Vasculopathy

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It is suggested that change of peritoneal vascular characteristics develops in PD patients. Honda et al. has reported that peritoneal vascular hyalinization is observed especially in the media of postcapillary venules to small venules in long-term PD patients with high PSTR. They observed that formation of carboxymethyl lysine (CML), an advanced glycation end product (AGE), in the peritoneum correlates with the development of microvascular sclerosis in PD patients, and this vascular change is associated with high PSTR. They also pointed out that the morphological changes of the peritoneal vasculature are similar to those associated with diabetic microangiopathy.

AGE accumulation in CAPD peritoneum, especially in the vascular area, increases with time on CAPD, and it may be directly related with PSTR and peritoneal fluid absorption rate. AGE formation could be driven by several factors such as high-glucose solutions, glucose degradation products (GDPs), which are present in the unused PD solution as well as the uremic circulation. It was reported that GDPs could induce VEGF production; on the other hand, NO inhibits AGE (pentosidine) formation by scavenging free radicals and by inhibiting carbonyl compound formation.

AGEs influence cellular properties that allow the binding of AGEs to specific receptors, of which the best characterized is the receptor for AGEs (RAGE). RAGE is a member of the immunoglobulin superfamily and is expressed by the endothelium, smooth muscle cells, and mononuclear phagocytes, cells central to both vascular homeostasis and patho-genesis of vascular lesions. Recently it was reported that RAGE is expressed in peritoneal mesothelial cells and that anti-RAGE antibody does not affect the PSTR, but does affect submesothelial fibrosis in diabetic rat. These findings suggest the possible role of mesothelium for developing high PSTR through AGE-RAGE interaction.

In summary, it is suggested that the dilatation of microvessel, the increasing number of microvessels, and the progression of vasculopathy play a role in increased PSTR. However, at present, there is little clinical information about cause(s) and mechanisms for the observed alterations in the peritoneal microvessels in PD patients. Further studies are needed in this area.

Glossary

Advanced Glycation Endproduct: The products by non enzymatic chemical reaction between glucose or glucose degradation products and proteins.

Peritoneal dialysis: Dialysis method using peritoneal membrane. Dialysate are infused in and remain in the peritoneal cavity for a time and are drained. The wall of microvessels is considered to be the main functional barrier to the solute transport between dialysate and blood.

Peritoneal solute transport rate: It is associated with an increased surface area of peritoneal microvessels. At the same time, other factors such as increases in the peritoneal contact area and tissue diffusivity could conceivably explain an increase in PSTR.

References

Combet, S., Miyata, T., Moulin, P., Pouthier, D., Goffin, E., and Devuyst, O. (2000). Vascular proliferation and enhanced expression of endothe-

lial nitric oxide synthase in human peritoneum exposed to long-term peritoneal dialysis. J. Am. Soc. Nephrol. 11, 717-728. De Vriese, A. S., Tilton, R. G., Stephan, C. C., and Lameire, N. H. (2001). Vascular endothelial growth factor is essential for hyperglycemia-induced structural and functional alterations of the peritoneal membrane. J. Ami. Soc. Nephrol. 12(8), 1734-1741. Flessner, M. F. (1991). Peritoneal transport physiology: Insights from basic research. J. Am. Soc. Nephrol. 2(2), 122-135. This article provides a detailed review of the mechanisms of peritoneal solute transport using some models.

Honda, K., Nitta, K., Horita, S., Yumura, W., and Nihei, H. (1996). Morphological changes in the peritoneal vasculature of patients on CAPD with ultrafiltration failure. Nephron 72(2), 171-176. Honda, K., Nitta, K., Horita, S., Yumura, W., and Nihei, H. (1999). Accumulation of advanced glycation end products in the peritoneal vascula-ture of continuous ambulatory peritoneal dialysis patients with low ultra-filtration. Nephrol. Dial. Transplant. 14(6), 1541-1549. This article elucidates the relationship between peritoneal transport and vasculopathy.

Nakayama, M., Kawaguchi, Y., Yamada, K., Hasegawa, T., Takazoe, K., Katoh, N, et al. (1997). Immunohistochemical detection of advanced glycosylation end-products in the peritoneum and its possible patho-physiological role in CAPD. Kidney Int. 51(1), 182-186. Nakayama, M., Yamamoto, H., Ikeda, M., Hasegawa, T., Kato, N., Takahashi, H., Otsuka, Y., Yokoyama, K., Yamamoto, R., Kawaguchi, Y., and Hosoya, T. (2002). Risk factors and preventive measures for encapsulating peritoneal sclerosis—Jikei experience 2002. Adv. Perit. Dial. 18: 144-148. Numata, M., Nakayama, M., Nimura, S., Kawakami, M., Lindholm, B., and Kawaguchi, Y. (2003). Association between an increased surface area of peritoneal microvessels and a high peritoneal solute transport rate. Perit. Dial. Int. 23, 116-122. This article elucidates the relationship between peritoneal solute transport rate and vascular surface area with human subjects. Wong, T. Y.-H., Szeto, C.-C., Szeto, C. Y.-K., Lai, K.-B., Chow, K.-M., and Li, P. K.-T. (2003). Association of ENOS polymorphism with basal peritoneal membrane function in uremic patients. Am. J. Kidney Dis. 42, 781-786.

Zweers, M. M., de Waart, D. R., Smit, W., Struijk, D. G., and Krediet, R. T. (1999). Growth factors VEGF and TGF-beta1 in peritoneal dialysis. J. Lab.. Clin. Med. 134, 124-132.

Capsule Biography

Miwako Numata, M.D., PhD, is a nephrologist in Jikei University Hospital, Tokyo, Japan. She worked at Baxter Novum, Karolinska Institutet, as guest scientist in 2001-2003. Her research focuses on alteration of peritoneal function and peritoneal structure in peritoneal dialysis patients.

Masaaki Nakayama, M.D., Ph.D., is a lecturer in the Department of Nephrology and Hypertension, Jikei University School of Medicine, which is one of the leading centers of peritoneal dialysis in Japan. His research focuses on the pathology of peritoneal injury in CAPD patients.

Bengt Lindholm, M.D., Ph.D., has been head of the Division of Baxter Novum, Karolinska Institutet, Stockholm, Sweden, since 1993. His research focuses on peritoneal dialysis, malnutrition, inflammation, and atherosclerosis and the role of genetics in these conditions in end-stage renal disease patients. His work is supported by Baxter Healthcare and Karolinska Institutet.

Makio Kawakami, M.D., PhD is a pathomorphologist in the Department of Pathology, Clinical Service, at Jikei University Hospital. He has long worked on the functional unit of the various organs from the viewpoint of structural alteration. Now, his interest is focusing on the peritoneal device as an analog of the nephron.

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