Background: The issue of icodextrin biocompatibility is somehow ambiguous. Whereas some experimental data point at better bicompatibility of icodextrin compared with high glucose concentration fluid, other reports showed substantial cytotoxic effects upon monocytes and cultured mesothelial cells. The present investigation exposes the first attempt to investigate the biocompatibility issue in an in vivo and in situ setup. Methods: Mice were intraperitoneally injected once a day with the 7.5% icodextrin solution, during 30 consecutive days. Imprints of the mesothelial monolayer covering the anterior liver surface were taken after 2 h, 15 and 30 injections, as well as after recovery periods of 7, 30 and 60 days. Changes on the cell population were evaluated as a function of: density, cell surface area, cell radius, nuclear surface area, number of nucleoli per nucleus, nuclear cytoplasmic index, as well as for prevalence of multinucleation, mitosis, non-viable cells and apoptotic bodies. Additionally, peritoneal dialysis was performed in 3 groups of rats exposed to 4.25% glucose dialysis fluid, 1.1% amino acids solution, or to 7.5% icodextrin. Samples were taken for thiobarbituric acid reactive substances (TBARS) from each group. Results: Mesothelial cell populations of mice exposed to 7.5% icodextrin displayed significantly reduced density, increased cell size, higher increased nuclear/cytoplasmic index, increased numbers of heterogeneous nucleoli, extremely low prevalence of mitosis, atypical mitosis, micronuclei, reduced cell viability as well as a significantly higher prevalence of apoptosis. Rats exposed to the same experimental solution showed significantly higher levels of TBARS (basically malondialdehyde), testifying for an undergoing process of lipid peroxidation. Conclusions: Overall, these results suggest that the 7.5% icodextrin dialysis solution induced, through a mechanism of lipid peroxidation, substantial DNA injury, leading the exposed monolayer to commit protective cellular suicide. Consequently, this information raises some doubts about the safety of 7.5% icodextrin solution in peritoneal dialysis patients.

Mistry CD, Mallick NP, Gokal R: Ultrafiltration with an isosmotic solution during long peritoneal dialysis exchanges. Lancet 1987;ii:178–182.
Posthuma N, Ter Wee PM, Donker AJ, Oe PL, Van Dorp W, Peers EM, Verbrugh HA: Serum disaccharide and osmolality in CCPD patients using icodextrin or glucose as daytime dwell. Perit Dial Int 1997;17:602–607.
Mistry CD, Gokal P, Peers E, MIDAS Study Group: A randomized multi-center trial comparing isosmolar Icodextrin with hyperosmolar glucose solutions in CAPD. Kidney Int 1994;46:496–503.
Krediet RT: Prevention and treatment of peritoneal dialysis membrane failure. Adv Ren Replace Ther 1998;5:212–217.
Thodis E, Passadakis P, Panagoutsos S, Marinopoulos D, Vargemezis V: Failure of icodextrin to provide adequate ultrafiltration in continuous ambulatory peritoneal dialysis patients. Adv Perit Dial 1999;15:171–174.
Lam P, Tang MKL, Kwan JTC: Icodextrin hypersensitivity in a CAPD patient. Perit Dial Int 1997;17:82–84.
Fletcher S, Stables GA, Turney JH: Icodextrin allergy in a peritoneal dialysis patient. Nephrol Dial Transplant 1988;13:2656–2658.
Queffeulou G, Bernard M, Vrtovsnik F, Skhiri H, Lebrun-Vigne B, Hufnager G, Michel G, Mignon F: Severe cutaneous hypersensitivity requiring permanent icodextrin withdrawal in a CAPD patient. Clin Nephrol 1999;51:184–186.
Pinerolo MC, Porri MT, D’Amico G: Recurrent sterile peritonitis at onset of treatment with icodextrin solution. Perit Dial Int 1999;19:491–492.
Cooker LA, Choo CG, Luneburg P, Lamela J, Holmes CJ: Effect of icodextrin peritoneal dialysis solution on cell proliferation in vitro. Adv Perit Dial 1999;15:17–20.
Barre DE, Chen C, Cooker L, Moberly JB: Decreased in vitro formation of AGEs with extraneal solution compared to dextrose-containing peritoneal dialysis solutions. Adv Perit Dial 1999;15:12–16.
Posthuma N, Ter Wee P, Donker AJ, Deckker HA, Oe PL, Verbrugh HA: Peritoneal defense using icodextrin or glucose for daytime dwell in CCPD patients. Perit Dial Int 1999;19:334–342.
Rooney OB, Dood PD, Gokal R, Walker MG: Dialysis fluid cytotoxicity and inhibition of host defense in cultured human mesothelial cells are neutralized rapidly with incubation in the peritoneum. Nephrol Dial Transplant 1996;11:2472–2477.
