Peritoneal Dialysis Solutions Low in Glucose Degradation Products

Abstract

In Japan, two types of new peritoneal dialysis fluid (PDF) are ordinarily used: two-chambered PDF, and icodextrin PDF. Two-chambered PDF has several biocompatible characteristics, one being low glucose degradation products (GDPs). Of the several GDPs in PDF, 3,4-dideoxyglucosone-3-ene (3,4-DGE) is thought to be strongly associated with the cytotoxicity of standard PDF. Using a PDF low in GDPs may reduce exposure of the peritoneum to 3,4-DGE, helping to preserve peritoneal function in PD patients. Additionally, use of a PDF low in GDPs may reduce plasma levels of advanced glycosylation end-products in PD patients, a change that may help to preserve vascular function in PD patients.

Peritoneal rest for 24 hours after exposure to a PDF with low GDPs improves the activity of human peritoneal mesothelial cells. As compared with the use of standard PDF, the use of low-GDP PDF in combination therapy (peritoneal dialysis plus hemodialysis) may more effectively preserve peritoneal function. The new PDF low in GDPs has bio-compatible characteristics relative to peritoneum and system that may help to preserve peritoneal function or reduce complications such as atherosclerosis or dialysis-related amyloidosis in dialysis patients.

Keywords

Glucose degradation products GDPs 3,4-dideoxyglucosone-3-ene 3,4-DGE combination therapy PD–HD combination therapy

Peritoneal dialysis fluid (PDF) typically has a low pH and contains non physiologic factors, including high concentrations of glucose, glucose degradation products (GDPs), and high concentrations of lactate. Persistent exposure of the intraperitoneal tissues to these non physiologic compounds may induce peritoneal dysfunction with subsequent loss of ultrafiltration, and in some cases, the result may be complications such as encapsulating peritoneal sclerosis (EPS) (10 -17).

In Japan, two types of new peritoneal dialysis fluid (PDF) are now available: icodextrin PDF, and two-chambered PDF. The present paper discusses the various aspects and the usefulness of two-chambered PDF with a significantly lower concentration of GDPs as compared with standard PDF.

Discussion

Biocompatibility Of Two-Chambered Pdf

Two-chambered PDF has several characteristics that differentiate it from single-chambered PDF: low GDPs, and a more physiologic pH as compared with standard PDF. A more biocompatible and beneficial effect for the patient's peritoneum and system is expected with the use of two-chambered PDF, as is better preservation of peritoneal membrane function.

In experiments, the viability, as measured by production of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], of human peritoneal mesothelial cells (HPMCs) exposed to two-chambered PDF was comparable to that of cells in control conditions. However, the viability of HPMCs exposed to standard PDF was very low (Figure 1). Moreover, the viability (by MTT production) of cultured HPMCs under three different pH conditions (pH 7, pH 6, pH 5) were observed to be comparable (data not shown). Acidity alone therefore does not affect cell viability. Hence, GDPs were suggested to be an important contributor to the cytotoxicity of standard PDF.

Figure 1

(A) Cell viability, as measured by percentage MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] production compared with controls, of human peritoneal mesothelial cells (HPMCs) exposed to peritoneal dialysis fluid (PDF) from standard single-chambered bags (n = 6) at two glucose concentrations. The percentages of MTT for cells exposed to these PDFs for 30 minutes were 100.1% ± 1.2% (1.36% glucose concentration) and 96.5% ± 9.1% (3.86% glucose concentration); for cells exposed for 240 minutes, the respective percentages were 20.0% ± 5.7% and 16.1% ± 6.3%. (B) Cell viability, as measured by percentage MTT production compared with controls, of HPMCs exposed to PDFs from dual-chambered bags (n = 6) at two glucose concentrations. The percentages of MTT for cells exposed to these PDFs for 30 minutes were 95.2% ± 3.8% (1.36% glucose concentration) and 93.8% ± 6.8% (3.86% glucose concentration); for cells exposed for 240 minutes, the respective percentages were 61.8% ± 6.9% and 41.0% ± 8.4%. ^* p < 0.01 compared with control.

