Deposition of advanced glycation end products (AGEs) is frequently found in the peritoneum of patients on peritoneal dialysis (PD). Angiogenesis is also observed in the peritoneum. However, the clinical significance of AGEs and angiogenesis in the peritoneum is not fully understood. We evaluated the maturation of capillary vessels and investigated whether AGEs are associated with angiogenesis and peritoneal function in the peritoneal membrane.
Methods:
Peritoneum obtained when PD catheters were removed from 61 patients with PD was analyzed. The peritoneum was immunohistochemically stained with anti-CD34 (for endothelial cells), anti-alpha smooth muscle actin (αSMA) (for pericytes), and anti-AGE antibodies. We defined CD34-positive and αSMA-negative vessels as immature capillary vessels in peritoneal membranes using serial sections. We evaluated the associations between vessel density, peritoneal function (dialysate-to-plasma ratio for creatinine (D/P creatinine)), and the degree of AGE deposition.
Results:
AGE accumulation in the interstitium was positively associated with the duration of PD (p < 0.01). AGE accumulation in the interstitium and vascular wall was positively correlated with the use of acidic solution (p < 0.05) and the maximum value of D/P creatinine (p < 0.05). AGE accumulation in the vascular wall was significantly associated with immature capillary density (CD34+/αSMA−) in the peritoneum (p < 0.01). Vessel density was not significantly correlated with the last measurement of D/P creatinine (p = 0.126, r = 0.202), However, immature capillary density was positively correlated with the last measurement of D/P creatinine (p < 0.05, r = 0.278).
Conclusions:
AGE accumulation is significantly associated with immature angiogenesis and peritoneal dysfunction in patients undergoing PD.
MakitaZRadoffSRayfieldEJ, et al.Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med1991; 325: 836–842.
2.
FriedlanderMAWuYCElgawishA, et al.Early and advanced glycosylation end products. Kinetics of formation and clearance in peritoneal dialysis. J Clin Invest1996; 97: 728–735.
3.
MiyataTvan Ypersele de StrihouCKurokawaK, et al.Alterations in nonenzymatic biochemistry in uremia: origin and significance of “carbonyl stress” in long-term uremic complications. Kidney Int1999; 55: 389–399.
4.
NakayamaMKawaguchiYYamadaK, et al.Immunohistochemical detection of advanced glycosylation end-products in the peritoneum and its possible pathophysiological role in CAPD. Kidney Int1997; 51: 182–186.
5.
HondaKNittaKHoritaS, et al.Accumulation of advanced glycation end products in the peritoneal vasculature of continuous ambulatory peritoneal dialysis patients with low ultra-filtration. Nephrol Dial Transplant1999; 14: 1541–1549.
6.
InagiRMiyataTYamamotoT, et al.Glucose degradation product methylglyoxal enhances the production of vascular endothelial growth factor in peritoneal cells: role in the functional and morphological alterations of peritoneal membranes in peritoneal dialysis. FEBS Lett1999; 463: 260–264.
7.
MateijsenMAvan der WalACHendriksPM, et al.Vascular and interstitial changes in the peritoneum of CAPD patients with peritoneal sclerosis. Perit Dial Int1999; 19: 517–525.
8.
WilliamsJDCraigKJTopleyN, et al.Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol2002; 13: 470–479.
9.
NumataMNakayamaMNimuraS, et al.Association between an increased surface area of peritoneal microvessels and a high peritoneal solute transport rate. Perit Dial Int2003; 23: 116–122.
OnimaruMYonemitsuYFujiiT, et al.VEGF-C regulates lymphangiogenesis and capillary stability by regulation of PDGF-B. Am J Physiol Heart Circ Physiol2009; 297: H1685–H1696.
12.
Gianni-BarreraRBartolomeoMVollmarB, et al.Split for the cure: VEGF, PDGF-BB and intussusception in therapeutic angiogenesis. Biochem Soc Trans2014; 42: 1637–1642.
13.
CaporaliAMartelloAMiscianinovV, et al.Contribution of pericyte paracrine regulation of the endothelium to angiogenesis. Pharmacol Ther2017; 171: 56–64.
14.
MizumasaTHirakataHKurokiY, et al.Diabetes influences peritoneal morphology in uremic patients at the initiation of peritoneal dialysis. Perit Dial Int2013; 33: 175–181.
15.
MizumasaTHodaKAokiS, et al.Proposal regarding peritoneal biopsy methods for peritoneal dialysis patients. J Jpn Soc Dial Ther2018; 51: 77–86 (Japanese).
16.
MoriishiMKawanishiHKawaiT, et al.Preservation of peritoneal catheter for prevention of encapsulating peritoneal sclerosis. Adv Perit Dial2002; 18:149–153.
17.
