In early clinical testing, acute addition of alanyl-glutamine (AlaGln) to glucose-based peritoneal dialysis (PD) fluids restored peritoneal cellular stress responses and leukocyte function. This study was designed to test the effect of extended treatment with AlaGln-supplemented PD fluid on biomarkers of peritoneal health. In a double-blinded, randomized crossover design, stable PD patients were treated with AlaGln (8 mM) or placebo added to PD fluid for eight weeks. As primary outcome measures, dialysate cancer-antigen 125 (CA-125) appearance rate and ex vivo stimulated interleukin-6 (IL-6) release were assessed in peritoneal equilibration tests. In 8 Austrian centers, 54 patients were screened, 50 randomized, and 41 included in the full analysis set. AlaGln supplementation significantly increased CA-125 appearance rate and ex vivo stimulated IL-6 release. AlaGln supplementation also reduced peritoneal protein loss, increased ex vivo stimulated tumor necrosis factor (TNF)-α release, and reduced systemic IL-8 levels. No adverse safety signals were observed. All 4 peritonitis episodes occurred during standard PD fluid treatment. A novel AlaGln-supplemented PD fluid improves biomarkers of peritoneal membrane integrity, immune competence, and systemic inflammation compared to unsupplemented PD fluid with neutral pH and low-glucose degradation. A phase 3 trial is needed to determine the impact of AlaGln supplementation on hard clinical outcomes.

Peritonitis and ultrafiltration failure remain serious complications of chronic peritoneal dialysis (PD). Dysfunctional cellular stress responses aggravate peritoneal injury associated with PD fluid exposure, potentially due to peritoneal glutamine depletion. In this randomized cross-over phase I/II trial we investigated cytoprotective effects of alanyl-glutamine (AlaGln) addition to glucose-based PDF. In a prospective randomized cross-over design, 20 stable PD outpatients underwent paired peritoneal equilibration tests 4 weeks apart, using conventional acidic, single chamber 3.86% glucose PD fluid, with and without 8 mM supplemental AlaGln. Heat-shock protein 72 expression was assessed in peritoneal effluent cells as surrogate parameter of cellular stress responses, complemented by metabolomics and functional immunocompetence assays. AlaGln restored peritoneal glutamine levels and increased the primary outcome heat-shock protein expression (effect 1.51-fold, CI 1.07–2.14; p = 0.022), without changes in peritoneal ultrafiltration, small solute transport, or biomarkers reflecting cell mass and inflammation. Further effects were glutamine-like metabolomic changes and increased ex-vivo LPS-stimulated cytokine release from healthy donor peripheral blood monocytes. In patients with a history of peritonitis (5 of 20), AlaGln supplementation decreased dialysate interleukin-8 levels. Supplemented PD fluid also attenuated inflammation and enhanced stimulated cytokine release in a mouse model of PD-associated peritonitis. We conclude that AlaGln-supplemented, glucose-based PD fluid can restore peritoneal cellular stress responses with attenuation of sterile inflammation, and may improve peritoneal host-defense in the setting of PD.

