Peritoneal Function After Exposure to PD
The adequacy and duration of peritoneal dialysis (PD) therapy may be limited by structural alterations of the peritoneal membrane that occur over time. These changes may lead to inadequate solute transport, impaired ultrafiltration, and eventual technique failure, necessitating a transfer of patients to hemodialysis therapy1. Studies have shown that structural changes of the peritoneal membrane increase with the time spent on PD therapy2–4 and are attributed to recurrent peritonitis, chronic uremia, and long-term exposure of the peritoneal membrane to conventional PD fluids (PDFs)1,5,6.
Conventional PDFs and Structural and Functional Changes of the Peritoneum
Several properties of conventional PDFs may contribute to changes in peritoneal membrane viability over time, including: acidic pH, high osmolality and glucose concentrations, the use of lactate as a buffering agent, and the presence of contaminants such as glucose degradation products (GDPs) that are formed during heat sterilization of glucose-containing dialysate solutions5,7.
In an in vitro study, Wieslander and colleagues showed that low pH and GDPs were largely responsible for the bioincompatibility of conventional PD solutions8. However, the authors speculated that the effects of low pH could be attenuated in a clinical setting by rapid equilibration of dialysate pH after infusion into the peritoneal cavity. Thus, clinical cytotoxicity of conventional solutions might be, at least in part, mediated by GDPs.
The relationship between glucose or GDP exposure and impaired peritoneal membrane function was further defined in a retrospective, single-center cohort study of 22 PD patients9. The authors found that patients with high glucose exposure had increased solute transport over time and that glucose exposure preceded changes in transport status. In contrast, patients who received therapy with lower dialysate glucose concentrations had stable solute transport over time. These findings suggested that exposure to concentrated glucose solutions may directly contribute to long-term changes in peritoneal membrane function. However, the results of the study were limited by potential confounding effects of residual renal function (RRF) and ultrafiltration requirements.
Over time, exposure of the peritoneum to GDPs leads to the generation of toxins and inflammatory mediators that promote structural changes of the peritoneal membrane1,10. Several studies have identified correlations between GDPs and increased synthesis of transforming growth factor β1 (TGFβ1). TGFβ1 mediates the conversion of epithelial cells to mesenchymal cells within the peritoneum. Mesenchymal cells secrete vascular endothelial growth factor (VEGF) in response to inflammatory cytokines and GDPs, leading to angiogenesis and increased perfusion of the peritoneum. This leads to increased solute transport and reduced ultrafiltration during PD. Mesenchymal cells also increase the production of extracellular matrix, resulting in fibrosis7. Fibrotic tissue can further limit the ultrafiltration capacity of the peritoneal membrane and may impair solute transport.
Glucose and GDPs may react with proteins in the peritoneum to form advanced glycosylation end products (AGEs). While both glucose and GDPs contribute to AGE formation, an in vitro study by Igaki and colleagues demonstrated that AGE generation was higher following exposure of bovine serum albumin to 3-deoxyglucosone (a major GDP) than to glucose11. Thus, toxic effects of GDPs are linked to downstream AGE formation. AGEs exert a variety of local and systemic effects that contribute to peritoneal membrane dysfunction and RRF decline. AGEs bind to the receptor for advanced glycation end products (RAGE) that is located on peritoneal mesothelial cells and in the endothelium of blood vessels. Binding of AGEs to RAGE leads to increased secretion of VEGF and expression of adhesion molecules that promote leukocyte activity within the peritoneum. Receptor binding in the endothelium increases vascular permeability, which may contribute to increased solute transport across the peritoneal membrane1. AGEs may enter the systemic circulation and become lodged in the renal vasculature, contributing to loss of RRF in PD patients12. Use of PDFs with higher glucose concentrations to achieve adequate ultrafiltration as RRF declines might further increase the exposure of and damage to the peritoneal membrane by GDPs and AGEs5.
Measuring Changes in Peritoneal Membrane Morphology
Changes in peritoneal membrane morphology are assessed through the measurement of surrogate biomarkers in effluent dialysate. Biomarkers provide an indirect measure of changes in peritoneal structure and are used in lieu of peritoneal membrane biopsy due to feasibility and safety limitations. Although a variety of biomarkers are measured in clinical practice, it is uncertain whether effluent concentrations of these molecules accurately reflect structural membrane changes. Table I provides a list of commonly measured biomarkers and their associated processes1,5.
