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Trials (and Tribulations) of Biocompatible Peritoneal Dialysis Fluids

A key factor implicated in the local and systemic complications of peritoneal dialysis (PD) is the “unphysiologic” nature of conventional PD fluids, particularly acidic pH (5.0 – 5.8) and high concentrations of glucose degradation products (GDPs) generated as a byproduct of the heat sterilization process (1,2). Acidic PD fluid promotes mesothelial cell damage and neoangiogenesis in vitro (3) and infusion pain in the clinical setting (4). Exposure to GDPs also results in reduced growth and viability of peritoneal cell populations (mesothelial cells, fibroblasts, macrophages, and leukocytes), increased collagen deposition, augmented secretion of proinflammatory cytokines such as vascular endothelial growth factor, local production of damaging advanced glycation endproducts (AGEs) (5), and stimulation of epithelial– mesenchymal transition (6–9). The GDPs in standard PD fluids are also known to be absorbed systemically, possibly accelerating loss of residual renal function because of the proinflammatory, proapoptotic, and pro-oxidative effects of AGEs (10). Concerns about the deleterious effects of conventional PD fluids have led, over the last 15 years, to the development of newer “biocompatible” PD fluids, which have a neutral pH and are low in GDPs (11). These novel solutions have been shown, in both in vitro and in vivo studies, to largely abrogate most of the adverse effects of conventional solutions on the peritoneal membrane (1,7,12–14). Furthermore, several large observational retrospective cohort studies in Korea have reported that, compared with administration of conventional solutions, administration of neutral-pH low-GDP fluids buffered with either lactate (15,16) or lactate/bicarbonate (17) is associated with improved patient survival—although those findings are potentially limited by confounding by indication (18). A number of small, short-duration randomized controlled trials have demonstrated significant improvements in the effluent biomarkers of peritoneal membrane integrity, but those studies have not identified any benefits with respect to patient or technique survival, and they failed to show consistent effects on other clinically important outcomes, such as peritonitis rates, small-solute clearance, peritoneal ultrafiltration, or decline in residual renal function. Those trials, summarized in Table 1, were limited by inadequate statistical power, low event rates, high drop-out rates, treatment-associated changes in fluid status, and often, poor methodologic quality, enrolment of prevalent PD patients, and single-center designs. Recently, our group published the findings of the BalANZ study, an investigator-initiated prospective, open-label, randomized placebo-controlled phase IV trial of neutral-pH lactate-buffered low-GDP fluid (Balance: Fresenius Medical Care, Bad Homburg, Germany) compared with conventional lactate-buffered standard PD solutions (Stay•Safe: Fresenius Medical Care). The 185 patients involved came from 16 centers across Australia, New Zealand, and Singapore (29). The principal findings of the trial were that, compared with administration of conventional fluid, administration of the biocompatible fluid resulted in a significant delay in the onset of anuria, a significant 36% reduction in peritonitis rates, and a numerically slower, though not statistically significant, decline in residual renal function (particularly in the first year). Patients in the biocompatible group also experienced an early rise in peritoneal solute transport rate, accompanied by lower peritoneal ultrafiltration volumes and higher urine volumes. However, the two groups showed no differences with respect to indices of overall fluid status. The trial was not adequately powered to assess technique or patient survival. In the current issue of Peritoneal Dialysis International, Lai et al. (30) report the results of a randomized controlled trial, conducted in four Hong Kong centers, in which 125 incident PD patients assigned to receive either biocompatible fluid [Gambrosol Trio: Gambro Lundia AB, Lund, Sweden (n = 41); Physioneal 40, Baxter Healthcare Corporation, Deerfield, IL, USA (n = 12); Balance (n = 5)] or conventional fluid [Dianeal PD-2: Baxter Healthcare Corporation (n = 43); ANDY-Disc: Fresenius Medical Care (n = 24)] for an average period of 3.6 years. The composite co-primary outcomes of the study were a biochemical profile of 18 cytokines, growth factors, adipokines, and cardiac biomarkers in both serum and dialysate effluent, evaluated at an average period of 2.3 years; and dialysis adequacy [residual glomerular filtration rate (GFR), daily urine output, total and peritoneal Kt/V, total and peritoneal creatinine clearance] evaluated at an average duration of 3.6 years. Compared with controls, patients