Plum J, Lordnejad MR, Grabensee P: Effect of alternative peritoneal dialysis solutions on cell viability, apoptosis/necrosis and cytokine expression in human monocytes. Kidney Int 1998;54:224–235.
Gotloib L, Wajsbrut V, Shostak A, Kushnier R: Acute and long-term changes observed in imprints of mouse mesothelium exposed to glucose-enriched, lactated, buffered dialysis solutions. Nephron 1995;70:466–477.
Institute of Laboratory Animal Resources: Guide for the Care and Use of Laboratory Animals. DHEW Pub. No. (NIH) 72–73. Washington, National Institute of Health, 1972.
Gotloib L, Shostak A, Wajsbrot V, Kushnier R: High glucose induces a hypertrophic, senescent mesothelial cell phenotype after long in vivo exposure. Nephron 1999;82:164–173.
Shostak A, Wajsbrot V, Gotloib L: High glucose accelerates the life cycle of the in vivo exposed mesothelium. Kidney Int 2000;58:2044–2052.
Gotloib L, Wajsbrot V, Shostak A, Kushnier R: Effect of hyperosmolality upon the mesothelial monolayer exposed in vivo and in situ to a mannitol-enriched dialysis solution. Nephron 1999;81:301–309.
Weibel ER, Staubl W, Gnagi HR, Hess FA: Correlated morphometric and biochemical studies on the liver cell. I. Morphometric model, stereological methods and normal morphometric data for rat liver. J Cell Biol 1969;42:68–91.
O’Brien R, Gottlieb-Rosenkrantz P: An automatic method for viability assay of cultured cells. J Histochem Cytochem 1970;18:581–589.
Montanaro F, Lindenbaum M, Carbonetto S: Alpha-dystroglycan is a laminin receptor involved in extracellular matrix assembly on myotubes and muscle cell viability. J Cell Biol 1999;146:1325–1340.
Kerr JF, Wyllie AH, Currie AR: Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239–257.
Nilsson-Thorell CB, Muscalu N, Andren AH, Kjellstrand PT, Weislander AP: Heat sterilization of fluids for peritoneal dialysis gives rise to aldehydes. Perit Dial Int 1993;13:208–213.
Bollag DM, Edelstein SJ: Protein Methods. New York, Wiley-Liss, 1991, p 50.
Zima T, Stipek S, Crkovska J, Platenic J: Measurement of lipid peroxidation product, malondialdehyde in biological samples by spectrophotometric and HPLC assay. Klein Biochem Metab 1995;3:98–102.
Glanz SA: Primer of Biostatistics. New York, McGraw-Hill, 1992, pp 91–109.
Glanz SA: Primer of Biostatistics. New York, McGraw-Hill, 1992, pp 155–187.
Dallal GE, Wilkinson L: An analytical approximation to the distribution of Lilliefor’s test statistic for normality. Am Statist 1986;40:294–296.
Rios Insua D, French S: A framework for sensitivity analysis in discrete multiobjective decision making. Eur J Operational Res 1991;54:176–190.
Koss LG: Diagnostic Cytology and Histopathologic Basis. Philadelphia, Lippincott, 1961, p 111.
Leaf H: Regulation of intracellular fluid volume and disease. Am J Med 1970;49:291–295.
Valsa JO, Felzenszwalb I, de-Araujo AC, Alcantara-Gomes R: Genotoxic effect of a keto-aldehyde produced by thermal degradation of reducing sugars. Mutat Res 1990;231:31–35.
Miyata T, Horie K, Veda Y, Fujita Y, Izuhara Y, Hirano H, Uchida K, Saito A, van Ypersele de Strihou G, Kurokawa K: Advanced glycation and lipidoxidation of the peritoneal membrane: Respective roles of serum and peritoneal fluid reactive carbonyl compounds. Kidney Int 2000;58:425–435.
Di Paolo N, Sacchi G, De Mia M, Gaggiotti E, Capotondo L, Rossi P, Bernini M, Pucci AM, Ibba L, Sabatelli P, et al: Morphology of the peritoneal membrane during continuous ambulatory peritoneal dialysis. Nephron 1986;44:204–211.
Gotloib L, Shostak A, Bar Sella P, Kohan R: Continuous mesothelial injury and regeneration during long term peritoneal dialysis. Perit Dial Bull 1987;7:148–155.
Topley N, Alobaidi HM, Davies M, Coles GA, Williams JD, Lloyd D: The effect of dialysate on peritoneal phagocyte oxidative metabolism. Kidney Int 1988;34:404–411.
Gotloib L, Shostak A, Wajsbrot V, Kuschnier R: The cytochemical profile of visceral mesothelium under the influence of lactated-hyperosmolar peritoneal dialysis solutions. Nephron 1995;69:466–471.
Ho-dac-Pannekeet MM, Hiralall JK, Struijk DG, Krediet RTZ: Longitudinal follow-up of CA125 in peritoneal effluent. Kidney Int 1997;51:888–893.
