis solution in peritoneal transport and ultrafiltration: a prospective, cross-over single-dwell study. Perit Dial Int 2008; 28: 35–43.

43.

Krediet

van Diepen

ATN

Coester

, et al. Peritoneal vasculopathy in the pathophysiology of long-term ultrafiltration failure: a hypothesis based on clinical observations. Clin Nephrol 2019; 91: 1–8.

44.

Van Esch

Struijk

Krediet

. The natural time-course of membrane alterations during peritoneal dialysis is partly altered by peritonitis. Perit Dial Int 2016; 36: 448–456.

45.

Jones

Holmes

Mackenzie

, et al. Continuous dialysis with bicarbonate/lactate-buffered peritoneal dialysis fluids results in a long-term improvement in ex vivo peritoneal macrophage function. J Am Soc Nephrol 2002; 13: S92–S103.

46.

Parikova

Hrubra

Krejcik

, et al. Peritoneal dialysis induces alterations in the transcriptome of peritoneal cells before detectible peritoneal functional changes. Am J Physiol Renal Physiol 2020; 318: F229–F237.

47.

Parikova

Krediet

. Non-invasive assessment of peritoneal membrane alterations. Bull Dial Dom 2020; 3: 51–57.

48.

Pannekeet

Zemel

Koomen

GCM

, et al. Dialysate markers of peritoneal tissue during peritonitis and stable CAPD. Perit Dial Int 1995; 15: 217–225.

49.

Ho-dac- Pannekeet

Hirallall

Struijk

, et al. Longitudinal follow-up of CA 125 in peritoneal effluent. Kidney Int 1997; 51: 888–893.

50.

Rippe

Simonsen

Heimburger

, et al. Long-term clinical effects of a peritoneal dialysis fluid with less glucose degradation products. Kidney Int 2001; 59: 348–357.

51.

Jones

Holmes

Krediet

, et al. Bicarbonate/lactate-based peritoneal dialysis solution increases cancer antigen and decreases hyaluronic acid levels. Kidney Int 2001; 59: 1529–1538.

52.

Williams

Topley

Craig

, et al. The Euro-balance trial: the effect of a new biocompatible peritoneal dialysis fluid (balance) on the peritoneal membrane. Kidney Int 2004; 66: 408–418.

53.

Lopes Barreto

Coester

Noordzij

, et al. Variability of effluent cancer antigen 125 and interleukin-6 determination in peritoneal dialysis patients. Nephrol Dial Transplant 2011; 26: 3739–3744.

54.

Archie

JP.

Mathematic coupling of data. A common source of error. Ann Surg 1981; 93: 296–303.

55.

Rodrigues

Martins

Korevaar

, et al. Evaluation of peritoneal transport and membrane status in peritoneal dialysis: focus on incident fast transporters. Am J Nephrol 2007; 27: 84–91.

56.

Cho

Johnson

Vesey

, et al. Dialysate interleukin-6 predicts increasing peritoneal solute transport rate in incident peritoneal dialysis patients. BMC Nephrol 2014; 15: 18.

57.

Katsutani

Ito

Kohno

, et al. Glucose-based PD solution, but not icodextrin-based PD solution, induces plasminogen activator inhibitor-1 and tissue-type plasminogen activator in human peritoneal mesothelial cells via ERK1/2. Ther Apher Dial 2007; 11: 94–100.

58.

Lopes Barreto

Coester

Struijk

, et al.

Can effluent matrix metalloproteinase-2 and plasminogen activator inhibitor-1 be used as biomarkers of peritoneal membrane alterations in peritoneal dialysis patients?

Perit Dial Int 2013; 33: 529–537.

59.

Lopes Barreto

Sampimon

Struijk

, et al.

Early detection of imminent encapsulating peritoneal sclerosis. Free water transport, selected effluent proteins or both?

Perit Dial Int 2019; 39: 83–89.

60.

Garosi

. Different aspects of peritoneal damage: fibrosis and sclerosis. Contrib Nephrol 2009; 163: 45–53.

61.

Teide

Linder

Karlsberg

, et al. The use of biocompatible solutions does not prevent development of encapsulating peritoneal sclerosis. Perit Dial Int 2010; 30: 113–114.

62.

Morelle

Sow

Houtem

, et al. Interstitial fibrosis restricts osmotic water transport in encapsulating peritoneal sclerosis. J Am Soc Nephrol 2015; 26: 2521–2531.

63.

Sampimon

Coester

Struijk

, et al. The time course of peritoneal transport parameters in peritoneal dialysis patients who develop encapsulating peritoneal sclerosis. Nephrol Dial Transplant 2011; 26: 291–298.

64.

Krediet

Lopes Barreto

Struijk

. Can free water transport be used as a clinical parameter for peritoneal fibrosis in long-term PD patients? Perit Dial Int 2016; 36: 124–128.

65.

Hendriks

PEM

Ho-dac-Pannekeet

van Gulik

, et al. Peritoneal sclerosis in peritoneal dialysis patients: analysis of clinical presentation, risk factors and peritoneal transport kinetics. Perit Dial Int 1997; 17: 136–143.

66.

Sampimon

Vlijm

Struijk

, et al. Encapsulating peritoneal sclerosis in patients on peritoneal dialysis. Neth J Med 2008; 66: 396.

67.

Sampimon

Vlijm

Phoa

, et al.

Encapsulating peritoneal sclerosis in a peritoneal dialysis patient using biocompatible fluids: is Alport syndrome a risk factor?

Perit Dial Int 2010; 30: 240–242.

68.

Betjes

MGH

Habib

Boeschoten

, et al. Significant decreasing incidence of encapsulating peritoneal sclerosis in the Dutch population of peritoneal dialysis patients. Perit Dial Int 2017; 37: 230–234.

69.

Nakayama

Miyasaki

Honda

, et al. Encapsulating peritoneal sclerosis in the era of a multidisciplinary approach based on biocompatible solutions: the next-pd study. Perit Dial Int 2014; 34: 766–774.

70.

Kitterer

Braun

Alscher

, et al. The number of patients with severe encapsulating sclerosis is decreasing in a large referral center in Germany. Int J Nephrol Renovasc Dis 2016; 5: 183–186.

71.

Srivastava

Hildebrand

Fan

L-S

. Long-term follow-up of patients randomized to biocompatible or conventional peritoneal dialysis solutions show no difference in peritonitis or technique survival. Kidney Int 2011; 80: 986–991.

72.

Yohanna

Alkateeri

AMA

Brimble

, et al. Effect of neutral-pH, low glucose degradation product peritoneal dialysis solutions on residual renal function, urine volume, and ultrafiltration: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2015; 10: 1380–1388.

73.

Htay

Johnson

Wiggins

, et al. Biocompatible dialysis solutions for peritoneal dialysis (review). Cochrane Database Syst Rev 2018: CD007554.