Impact Of 3,4-Dge On Cytotoxicity Of Standard Pdf

The concentrations of various GDPs—3,4-di-deoxyglucosone-3-ene (3,4-DGE), glyoxal (GO), methylglyoxal (MGO), 3-deoxyglucosone (3-DG), formaldehyde (FA), acetaldehyde (AA), and 2-furfural (FF), but not 5-hydroxymethylfurfural (5-HMF)—are markedly lower in two-chambered PDF than in standard PDF (Table 1). Among the various GDPs in PDF, the novel GDP 3,4-DGE was recently reported by Linden et al. to have potent cytotoxicity at low concentrations (8).

Table 1

Glucose Degradation Products^a in Four Kinds of Peritoneal Dialysis Fluid

		Glucose peritoneal dialysis solutions
	Single-chamber bag, low pH		Dual-chamber bag, neutral pH
	1.36%	3.86%	1.36%	3.86%
Glyoxal	3.0	5.3	<0.11	<0.11
Methylglyoxal	11.6	18.2	<0.11	<0.11
3-Deoxyglucosone	247	564.4	40.6	40.6
Formaldehyde	3.5	6.4	0.7	0.7
Acetaldehyde	104.6	174.3	<0.5	<0.5
5-HMF	3.3	9.8	10.9	25.8
2-Furfural	0.5	1.4	0.2	2.7
3,4DGE	15.3	35.5	1.2	2.7

5-HMF = 5-hydroxymethyl-furfural; 3,4DGE = 3,4-dideoxyglucosone-3-ene.

All values are the mean of 3 samples, expressed in μmol/L.

My group investigated the influence of 3,4-DGE on the cytotoxicity of standard PDF in the following experiment. We first prepared acidified filtration-sterilized dialysis fluid (pH 5.5, 3.86% glucose) containing 7 GDPs (GO, MGO, 3-DG, FA, AA, 5-HMF, FF). We then prepared acidified filtration-sterilized dialysis fluid (pH 5.5, 3.86% glucose) containing 8 GDPs (3,4-DGE, GO, MGO, 3-DG, FA, AA, 5-HMF, FF). We added the GDPs at a concentration equivalent to their respective concentrations in standard 3.86% glucose PDF. We then exposed HPMCs to these two solution types and to standard PDF (3.86% glucose) for 4 hours and afterwards determined cell viability by MTT assay.

When HPMCs were treated with the acidified filtration-sterilized dialysis fluid containing 7 GDPs (excluding 3,4-DGE), MTT viability was assessed as 73.7% ± 10.1%. In contrast, MTT viability was assessed at 36.2% ± 21.3% with acidified filtration-sterilized dialysis fluid containing 8 GDPs (including 3,4-DGE), a result that was comparable to that for HPMCs treated with standard PDF (32.8% ± 5.9%; Figure 2). Two-chambered PDF that has a low concentration of GDPs would therefore be expected to be more biocompatible for HPMCs than would standard PDF. Among the various GDPs in PDF, 3,4-DGE is suggested to more markedly affect the cytotoxicity of standard PDF (9).

Figure 2

Cell viability, as measured by percentage MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] production compared with controls, of human peritoneal mesothelial cells (HPMCs) exposed to acidified filtration-sterilized dialysis fluid (3.86% glucose concentration) containing 7 or 8 glucose degradation products (GDPs). For HPMCs exposed to 7 GDPs for 240 minutes (n = 5), the MTT percentage was 73.7% ± 10.1%; for HPMCs exposed to 8 GDPs for 240 minutes (n = 5), it was 36.2% ± 21.3%. For HPMCs exposed to standard PDFs (control, 3.86% glucose concentration) for 240 minutes, the MTT percentage was 32.8% ± 5.9%. Statistical analyses used the Mann–Whitney U-test or Tukey–Kramer test, and differences with a probability of 1% (p < 0.01) were considered statistically significant.

Systemic Benefits Of Pdf Low In Gdps

In the peritoneal cavity, the preceding study suggests substantial local toxicity resulting from the GDPs in standard PDF. But the GDPs in PDF may exert important systemic effects, too. Some GDPs in standard PDF are converted into advanced glycation end-products (AGEs) through reactions with lysine or other amino bases in the peritoneal cavity. The AGEs thus synthesized may enter the systemic circulation and result in an increase of the AGE concentrations in blood.