HommaSMasunagaYKurosuM, et al.Changes in peritoneal coagulation and fibrinolysis after discontinuation of chronic peritoneal dialysis. Perit Dial Int2002; 22: 178–183.
18.
OtsukaYNakayamaMIkedaM, et al.Restoration of peritoneal integrity after withdrawal of peritoneal dialysis: characteristic features of the patients at risk of encapsulating peritoneal sclerosis. Clin Exp Nephrol2005; 9: 315–359.
19.
YamamotoTNagasueKOkunoS, et al.The role of peritoneal lavage and the prognostic significance of mesothelial cell area in preventing encapsulating peritoneal sclerosis. Perit Dial Int2010; 30: 343–352.
20.
NakanoTNakashimaYYonemitsuY, et al.Angiogenesis and lymphangiogenesis and expression of lymphangiogenic factors in the atherosclerotic intima of human coronary arteries. Hum Pathol2005; 36: 330–340.
21.
MasakiIYonemitsuYYamashitaA, et al.Angiogenic gene therapy for experimental critical limb ischemia: acceleration of limb loss by overexpression of vascular endothelial growth factor 165 but not of fibroblast growth factor-2. Circ Res2002; 90: 966–973.
22.
HondaKHamadaCNakayamaM, et al.Impact of uremia, diabetes, and peritoneal dialysis itself on the pathogenesis of peritoneal sclerosis: a quantitative study of peritoneal membrane morphology. Clin J Am Soc Nephrol2008; 3: 720–728.
23.
BrownleeM. Advanced protein glycosylation in diabetes and aging. Annu Rev Med1995; 46: 223–234.
24.
le PooleCYvan IttersumFJValentijnRM, et al.“NEPP” peritoneal dialysis regimen has beneficial effects on plasma CEL and 3-DG, but not pentosidine, CML, and MGO. Perit Dial Int2012; 32: 45–54.
25.
KawanishiKHondaKTsukadaM, et al.Neutral solution low in glucose degradation products is associated with less peritoneal fibrosis and vascular sclerosis in patients receiving peritoneal dialysis. Perit Dial Int2013; 33: 242–251.
26.
Passlick-DeetjenJLageC. Lactate-buffered and bicarbonate-buffered solutions with less glucose degradation products in a two-chamber system. Perit Dial Int2000; 20(suppl 2): S42–S47.
27.
HamadaCHondaKKawanishiK, et al.Morphological characteristics in peritoneum in patients with neutral peritoneal dialysis solution. J Artif Organs2015; 18: 243–250.
28.
PaulJThornalleyCJDoblerD, et al.Concentrations of glucose degradation products, glyoxal, methylglyoxal and 3-deoxyglucosone, in current generation peritoneal dialysis fluids determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). J Am Soc Nephrol2005; 16: 268A.
29.
TawadaMItoYHamadaC, et al.Vascular endothelial cell injury is an important factor in the development of encapsulating peritoneal sclerosis in long-term peritoneal dialysis patients. PLoS One2016; 11: e0154644.
30.
EdelmanDAJiangYTyburskiJ, et al.Pericytes and their role in microvasculature homeostasis. J Surg Res2006; 135: 305–311.
31.
LiuSAgalliuDYuC, et al.The role of pericytes in blood-brain barrier function and stroke. Curr Pharm Des2012; 18: 3653–3662.
32.
TaniiMYonemitsuYFujiiT, et al.Diabetic microangiopathy in ischemic limb is a disease of disturbance of the platelet-derived growth factor-BB/protein kinase C axis but not of impaired expression of angiogenic factors. Circ Res2006; 98: 55–62.
33.
KriehuberEBreiteneder-GeleffSGroegerM, et al.Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J Exp Med2001; 194: 797–808.
34.
WigleJTHarveyNDetmarM, et al.An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J2002; 21: 1505–1513.
35.
LaiJHZhouYJBinD, et al.Clinical significance of detecting lymphatic and blood vessel invasion in stage II colon cancer using markers D2-40 and CD34 in combination. Asian Pac J Cancer Prev2014; 15: 1363–1367.
36.
FrankeFEStegerKMarksA, et al.Hobnail hemangiomas (targetoid hemosiderotic hemangiomas) are true lymphangiomas. J Cutan Pathol2004; 31: 362–367.
37.
TomoTOkabeEYamamotoT, et al.Synergistic cytotoxicity of acidity and 3,4-dideoxyglucosone-3-ene under the existence of lactate in peritoneal dialysis fluid. Ther Apher Dial2005; 9: 182–187.
38.
AtkinsGBJainMKHamikA. Endothelial differentiation: molecular mechanisms of specification and heterogeneity. Arterioscler Thromb Vasc Biol2011; 31: 1476–1484.
39.
BergersGSongS. The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol2005; 7: 452–464.
