Abstract
Peritonitis remains a major cause of morbidity and mortality during chronic peritoneal dialysis (PD). Glucose-based PD fluids reduce immunological defenses in the peritoneal cavity. Low concentrations of peritoneal extracellular glutamine during PD may contribute to this immune deficit. For these reasons we have developed a clinical assay to measure the function of the immune-competent cells in PD effluent from PD patients. We then applied this assay to test the impact on peritoneal immune-competence of PD fluid supplementation with alanyl-glutamine (AlaGln) in 6 patients in an open-label, randomized, crossover pilot trial (EudraCT 2012-004004-36), and related the functional results to transcriptome changes in PD effluent cells. Ex-vivo stimulation of PD effluent peritoneal cells increased release of interleukin (IL) 6 and tumor necrosis factor (TNF) α. Both IL-6 and TNF-α were lower at 1 h than at 4 h of the peritoneal equilibration test but the reductions in cytokine release were attenuated in AlaGln-supplemented samples. AlaGln-supplemented samples exhibited priming of IL-6-related pathways and downregulation of TNF-α upstream elements. Results from measurement of cytokine release and transcriptome analysis in this pilot clinical study support the conclusion that suppression of PD effluent cell immune function in human subjects by standard PD fluid is attenuated by AlaGln supplementation.
Highlights
The prohibitive costs of clinical peritoneal dialysis (PD) trials based on hard outcomes such as peritonitis require development of reliable surrogate outcome parameters for early clinical development of improved formulations of PDFs
In previous studies focusing on different aspects of systemic immune-competence, whole-blood culture assays were developed and cytokine content was analyzed in diluted heparinized blood after ex-vivo exposure to toll-like receptor (TLR) agonists[15]
Tumor necrosis factor alpha (TNF-α) release was measured in the cell-free supernatants
Summary
In this study we test the feasibility of a simple method for monitoring function of peritoneal immune-competent cells in clinical practice, based on an adaptation of the ex-vivo lipopolysaccharide (LPS)-stimulated cytokine release assay[6, 22, 23]. We use this streamlined assay in a randomized pilot-feasibility trial to assess effects of a novel PDF supplemented with the stable Gln dipeptide alanyl-glutamine (AlaGln).
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