Some studies have reported beneficial effects for plasma AGE reduction with the use of PDF low in GDPs. In adults, use of low-GDP PDF resulted in a significant reduction in circulating AGE levels (10). Schmitt et al. (11) also reported a reduction in systemic AGEs in children receiving peritoneal dialysis (PD) with low-GDPs PDF. In that study, switching the patients to the low-GDP solution resulted in 17% and 23% reductions in levels of plasma AGEs and N_ε-carboxymethyllysine respectively. The authors suggested that the observed improvement in AGE plasma profile may be the result of the markedly reduced exposure of the patients to GDPs. And reductions in systemic AGEs may subsequently reduce the complications of atherosclerosis and dialysis-related amyloidosis (12,13).

Outcome In Pd Patients Using Low-Gdp Pdf

A few reports have evaluated outcomes in PD patients using low-GDP PDF as compared with patients using standard PDF. In Korea, Lee et al. (14) noted the marked good prognosis of PD patients using PDF low in GDPs as compared the progress of patients using standard PDF. The survival percentage of the patients using low-GDP PDF was 64.2% as compared with 43.4% in patients using standard PDF. Those authors also suggested that the improved outcome in PD patients using low-GDP PDF might be attributable to a reduction in plasma AGE levels. Patients who switch to low-GDP PDF from standard PDF may experience improved outcomes. Regrettably, this study by Lee and colleagues was not a randomized controlled study (RCT). Studies of the outcomes of PD patients using low-GDP PDF in RCTs is desirable.

Probable Benefit Of Low-Gdp Pdf In Combination Therapy

Combination therapy using both PD and hemodialysis (HD) is becoming common in Japan. Alvaro et al. reported that 4 weeks of peritoneal rest helped to reduce increases in peritoneal permeability and thus improved ultrafiltration (15). Those results suggest that peritoneal rest may be an effective technique for ameliorating the deterioration of peritoneal function.

In Japan, HD treatment performed once weekly is used to compensate for insufficient dialysis from PD alone (16 -19). In this combined therapy, PD is not performed on the HD day. In addition, depending on the patient's condition, PD may not be performed the day after HD and is thus omitted 1 or 2 days each week. If the peritoneal rest proposed by Alvaro et al. is considered continuous, the combination therapy with a 1- or 2-day break in PD might be considered intermittent short-term peritoneal rest.

My group used the cultured HPMC model to investigate the effects of peritoneal rest for 24 hours during combined PD and HD therapy. We investigated cell activity by MTT assay after exposing HPMCs to PDFs at various pH levels. Cells were exposed to the experimental fluids (50 μL/well) for durations of 30 or 240 minutes. The PDFs used were acidic heat-sterilized PDF (standard PDF, pH 5.5) and neutral heat-sterilized PDFs (low-GDP PDF, pH 6.7). Control wells were exposed to M199 Hanks medium containing 20% fetal bovine serum (FBS) for 30 or 240 minutes. Supernatants were then aspirated from each well and M199 culture medium containing 20% FBS (50 μL) was then added to each well so that the HPMCs could “rest” for 24 hours before MTT activity was investigated.

The activity of HPMCs exposed to standard PDF at glucose concentrations of 1.36% and 3.86% for 240 minutes decreased to approximately 20% and 15% respectively as compared with controls (p < 0.01, Tukey–Kramer test), and the activity of cells exposed to low-GDP PDF at glucose concentrations of 1.36% and 3.86% for 240 minutes decreased to approximately 60% and 40% respectively (p < 0.01). The activity of HPMCs exposed to standard PDF at glucose concentrations of 1.36% and 3.86% for 240 minutes, followed by a “rest,” was approximately 20% and 4% as compared with controls (p < 0.01); in control HPMCs exposed to low-GDP PDF at glucose concentrations of 1.36% and 3.86% for 240 minutes, followed by “rest,” the equivalent activities were 93% and 96% (Figure 3). These findings suggest that rest for 24 hours after exposure to low-GDP PDF improves the activity of HPMCs (20). Therefore, the peritoneal rest in combination PD and HD therapy in which low-GDP PDF is used may preserve peritoneal function better than does combination therapy in which standard PDF is used.