Flores J, DiBona DR, Frega N, Leaf A: Cell volume regulation and ischemic tissue damage. J Membr Biol 1972;29:331–342.
Parker JC: In defense of cell volume? Am J Physiol 1993;265:C1191–C1200.
Bodnar AG, Ovellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JE, Lichtsteiner S, Wright WE: Extension of life span by introduction of telomerase into normal cells. Science 1988;279:349–352.
DeMay RM: The Art and Science of Cytopathology. Chicago, ASCP Press, 1996, pp 90–300.
Selvaggi SM, Migdal S: Cytologic features of atypical mesothelial cells in peritoneal dialysis fluid. Diagn Cytopathol 1990;6:22–26.
Yamamoto T, Izumotani T, Otoshi T, Kim M: Morphological studies of mesothelial cells in CAPD effluent and their clinical significance. Am J Kidney Dis 1998;32:946–952.
Selgas R, Fernandez de Castro M, Viguer JM, Burgos E, Bajo MA, Carcamo G, Vara F: Transformed mesothelial cells in patients on CAPD for medium to long-term periods. Perit Dial Int 1995;15:305–311.
Wolf T, Leupke NP: Formation of micronuclei in incubated hen’s eggs as a measure of genotoxicity. Mutat Res 1997;394;163–175.
Van de Molengraft FJ, Van’t Hof MA, Herman CJ, Vooijs PG: Quantitative light microscopy of atypical mesothelial cells and malignant cells in ascitic fluid. Anal Quant Cytol 1982;4:217–220.
Didac M, Mandrup-Poulsen T: Apoptosis and the pathogenesis of IDDM. Diabetes 1998;47:1537–1543.
Bottles K, Reznicek MJ, Holly EA, Ahn DK, Layfield LJ, Cohen MB: Cytologic criteria used to diagnose adenocarcinoma in pleural effusions. Mod Pathol 1991;4:677–681.
Newman SL, Henson JE, Henson PM: Phagocytosis of senescent neutrophils by human monocyte-derived macrophages and rabbit inflammatory macrophages. J Exp Med 1982;156:430–442.
Janssen YM, Van Houten B, Borm PJ, Mossman BT: Cell and tissue responses to oxidative damage. Lab Invest 1993;69:216–274.
Wiese AG, Pacifici RE, Davies KJ: Transient adaptation of oxidative stress in mammalian cells. Arch Biochem Biophys 1995;318:231–240.
Shostak A, Pivnik E, Gotloib L: Cultured rat mesothelial cells generate hydrogen peroxide: A new player in peritoneal defense? J Am Soc Nephrol 1996;7:2371–2378.
Sister TF: Free radical mechanisms in tissue injury. Biochem J 1984;222:1–15.
Holley AE, Cheeseman KH: Measuring free radical reactions in vivo. Br Med Bull 1993;49:494–505.
Sato Y, Hotta N, Sakamoto N, Matsvoka S: Oshimi N, Yagi K: Lipid peroxide level in plasma of diabetic patients. Biochemistry 1979;21:104–107.
Estebaver H, Zollner H: Methods for determination of aldehytic lipid peroxidation products. Free Rad Biol Med 1989;7:197–203.
Milner J: US patent 4.886.789. December, 1989, pp 1–26.
Kramholler B, Pischetsriedr M, Severin T: Maillard reactions of lactose and maltose. J Agric Food Chem 1993;41:347–351.
Stich HF, Stich W, Rosin MP, Powrie WD: Clastogenic activity of caramel and caramelized sugars. Mutat Res 1981;9:129–136.
Mistry CD, Fox JE, Mallick NP, Gokal R: Circulating maltose and isomaltose in chronic renal failure. Kidney Int 1987;22(suppl):S210–S214.
Mistry CD, Gokal R: Optimal use of glucose polymer (Icodextrin) in peritoneal dialysis. Perit Dial Int 1996;16(suppl 1):S104–S108.
Abdella PM, Ritchey JM, Tam JWO, Klotz IM: Glycosylation of hemoglobin S by reducing sugars and its effects on glycation. Biochem Biophys Acta 1972;490:462–470.
Kato Y, Matsuda T, Kato N, Nakamura R: Maillard protein reactions in sugar-protein systems; in Finot PA, Aeschbacher HV, Hurrell RF, Liardson (eds): The Maillard Reaction in Food Processing, Human Nutrition and Physiology. Basel, Birkhäuser, 1990, pp 97–102.
Wolff SP, Jiang ZY, Hunt JV: Protein glycation and oxidative stress in diabetes mellitus and ageing. Free Radic Biol Med 1991;10:339–352.
Mistry CD: Glucose Polymer as an Osmotic Agent in Continuous Peritoneal Dialysis; MD thesis, London, 1999.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.