Sufficient iron substitution is critical for adequate treatment of anemia, especially in erythropoietin-treated renal failure patients [ 1. x 1. Sunder-Plassmann, G. and HaRl, W.H. Importance of iron supply for erythropoietin therapy. Nephrol Dial Transplant. 1995; 10: 2070–2076 PubMed | Google Scholar See all References , 2. x 2. Ahsan, N. Intravenous infusion of total dose iron is superior to oral iron in treatment of anemia in peritoneal dialysis patients: A single center comparative study. J Am Soc Nephrol. 1998; 9: 664–668 PubMed | Google Scholar See all References , 3. x 3. Vychytil, A. and Haag-Weber, M. Iron status and iron supplementation in peritoneal dialysis patients. Kidney Int. 1999; 55: S71–78 Abstract | Full Text | Full Text PDF | PubMed | Google Scholar See all References , 4. x 4. Dittrich, E., Schillinger, M., Sunder-Plassmann, G. et al. Efficacy of a low-dose intravenous iron sucrose regimen in peritoneal dialysis patients. Perit Dial Int. 2002; 22: 60–66 PubMed | Google Scholar See all References ]. Because oral iron is poorly absorbed, intravenous iron supplementation is preferred in most of these patients [ 5 x 5. Kooistra, M.P. and Marx, J.J. The absorption of iron is disturbed in recombinant human erythropoietin-treated peritoneal dialysis patients. Nephrol Dial Transplant. 1998; 13: 2578–2582 Crossref | PubMed | Scopus (34) | Google Scholar See all References 5 ]. While the prevalence of iron deficiency is lower in peritoneal dialysis (PD) compared to hemodialysis (HD) patients, PD patients receive higher bolus doses of iron at longer intervals since they only visit the center every four to six weeks. Furthermore, unlike HD patients, PD patients often have limited venous access and their forearm veins need to be kept permeable. When infused over a period of two hours, iron sucrose in single doses of up to 300 mg has been well tolerated in dialysis patients [ 6 x 6. Chandler, G., Harchowal, J., and Macdougall, I.C. Intravenous iron sucrose: Establishing a safe dose. Am J Kidney Dis. 2001; 38: 988–991 Abstract | Full Text | Full Text PDF | PubMed | Scopus (146) | Google Scholar See all References 6 ]. There are, however, concerns about intravenous iron administration. A single bolus of 300 mg of intravenous iron sucrose has been reported to depress phagocyte function in PD patients [ 7 x 7. Deicher, R., Ziai, F., Cohen, G. et al. High-dose parenteral iron sucrose depresses neutrophil intracellular killing capacity. Kidney Int. 2003; 64: 728–736 Abstract | Full Text | Full Text PDF | PubMed | Scopus (68) | Google Scholar See all References 7 ]. Impairment of neutrophil function is also present in chronic HD patients receiving intravenous iron therapy, especially in those with ferritin levels above 650 μg/L [ 8 x 8. Patruta, S.I., Edlinger, R., Sunder-Plassmann, G., and HaRl, W.H. Neutrophil impairment associated with iron therapy in hemodialysis patients with functional iron deficiency. J Am Soc Nephrol. 1998; 9: 655–663 PubMed | Google Scholar See all References 8 ]. Therefore, high-dose or long-term intravenous iron administration may be associated with an increased risk of infection [ 9 x 9. Sunder-Plassmann, G., Patruta, S.I., and HaRl, W.H. Pathobiology of the role of iron in infection. Am J Kidney Dis. 1999; 34: S25–29 Abstract | Full Text | Full Text PDF | PubMed | Google Scholar See all References 9 ]. Furthermore, increased blood levels of non-transferrin-bound iron (NTBI) or its redox-active part may cause endothelial dysfunction and platelet activation by generation of reactive oxygen species, inactivation of endothelium-derived nitric oxide (NO), and oxidation of low-density lipoproteins (LDL) [ 10. x 10. Smith, C., Mitchinson, M.J., Aruoma, O.I., and Halliwell, B. Stimulation of lipid peroxidation and hydroxyl-radical generation by the contents of human atherosclerotic lesions. Biochem J. 1992; 286: 901–905 Crossref | PubMed | Scopus (385) | Google Scholar See all References , 11. x 11. Cooper, C.E. Nitric oxide and iron proteins. Biochim Biophys Acta. 1999; 1411: 290–309 Crossref | PubMed | Scopus (388) | Google Scholar See all References , 12. x 12. Roob, J.M., Khoschsorur, G., Tiran, A. et al. Vitamin E attenuates oxidative stress induced by intravenous iron in patients on hemodialysis. J Am Soc Nephrol. 2000; 11: 539–549 PubMed | Google Scholar See all References ]. These are important mechanisms in the pathogenesis of atherosclerosis [ 13 x 13. Ross, R. Atherosclerosis—An inflammatory disease. N Engl J Med. 1999; 340: 115–126 Crossref | PubMed | Scopus (16768) | Google Scholar See all References 13 ].

In patients with refractory heart failure (HF) peritoneal dialysis (PD) is associated with improved functional status and decrease in hospitalization. However, previous studies did not focus on right ventricular dysfunction as an important pathophysiologic component of cardiorenal syndrome. In a prospective cohort study PD was started in 40 patients with refractory right HF (with/without left HF). Refractoriness to conservative therapy was defined as persistent right heart congestion/ascites with intensified diuretic treatment and/or ≥2 hospitalizations within 6 months because of cardiac decompensation despite optimal medical treatment, and/or acute renal failure during intensified conservative treatment of cardiac decompensations. Patient survival was 55.0% at 1 year, 35.0% at 2 years and 27.5% at 3 years. The number of hospitalization days declined after initiation of PD for both cardiac [13 (IQR 1–53) days before vs. 1 (IQR 0–12) days after start of PD, p<0.001] and unplanned reasons [12 (IQR 3–44) days before vs. 1 (IQR 0–33) days after start of PD, p = 0.007]. Using a combined endpoint including survival time of ≥1 year and either improvement in quality of life or decline in hospitalizations we found that patients with extended ascites, higher systolic pulmonary artery pressure, more marked impairment of right ventricular function and tricuspid valve insufficiency, higher residual renal function as well as those who could perform PD without assistance have benefited most from this therapy. Patients with more pronounced backward failure, less marked residual renal functional impairment and those not depending on assistance for therapy are likely to profit most from PD.