Table I: Biomarkers for Analysis of Peritoneal Membrane Morphology
|Cancer antigen-125 (CA-125)||A glycoprotein expressed on mesothelial cells in the peritoneum. Increased levels correspond to better mesothelial cell viability.|
|Interleukin-6 (IL-6)||Produced locally by mesothelial cells. Effluent levels are thought to correlate with solute transport. Also provides an indication of inflammation.|
|Vascular endothelial growth factor (VEGF)||Growth factor secreted by mesothelial cells. Stimulates the formation of new blood vessels within the peritoneal cavity. Associated with increased small solute transport.|
|Transforming growth factor β (TGFβ)||Stimulates epithelial-to-mesenchymal transition (EMT) of mesothelial cells. Promotes peritoneal fibrosis.|
Consequences of Peritoneal Membrane Dysfunction
Long-term exposure to GDPs and AGEs increases VEGF expression, leading to neovascularization and increased peritoneal perfusion. The formation of new blood vessels within the peritoneal cavity provides a larger surface area for solute diffusion, resulting in a more rapid equilibration of toxins between blood and dialysate compartments. An expanded vascular surface area can also increase the diffusive absorption of glucose from the dialysate into the bloodstream, leading to reduction in the osmotic gradient necessary for ultrafiltration and consequently, ultrafiltration failure (UFF)5,13. UFF can ultimately cause technique failure in patients on long-term PD therapy.
Prevention of Peritoneal Membrane Changes
Efforts to preserve the integrity of the peritoneal membrane and reduce the risk of long-term complications of PD therapy have led to the development of more biocompatible PDFs. These solutions are characterized by one or more of the following properties: a more physiologic pH, an alternative osmotic agent (i.e., polyglucose or amino acids), an alternative buffer such as bicarbonate, and lower GDP concentrations than conventional solutions1. Theoretically, these properties can minimize damage to the peritoneal membrane over time. However, actual data comparing the effects of biocompatible and standard PDFs on peritoneal membrane function are conflicting.
Results of a prospective, multicenter, 24-month cohort study of 177 anuric APD patients (European Automated Peritoneal Dialysis Outcomes Study; EAPOS) showed that patients receiving standard PDFs experienced significant increases in peritoneal solute transport and reductions in ultrafiltration compared to patients receiving biocompatible, icodextrin-based solutions14.
The authors of another 2-year, randomized controlled trial (RCT) found that there were no changes in peritoneal solute transport or ultrafiltration between standard and biocompatible treatment arms over the study period15. Similar results were observed in the DIUREST Study, a multicenter, randomized, controlled, parallel trial of 80 PD patients receiving standard or low-GDP glucose PDFs16. In that study, there were no changes in peritoneal transport in the standard or biocompatible groups over 18-months. Ultrafiltration increased in both groups throughout the study; however, there were differences in overfill volumes of PDFs that prevented interpretation of the results.
In contrast to the above studies, the authors of several subsequent RCTs have reported increased solute transport, reduced ultrafiltration, or both with biocompatible solutions (acid-based solutions, icodextrin-based solutions, and low-GDP glucose-based solutions), depending on the endpoints that were measured16-21. Some authors speculate that the results may be attributed to improved RRF or reduced intravascular volume in the groups receiving biocompatible PDFs. In fact, a systematic review of randomized controlled trials found that in the long term, biocompatible solutions can lead to preservation and improvement in RRF.
Interpretation of current data is complicated by significant heterogeneity between trials in terms of patient populations (e.g., anuric vs. non anuric, incident vs. prevalent), PD modality (APD vs. CAPD), dialysate solutions used, and study duration. Pathologic changes in peritoneal membrane function tend to become evident after years of PD therapy; therefore, even RCTs and cohort studies with relatively long durations (e.g., 2 years) may not provide an accurate estimate of the chronic effects of PDFs on solute transport and ultrafiltration. Also, most studies enrolled patients with varying levels of RRF, which may have influenced the observed effects of PDFs on solute transport and ultrafiltration. Therefore, most authors conclude that the effects of biocompatible PDFs on peritoneal membrane function are inconclusive and require further study.