Figure 3

(A) Cell viability, as measured by percentage MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] production compared with controls, of human peritoneal mesothelial cells (HPMCs) exposed to standard low-pH, heat-sterilized peritoneal dialysis fluids [PDFs (n = 6)] or to neutral-pH heat-sterilized fluids low in glucose degradation products (GDPs), and of HPMCs rested for 24 hours after such exposures (n = 6). (A) The percentages of MTT for cells exposed to standard PDFs for 30 minutes were 100.1% ± 1.2% (1.36% glucose concentration) and 96.5% ± 9.1% (3.86% glucose concentration); for cells exposed for 240 minutes, the respective percentages were 20.0% ± 5.7% and 16.1% ± 6.3%. The percentages of MTT for cells exposed to these PDFs for 30 minutes and then rested for 24 hours were 100.0% ± 7.0% (1.36% glucose concentration) and 97.9% ± 7.0% (3.86% glucose concentration); for HPMCs exposed for 240 minutes and then rested for 24 hours, the respective percentages were 20.0% ± 12.4% and 3% ± 9.6%. (B) The MTT production percentages for cells exposed to low-GDP PDFs for 30 minutes (n = 6) were 95.2% ± 3.8% (1.36% glucose concentration) and 93.8% ± 6.8% (3.86% glucose concentration); for HPMCs exposed for 240 minutes and then rested for 24 hours, the respective percentages were 61.8% ± 6.9% and 41.0% ± 8.4%. The percentages of MTT for cells exposed to low-GDP PDFs for 30 minutes and then rested for 24 hours were 100.0% ± 6.6% (1.36% glucose concentration) and 99.8% ± 6.7% (3.86% glucose concentration); for HPMCs exposed for 240 minutes and then rested for 24 hours, the respective percentages were 93.8% ± 11.1% and 96.6% ± 9.7%.

Conclusions

One of the biocompatible characteristics of two-chambered PDF is low GDPs. Of the several GDPs in PDF, 3,4-DGE is thought to be strongly associated with the cytotoxicity of standard PDF. Reduction of peritoneal exposure to 3,4-DGE will help to preserve peritoneal function in PD patients.

The use of low-GDP PDF may reduce plasma levels of AGEs in PD patients. That change may help to preserve vascular function in PD patients.

Peritoneal rest for 24 hours after exposure to low-GDP PDF improves the activity of HPMCs. The use of low-GDP PDF in combination PD and HD therapy may be more effective for the preservation of peritoneal function than is the use of standard PDF in such combination therapy.

The new low-GDP PDF has biocompatible characteristics for the patient's peritoneum and system that may help to preserve peritoneal function and to reduce complications such as atherosclerosis and dialysis-related amyloidosis in dialysis patients.

References

1. Witowski

Korybalska

Wisniewska

Breborowicz

Gahl

Frei

Effect of glucose degradation products on human peritoneal mesothelial cell function. J Am Soc Nephrol 2000; 11:729–39.

2. Di Paolo

Garosi

Traversari

Di Paolo

Mesothelial biocompatibility of peritoneal dialysis solutions. Perit Dial Int 1993; 13(Suppl 2):S109–12.

3. Breborowicz

Rodela

Karon

Martis

Oreopoulos

. In vitro simulation of the effect of peritoneal dialysis solution on mesothelial cells. Am J Kidney Dis 1997; 29:404–9.

4. Witowski

Wisniewska

Korybalska

Bender

Breborowicz

Gahl

. Prolonged exposure to glucose degradation products impairs viability and function of human peritoneal mesothelial cells. J Am Soc Nephrol 2001; 12:2434–41.

5. Lage

Pischetsrieder

Aufricht

Jörres

Schilling

Passlick–Deetjen

First in vitro and in vivo experiences with Stay•Safe; Balance, a pH-neutral solution in a dual-chambered bag. Perit Dial Int 2000; 20(Suppl 5):S28–32.

6. Topley

Kaur

Petersen

Jörres

Passlick–Deetjen

Coles

. Biocompatibility of bicarbonate buffered peritoneal dialysis fluids: influence on mesothelial cell and neutrophil function. Kidney Int 1996; 49:1447–56.

