Conventional lactate-buffered peritoneal dialysis (PD) fluids containing glucose and glucose degradation products are believed to contribute to the development of fibrosis and angiogenesis in the dialyzed peritoneum. To reduce potential negative effects of lactate, pyruvate was substituted as a buffer and its effects on peritoneal pathological alterations were studied in a chronic peritoneal exposure model in the rat.
Methods
20 Wistar rats were infused intraperitoneally with pyruvate-buffered (n = 9) or lactate-buffered PD fluid. After 20 weeks of daily infusion, peritoneal function was assessed. In omental peritoneal tissue, the number of blood vessels was analyzed following alpha-smooth muscle actin staining. The degree of fibrosis was quantitated in Picro Sirius Red-stained sections and by assessment of the hydroxyproline content. Plasma lactate/pyruvate and beta-hydroxybutyrate/acetoacetate (BBA/AA) ratios were determined. Plasma and dialysate vascular endothelial growth factor (VEGF) levels were quantitated by ELISA.
Results
The mass transfer area coefficient of creatinine was higher and the dialysate-to-plasma ratio of sodium was lower in pyruvate-treated animals compared to the lactatetreated group (0.11 vs 0.05 mL/min, p < 0.05, and 78% vs 89%, p < 0.05). The BBA/AA ratio tended to be lower in the pyruvate animals (p = 0.07). The number of blood vessels was lower in pyruvate-treated animals (16 vs 37 per field, p < 0.001). Total surface area, luminal area, and wall/total area of the vessels were larger in the pyruvate group. The degree of fibrosis was lower in intersegmental and perivascular areas of pyruvate-exposed animals. Effluent VEGF was higher in the pyruvate group.
Conclusions
Replacement of lactate by pyruvate resulted in changes in peritoneal solute transport, accompanied by a reduction in both peritoneal membrane angiogenesis and fibrosis, suggesting potentially novel mechanisms to reduce glucose-driven alterations to the peritoneal membrane in PD patients.
HeimburgerO., WaniewskiJ., WerynskiA., TranaeusA., LindholmB.Peritoneal transport in CAPD patients with permanent loss of ultrafiltration capacity.Kidney Int1990; 38: 495–506.
2.
DaviesS.J.Longitudinal relationships between solute transport and ultrafiltration capacity in peritoneal dialysis patients.Kidney Int2004; 66: 2437–45.
MateijsenM.A.M., van der WalA.C., HendriksPMEM, ZweersM.M., MulderJ., StruijkD.G.Vascular and interstitial changes in the peritoneum of CAPD patients with peritoneal sclerosis.Perit Dial Int1999; 19: 517–25.
5.
WilliamsJ.D., CraigK.J., TopleyN., Von RuhlandC., FallenM., NewmanG.R.Morphologic changes in the peritoneal membrane of patients with renal disease.J Am Soc Nephrol2002; 13: 470–9.
6.
PlumJ., HermannS., FusshollerA., SchoenickeG., DonnerA., RehrbornA.Peritoneal sclerosis in peritoneal dialysis patients related to dialysis settings and peritoneal transport properties.Kidney Int Suppl2001; 78: S42–7.
7.
ZweersM.M., SplintL.J., KredietR.T., StruijkD.G.Ultrastructure of basement membranes of peritoneal capillaries in a chronic peritoneal infusion model in the rat.Nephrol Dial Transplant2001; 16: 651–4.
8.
InagiR., MiyataT., YamamotoT., SuzukiD., UrahaniK., SaitoA.Glucose degradation product methylglyoxal enhances the production of vascular endothelial growth factor in peritoneal cells: role in the functional and morphological alterations of peritoneal mesothelial cells in peritoneal dialysis.FEBS Lett1999; 17: 260–4.
9.
SchlingemannR.O., van HinsberghV.W.Role of vascular permeability factor/vascular endothelial growth factor in eye disease.Br J Ophthalmol1997; 81: 501–12.
10.
Alvarez-ArroyoM.V., CarameloC., Angeles CastillaM., Gonzalez PachecoF.R., MartinO., AriasJ.Role of vascular endothelial growth factor in the response to vessel injury.Kidney Int Suppl1998; 68: S7–9.
11.
TiltonR.G., KawamuraT., ChangK.C., IdoY., BjerckeR.J., StephanC.C.Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor.J Clin Invest1997; 99: 2192–202.
12.
WilliamsonJ.R., OsrowE., EadesD., ChangK., AllisonW., KiloC.Glucose-induced microvascular functional changes in nondiabetic rats are stereospecific and are prevented by an aldose reductase inhibitor.J Clin Invest1990; 85: 1167–72.
13.