- Perl J, Nessim SJ, Bargman JM. The biocompatibility of neutral pH, low-GDP peritoneal dialysis solutions: benefit at bench, bedside, or both? Kidney Int. 2011;79(8):814-24. www.ncbi.nlm.nih.gov/pubmed/21248712
- Honda K, Hamada C, Nakayama M, Miyazaki M, Sherif AM, Harada T, Hirano H. 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 Nephrol. 2008;3(3):720-8. www.ncbi.nlm.nih.gov/pubmed/18272828
- Parikova A, Smit W, Struijk DG, Krediet RT. Analysis of fluid transport pathways and their determinants in peritoneal dialysis patients with ultrafiltration failure. Kidney Int. 2006;70(11):1988-94. www.ncbi.nlm.nih.gov/pubmed/17035948
- Williams JD, Craig KJ, Topley N, Von Ruhland C, Fallon M, Newman GR, Mackenzie RK, Williams GT. Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol. 2002;13(2):470-9. www.ncbi.nlm.nih.gov/pubmed/11805177
- Davies SJ, Mushahar L, Yu Z, Lambie M. Determinants of peritoneal membrane function over time. Semin Nephrol. 2011;31(2):172-82. www.ncbi.nlm.nih.gov/pubmed/21439431
- Pletinck A, Vanholder R, Veys N, Van Biesen W. Protecting the peritoneal membrane: factors beyond peritoneal dialysis solutions. Nat Rev Nephrol. 2012;8(9):542-50. www.ncbi.nlm.nih.gov/pubmed/22777203
- García-López E, Lindholm B, Davies S. An update on peritoneal dialysis solutions. Nat Rev Nephrol. 2012;8(4):224-33. www.ncbi.nlm.nih.gov/pubmed/22349485
- Wieslander A, Linden T, Kjellstrand P. Glucose degradation products in peritoneal dialysis fluids: how they can be avoided. Perit Dial Int. 2001;21 Suppl 3:S119-24. www.ncbi.nlm.nih.gov/pubmed/11887805
- Davies SJ, Phillips L, Naish PF, Russell GI. Peritoneal glucose exposure and changes in membrane solute transport with time on peritoneal dialysis. J Am Soc Nephrol. 2001;12(5):1046-51. www.ncbi.nlm.nih.gov/pubmed/11316864
- Kim Y-L. Update on mechanisms of ultrafiltration failure. Perit Dial Int. 2009;29 Suppl 2:S123-7. www.ncbi.nlm.nih.gov/pubmed/19270200
- Igaki N, Sakai M, Hata H, Oimomi M, Baba S, Kato H. Effects of 3-deoxyglucosone on the Maillard reaction. Clin Chem. 1990;36(4):631-4. www.ncbi.nlm.nih.gov/pubmed/2157564
- Thornalley PJ, Rabbani N. Highlights and hotspots of protein glycation in end-stage renal disease. Semin Dial. 2009;22(4):400-4. www.ncbi.nlm.nih.gov/pubmed/19708990
- Smit W, Schouten N, van den Berg N, Langedijk MJ, Struijk DG, Krediet RT. Analysis of the prevalence and causes of ultrafiltration failure during long-term peritoneal dialysis: a cross-sectional study. Perit Dial Int. 2004;24(6):562-70. www.ncbi.nlm.nih.gov/pubmed/15559486
- Davies SJ, Brown EA, Frandsen NE, Rodrigues AS, Rodriguez-Carmona A, Vychytil A, Macnamara E, Ekstrand A, Tranaeus A, Filho JCD. Longitudinal membrane function in functionally anuric patients treated with APD: data from EAPOS on the effects of glucose and icodextrin prescription. Kidney Int. 2005;67(4):1609-15. www.ncbi.nlm.nih.gov/pubmed/15780118
- Rippe B, Simonsen O, Heimbürger O, Christensson A, Haraldsson B, Stelin G, Weiss L, Nielsen FD, Bro S, Friedberg M, Wieslander A. Long-term clinical effects of a peritoneal dialysis fluid with less glucose degradation products. Kidney Int. 2001;59(1):348-57. www.ncbi.nlm.nih.gov/pubmed/11135090
- Haag-Weber M, Krämer R, Haake R, Islam MS, Prischl F, Haug U, Nabut JL, Deppisch R. Low-GDP fluid (Gambrosol trio) attenuates decline of residual renal function in PD patients: a prospective randomized study.Nephrol Dial Transplant. 2010;25(7):2288-96. www.ncbi.nlm.nih.gov/pubmed/20197284
P/N 102481-01 Rev. A 12/2014