7. Witowski

Topley

Jörres

Liberek

Coles

Williams

. Effect of lactate–buffered peritoneal dialysis fluids on human peritoneal mesothelial cell interleukin-6 and prostaglandin synthesis. Kidney Int 1995; 47:282–93.

8. Linden

Cohen

Deppisch

Kjellstrand

Wieslander

3,4-Dideoxyglucosone-3-ene (3,4-DGE): a cytotoxic glucose degradation product in fluids for peritoneal dialysis. Kidney Int 2002; 62:697–703.

9. Tomo

Okabe

Yamamoto

Namoto

Iwashita

Matsuyama

. Impact of 3,4-dideoxyglucosone-3-ene (3,4-DGE) on cytotoxicity of acidic heat-sterilized peritoneal dialysis fluid. J Artif Organs 2007; 10:47–51.

10.

10. Zeier

Schwenger

Deppisch

Haug

Weigel

Bahner

. Glucose degradation products in PD fluids: do they disappear from the peritoneal cavity and enter the systemic circulation? Kidney Int 2003; 63:298–305.

11.

11. Schmitt

von Heyl

Rieger

Arbeiter

Bonzel

Fischbach

. Reduced systemic advanced glycation end products in children receiving peritoneal dialysis with low glucose degradation product content. Nephrol Dial Transplant 2007; 22:2038–44.

12.

12. Miyata

Ueda

Yamada

Izuhara

Wada

Jadoul

. Accumulation of carbonyls accelerates the formation of pentosidine, an advanced glycation end product: carbonyl stress in uremia. J Am Soc Nephrol 1998; 9:2349–56.

13.

13. Rashid

Benchetrit

Fishman

Bernheim

Effect of advanced glycation end-products on gene expression and synthesis of TNF-alpha and endothelial nitric oxide synthase by endothelial cells. Kidney Int 2004; 66:1099–106.

14.

14. Lee

Choi

Park

Seo

Yun

. Changing prescribing practice in CAPD patients in Korea: increased utilization of low GDP solutions improves patient outcome. Nephrol Dial Transplant 2006; 21:2893–9.

15.

15. de Alvaro

Castro

Dapena

Bajo

Fernandez-Reyes

Romero

. Peritoneal resting is beneficial in peritoneal hyperpermeability and ultrafiltration failure. Adv Perit Dial 1993; 9:56–61.

16.

16. Kawanishi

Moriishi

Katsutani

Sakikubo

Tsuchiya

Hemodialysis together with peritoneal dialysis is one of the simplest ways to maintain adequacy in continuous ambulatory peritoneal dialysis. Adv Perit Dial 1999; 15:127–31.

17.

17. Kawanishi

Moriishi

Tsuchiya

Five years' experience of combination therapy: peritoneal dialysis with hemodialysis. Adv Perit Dial 2002; 18:62–7.

18.

18. Fukui

Hara

Hashimoto

Horiuchi

Ikezoe

Itami

. Review of combination of peritoneal dialysis and hemodialysis as a modality of treatment for end-stage renal disease. Ther Apher Dial 2004; 8:56–61.

19.

19. Agarwal

Clinard

Burkart

. Combined peritoneal dialysis and hemodialysis: our experience compared to others. Perit Dial Int 2003; 23:157–61.

20.

20. Tomo

Okabe

Matsuyama

Iwashita

Yufu

Nasu

The effect of peritoneal rest in combination therapy of peritoneal dialysis and hemodialysis: using the cultured human peritoneal mesothelial cell model. J Artif Organs 2005; 8:125–9.

Peritoneal Dialysis Solutions Low in Glucose Degradation Products—evidence for Clinical Benefits

Abstract

Keywords

Discussion

Biocompatibility Of Two-Chambered Pdf

Impact Of 3,4-Dge On Cytotoxicity Of Standard Pdf

Systemic Benefits Of Pdf Low In Gdps

Outcome In Pd Patients Using Low-Gdp Pdf

Probable Benefit Of Low-Gdp Pdf In Combination Therapy

Conclusions

References