MorriseyK., SteadmanR., WilliamsJ.D., PhilipsA.O.Renal proximal tubular cell fibronectin accumulation in response to glucose is polyol pathway dependent.Kidney Int1999; 55: 160–7.
14.
PhilipsA.O., MorriseyK., SteadmanR., WilliamsJ.Decreased degradation of collagen and fibronectin following exposure of proximal cells to glucose.Exp Nephrol1999; 7: 449–62.
ZweersM.M., de WaartD.R., SmitW., StruijkD.G., KredietR.T.Growth factors VEGF and TGF-beta1 in peritoneal dialysis.J Lab Clin Med1999; 134: 124–32.
17.
ZweersM.M., StruijkD.G., SmitW., KredietR.T.Vascular endothelial growth factor in peritoneal dialysis: a longitudinal follow-up.J Lab Clin Med2001; 137: 125–32.
18.
KredietR.T., van WestrhenenR., ZweersM.M., StruijkD.G.Clinical advantages of new peritoneal dialysis solutions.Nephrol Dial Transplant2002; 17(Suppl 3): 16–18.
19.
Kientsch-EngelR.I., SiessE.A.D-(-)-3-hydroxybutyrate and acetoacetate. In: BergmeyerH.U., ed. Methods of Enzymatic Analysis.3rd ed. Vol. 7. Weinheim: VHC Verlag; 1983: 60–9.
20.
PannekeetM.M., ImholzA.L., StruijkD.G., KoomenG.C., LangedijkM.J., SchoutenN.The standard peritoneal permeability analysis: a tool for the assessment of peritoneal permeability characteristics in CAPD patients.Kidney Int1995; 48: 866–75.
21.
ZweersM.M., SplintL.J., KredietR.T., StruijkD.G.Effect of fluid supplementation and modality on peritoneal permeability characteristics in a rat peritoneal dialysis model.Perit Dial Int2001; 21: 58–64.
22.
KoomenG.C.M., KredietR.T., LeegwaterA.C.J., StruijkD.G., AriszL., HoekF.J.A fast reliable method for the measurement of intra-peritoneal dextran 70, used to calculate lymphatic absorption.Adv Perit Dial1991; 7: 10–14.
23.
ZemelD., ImholzA.L.T., de WaartD.R., DinklaC., StruijkD.G., KredietR.T.Appearance of tumor necrosis factor-α and soluble TNF receptors I and II in peritoneal effluent of CAPD.Kidney Int1994; 46: 1422–30.
24.
KredietR.T., StruijkD.G., KoomenG.C., AriszL.Peritoneal fluid kinetics during CAPD measured with intraperitoneal dextran 70.ASAIO Trans1991; 37: 662–7.
25.
WaniewskiJ., WerynskiA., HeimburgerO., LindholmB.Simple models for description of small-solute transport in peritoneal dialysis.Blood Purif1991; 9: 129–41.
26.
ZweersM.M., ImholzA.L., StruijkD.G., KredietR.T.Correction of sodium sieving for diffusion from the circulation.Adv Perit Dial1999; 15: 65–72.
27.
Westrhenen vanR., de WaartD.R., AkmanS., KredietR.T.Assessment of peritoneal fibrosis by conventional light microscopy and hydroxyproline measurement.Perit Dial Int2004; 24: 290–2.
28.
HekkingL.H., ZareieM., DriesprongB.A., FaictD., WeltenA.G., de ZeeuwI.Better preservation of peritoneal morphologic features and defense in rats after long-term exposure to a bicarbonate/lactate buffered solution.J Am Soc Nephrol2001; 12: 2775–86.
29.
ZareieM., HekkingL.H., WeltenA.G., DriesprongB.A., Schadee-EestermansI.L., FaictD.Contribution of lactate buffer, glucose and glucose degradation products to peritoneal injury in vivo.Nephrol Dial Transplant2003; 18: 2629–37.
30.
MortierS., FaictD., SchalkwijkC.G., LameireN.H., De VrieseA.S.Long-term exposure to new peritoneal dialysis solutions: effects on the peritoneal membrane.Kidney Int2004; 66: 1257–65.
31.
BrunkhorstR., MahioutA.Pyruvate neutralizes peritoneal dialysate cytotoxicity: maintained integrity and proliferation of cultured human mesothelial cells.Kidney Int1995; 48: 177–81.
32.
ShostakA., GotloibL., KushnierR., WajsbrotV.Protective effect of pyruvate upon cultured mesothelial cells exposed to 2mM hydrogen peroxide.Nephron2000; 84: 362–6.
33.
