Possible involvement of cross-linking advanced glycation endproducts in long-term CAPD peritoneal degeneration

Sir,

It has been demonstrated that advanced glycation endproducts (AGEs) are generated in the peritoneal tissue of continuous ambulatory peritoneal dialysis (CAPD) patients [1], and they are closely related to pathological phenomena, such as enhanced solute transport state, ultrafiltration failure (UFF) and mesothelial damage. Sclerotic degeneration of the peritoneum, known as ‘tanned peritoneum’, has been observed in patients undergoing long-term CAPD treatment; however, the exact mechanism of its progression has not been elucidated. In this respect, whether AGE formation and furthermore what kind of AGE is involved in this pathology is a question that has yet to be answered. Among the characteristics for AGEs, cross-linking with proteins is well known. To explain this cross-linking phenomenon, dimer formation by carbonyl compounds has been reported. For these cross-linking substances, glyoxal lysine dimer (GOLD) and methylglyoxal lysine dimer (MOLD) have recently been cited [2]. Therefore, in the present study, representative non-cross-linking AGEs [N{epsilon}-(carboxymethyl)lysine (CML) and N{epsilon}-(carboxyethyl)lysine (CEL)], as well as cross-linking AGEs (GOLD and MOLD), were evaluated in the peritoneal tissue of four patients undergoing regular dialysis, including one suffering from encapsulating peritoneal sclerosis (EPS).

The clinical characteristics of the four patients were the following: case 1 was a 60-year-old male treated with CAPD for 2 years, CAPD was then discontinued because of abdominal surgery unrelated to PD. Case 2 was a 56-year-old male who was on maintenance haemodialysis (HD) for 6 years. He had never undergone PD. He succumbed to septicaemia caused by a pacemaker wire-related infection. Case 3 was a 57-year-old male on CAPD for 6 years. This treatment was subsequently discontinued due to UFF. Case 4 was a 59-year-old male on CAPD for 12 years. He was switched to HD because of UFF and developed EPS 1 year later. He received a corticosteroid treatment for 6 months, which failed to relieve ileus symptoms. Two years after the development of EPS, surgical enterolysis was performed. Tissue samples were collected from the parietal peritoneum of cases 1, 2 and 3. In case 4, the sclerotic serosa over the terminal ileum (a and b) was collected from a sample resected during surgery. The histological finding in case 4 was a thick sclerosis of the ileal surface with new collagenous layers over the surface and hyper-vascularization.

6 N HCl was added to samples, and they were completely hydrolysed for 24 h at 110°C. Then the product was concentrated by evaporation under reduced pressure to measure AGEs (CML and CEL:GC-MASS measurement, GOLD and MOLD:HPLC method). The results of the analysis for each AGE are shown in Figures 1 and 2. Non-cross-linking AGEs (CML and CEL) and cross-linking AGEs (GOLD and MOLD) could be measured in all cases, showing consistent predominance of CML over CEL and GOLD over MOLD. It was also found that the levels of cross-linking AGEs were much higher than those of non-cross-linking AGEs, especially in case with EPS.



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Fig. 1.

 


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Fig. 2.

 
Reports on CML, CEL, GOLD and MOLD contents in human tissue are very scarce. Degenhardt et al. [3] examined AGE contents in dermal collagen and lens protein in non-uraemic patients and found the following levels (mmol/mol Lys): CML, 1.70–4.95; CEL, 0.50–3.78; GOLD, 0.04–0.1; and MOLD, 32–0.38. In the present study, which was conducted on peritoneal tissue, it was interesting to see that levels of respective AGEs exceeded those reported by Degenhardt et al. Among them, especially GOLD was far above those reported by these investigators.

Regarding the origin of CML, the reaction between protein and GO is one of the chemical processes to form CML and GO is produced after the oxidative cleavage of glucose [4]. It has been reported that whatever the process of formation, whether originating from pentose or hexisose by autoxidation or from Amadori products, production of GO in vitro is predominant over that of than MGO (precursor of CEL) [5]. Accordingly, the predominance of CML and GOLD in the peritoneal issue suggests the possibility of enhanced axis of GO/CML/GOLD formation, probably in an environment in which a high glucose concentration and oxidative stress act as the prime factors, especially in those patients undergoing long-term CAPD (Figure 3).



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Fig. 3.

 
This study reports for the first time peritoneal CML, CEL, GOLD and MOLD levels in chronic dialysis patients. We suggest that AGE formation, especially the cross-linking type—GOLD, could be involved in the pathogenesis of peritoneal degeneration in long-term PD.

Conflict of interest statement. None declared.

Masaaki Nakayama, Kazunobu Yoshimura, Yukio Maruyama, Miwako Numata, Tatsuo Hosoya and Giichi Izumi1

Division of Kidney and  Hypertension The Jikei University  School of Medicine 3-19-18, Nishishimbashi Minato-ku, Tokyo, Japan Baxter Japan International Inc.1 4, Rolcobancho Chiyodaku Tokyo Japan Email: mnakayama{at}jikei.ac.jp

References

  1. Nakayama M, Kawaguchi Y, Yamada K et al. Immunohistochemical detection of AGEs in the peritoneum and its possible pathophysiological role in CAPD. Kidney Int 1997; 51: 182–186[ISI][Medline]
  2. Wells-Knecht KJ, Brinkmann E, Baynes JW. Characterization of an imidazolium salt formed from glyoxal and N{alpha}-hippuryllysine: a model for Maillard reaction crosslinks in proteins. J Org Chem 1995; 60: 6246–6247[ISI]
  3. Degenhard TP, Thorpe SR, Baynes JW. Chemical modification of proteins by methylglyoxal. Cell Mol Biol 1998; 44: 1139–1145[ISI]
  4. Wells-Knecht KJ, Zyzak DV, Litchfield JE, Thorpe SR, Baynes JW. Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of protein by glucose. Biochemistry 1995; 34: 3702–3709[ISI][Medline]
  5. Thornalley PJ, Langberg A, Minhas HS. Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the gycation of proteins by glucose. Biochem J 1999; 344: 109–116[CrossRef][ISI][Medline]
  6. Schwedler SB, Metzger T, Schinzel R, Wanner C. Advanced glycation end products and mortality in hemodialysis patients. Kidney Int 2002; 62: 301–310[CrossRef][ISI][Medline]




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