Addition of Alanyl-Glutamine to Dialysis Fluid Restores Peritoneal Cellular Stress Responses – A First-In-Man Trial

Abstract

BackgroundPeritonitis 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.MethodsIn 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.ResultsAlaGln 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.ConclusionWe 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.

A randomized controlled trial of alanyl-glutamine supplementation in peritoneal dialysis fluid to assess impact on biomarkers of peritoneal health

“…13,16,17 In 2 early clinical trials, short-term supplementation of PDF with glutamine added as stable, glutamine releasing dipeptide, alanyl-glutamine (AlaGln), resulted in restored stress responses and improved immune competence of peritoneal cells. 18,19 The main objective of this double-blinded, randomized, crossover study was to examine whether extended treatment with the novel AlaGln-supplemented PDF, compared with placebo added to PDF, provides benefits indicated by markers for peritoneal health (cancer-antigen 125 [CA-125] appearance rate and ex vivo-stimulated interleukin 6 [IL-6] release) in PD patients.…”

Biomarker research to improve clinical outcomes of peritoneal dialysis: consensus of the European Training and Research in Peritoneal Dialysis (EuTRiPD) network

“…currently tested in clinical trials and has been shown to restore adequate cellular stress responses (NCT01353638, EudraCT2013-000400-42) 84. This compound has recently been shown to increase the attachment of N-acetylglucosamine to proteins (O-GlcNAcylation) in mesothelial cells and improve the resistance against PD-fluid toxicity 85.…”

Does alanyl-glutamine supplementation offer potential to improve peritoneal dialysate biocompatibility?

“…This approach extends the existing concept of biocompatibility by replacing deficient glutamine in order to restore dysfunctional mesothelial cellular stress responses (Figure left panel). The rationale for the approach comes from clinical evidence of the benefit of glutamine supplementation in critically ill adults (5), and from experimental models of PD demonstrating that supplementing glucose-based peritoneal dialysis solutions with pharmacological doses of AlaGln protected mesothelial cells in-vitro and preserved peritoneal integrity in-vivo (6). The cellular mechanisms are complex, but include enhancement of expression of one of the best described cytoprotective human stress proteins, Heat-shock protein 72, thereby strengthening resistance of mesothelial cells against toxicity from peritoneal dialysis fluids (6).…”