IngT.S., ZhouX.J., YuA.W., ZhouF.Q., VaziriN.D.Effects of pyruvate-based or lactate-based peritoneal dialysis solutions on neutrophil intracellular pH.Int J Artif Organs1997; 20: 255–60.
34.
WuY.T., WuZ.L., JiangX.F., LiS., ZhouF.Q.Pyruvate preserves neutrophilic superoxide production in acidic, high glucose-enriched peritoneal dialysis solutions.Artificial Organs2003; 27: 276–81.
MahioutA., BrunkhorstR.Pyruvate anions in peritoneal dialysate solutions preserve the function of peripheral and peritoneal leukocytes in vitro.Nephrol Dial Transplant1995; 10: 391–4.
37.
MusiB., CarlssonO., RippeA., WieslanderA., RippeB.Effects of acidity, glucose degradation products, and dialysis fluid buffer choice on peritoneal solute and fluid transport in rats.Perit Dial Int1998; 18: 303–10.
38.
AlbrechtssonA., BazargoniF., WieslanderA., BraideA.Peritoneal dialysis fluid-induced angiogenesis in rat mesentery is increased by lactate in the presence or absence of glucose.ASAIO J2006; 52: 276–81.
39.
ZweersM.M., de WaartD.R., van der WalA.C., DekkerF.W., KredietR T., StruijkD.G.Structural and functional changes of the peritoneum in a chronic peritoneal infusion model in the rat. In: ZweersM.M., ed. Experimental and Clinical Studies on Peritoneal Physiology and Morphology During Chronic Peritoneal Dialysis [Thesis].University of Amsterdam; 2000: 77–96.
40.
ImholzA.L.T., KoomenG.C.M., StruijkD.G., AriszL., KredietR.T.Effect of dialysate osmolarity on the transport of low-molecular weight solutes and proteins during CAPD.Kidney Int1993; 43: 1339–46.
41.
NumataM., NakayamaM., NimuraS., KawakamiM., LindholmB., KawaguchiY.Association between an increased peritoneal surface area of peritoneal microvessels and a high peritoneal solute transport rate.Perit Dial Int2003; 23: 116–22.
WongT.Y., PhilipsA.O., WitowskiJ., TopleyN.Glucose-mediated induction of TGFbeta1 and MRCP 1 in mesothelial cells in vitro is osmolality and polyol pathway dependent.Kidney Int2003; 63: 1404–16.
44.
LindenT., CohenA., DeppischR., KjellstrandP., WieslanderA.3,4-dideoxyglucosone-3-ene (3,4-DGE): a cytotoxic glucose degradation product in fluids for peritoneal dialysis.Kidney Int2002; 62: 697–703.
45.
WitowskiJ., KorybalskaK., WisniewskaJ., BreborowiczA., GahlG.M., FreiU.Effect of glucose degradation products on human peritoneal mesothelial cell function.J Am Soc Nephrol2000; 11: 729–39.
46.
HondaK., NittaK., HoritasS., YumuraW., NiheiH., NagaiR.Accumulation of advanced glycation end products in the peritoneal vasculature of continuous ambulatory peritoneal dialysis patients with low ultrafiltration.Nephrol Dial Transplant1999; 14: 1541–9.
47.
MiayataT., HorieK., KedaY., FujitaY., IzuharaY., HiranoH.Advanced glycation and lipidoxidation of the peritoneal membrane: respective roles of serum and peritoneal fluid reactive carbonyl compounds.Kidney Int2000; 58: 425–35.
48.
DevuystO., van Ypersele de StrihouC.Nitric oxide, advanced glycation end products, and uremia.Kidney Int2000; 4: 1814–15.
49.
Van ErvenD.M.M., GabreëlsF.J.M., WeversR.A., DoesburgW.H., RuitenbeekW., RenierW.O.Intravenous pyruvate loading test in Leigh syndrome.J Neurol Sci1987; 77: 217–27.
50.
KristoG., YoshimuraY., NiuJ., KeithB.J., MentzerR.M.Jr., LasleyR.D.The intermediary metabolite pyruvate attenuates stunning and reduces infarct size in vivo porcine myocardium.Am J Physiol Heart Circ Physiol2004; 286: H517–H524.
51.
HermannH.P., ArpJ., PieskeB., KoglerH., BaronS., JanssenP.M.L.Improved systolic and diastolic myocardial function with intracoronary pyruvate in patients with congestive heart failure.Eur J Heart Fail2004; 6: 213–18.
52.
Olivencia-YurvatiA.H., BlairJ.L., BaigM., MalletR.T.Pyruvate-enhanced cardioprotection during surgery with cardiopulmonary bypass.J Cardiothorac Vasc Anesth2003; 17: 715–20.
