PD Solutions and Peritoneal Health

The success of peritoneal dialysis (PD) is critically dependent on a healthy, functional peritoneal membrane. However, the act of PD itself has been associated with progressive structural changes of the peritoneal membrane over time, including histopathologic evidence of mesothelial cell loss, submesothelial extracellular matrix expansion, and neoangiogenesis (1). In patients with rare but extreme cases, these pathologic changes can ultimately lead to the development of encapsulating peritoneal sclerosis. Functionally, these structural changes typically manifest as an increase in peritoneal solute transport rate (PSTR), which in turn, may lead to impaired peritoneal ultrafiltration, membrane failure, technique failure, and mortality (2). The structural and functional derangements of the peritoneal membrane with time on PD have been variously attributed to uremia, peritonitis episodes, and repeated exposure to PD solutions (1). Conventional PD solutions possess several unphysiologic characteristics, including acidic pH and high levels of glucose degradation products (GDPs), which in turn, have been shown to induce a range of deleterious membrane effects in experimental models of PD, including reduced mesothelial cell viability and growth, enhanced advanced glycation end product formation, epithelial-mesenchymal transdifferentiation, augmented fibroblast collagen synthesis, and reduced health and function of peritoneal phagocytic cells (1,3,4). In an attempt to mitigate these adverse effects of conventional PD solutions, manufacturers have developed neutral pH, low or ultralow GDP PD solutions (also called “biocompatible” solutions), which have consistently been shown to exert favorable effects on the peritoneal membrane in preclinical studies (5). Furthermore, they have been associated with an attenuation of peritoneal interstitial sclerosis and hyalinizing vasculopathy in a peritoneal membrane biopsy study (6) and a stabilization of PSTR trajectory over time in the Balance in Australia and New Zealand Peritoneal Dialysis Patients (BalANZ) Study, a multinational, multicenter, prospective, open label, randomized, controlled trial (RCT) involving 185 incident adult patients on PD who were randomly allocated to receive biocompatible or standard solutions for 2 years (7). A subsequent meta-analysis of RCTs comparing the effect of biocompatible solutions against conventional solutions has not been able to identify any significant difference in PSTR between these two treatment options (five studies; 363 patients; mean difference, 0.01; 95% confidence interval, −0.02 to 0.04; I2=41%; P=0.15) (8), although few studies have undertaken comprehensive longitudinal follow-up of PSTR. Therefore, the long-term effects of biocompatible PD solutions on the peritoneal membrane have not been well studied and remain controversial. In this issue of the Clinical Journal of the American Society of Nephrology, Elphick et al. (9) examined the relationship between PD solution type and PSTR trajectory in 366 patients on incident and prevalent PD followed long term (mean, 12.8 years conventional; 7.5 years biocompatible) as part of the Global Fluid Study, a multinational, multicenter, prospective, observational cohort study involving ten centers in the United Kingdom, Canada, and South Korea. Of the 960 patients enrolled in the study, 366 (38%) had exclusively used either conventional (n=295) or biocompatible (n=71) solutions and had two or more PSTR measurements (performed on an approximately 6-month basis), with at least one measurement within the first 12 months after PD commencement. The key findings of the study were that, compared with conventional solutions, biocompatible PD solutions were associated with a significantly lower mean adjusted PSTR 2 months after the start of PD (0.67 versus 0.72; P=0.02), which then increased for the first 2 years of PD followed by stabilization. In contrast, patients who received conventional PD solutions showed a continuous increase in PSTR over time. These effects were robust across a range of different analytic approaches, and they were independent of baseline inflammation or other predictors of increasing PSTR, including average dextrose exposure and peritonitis. Perhaps one of the most fascinating results from this study was a lack of peritonitis-induced rise in PSTR in patients receiving biocompatible solutions, which contrasted markedly with the appreciable rise observed in the conventional solutions group (0.02; 95% confidence interval, 0.01 to 0.03; P<0.001). Despite the fact that a smaller proportion of patients receiving biocompatible PD solutions experienced one or more peritonitis episodes during the study compared with those receiving conventional solutions (41% versus 57%, respectively), PSTR trend was examined against each peritonitis episode. Moreover, the causative organisms and outcomes after the first peritonitis episode were comparable, although it is possible that the peritonitis episodes may have been less severe in patients receiving biocompatible solutions, such as was shown in the BalANZ Study (10). The authors concluded that the findings “add weight to the notion that biocompatible solutions may have long-term clinical benefits” on the peritoneal membrane compared with conventional solutions (9). The strengths of the Global Fluid Study are its large sample size, relatively small amount of missing data (<5%), robust statistical methodology, prolonged follow-up duration, and the involvement of participants from varying countries and centers, which greatly improved its generalizability. Balanced against these strengths, the study was limited by its nonrandomized design (thereby preventing the drawing of causal inferences), an imbalance in baseline characteristics between the two groups (raising the possibility of indication bias with residual confounding), use of prevalent patients (raising the possibility of Neyman bias), variable timing of PSTR measurements, a lack of PSTR data within the first 2 months of PD, different follow-up durations between the two groups, and exclusion of 62% of the population due to either a lack of repeat PSTR measures or switches between conventional and biocompatible solutions (thereby raising the possibility of ascertainment bias). The findings of the Global Fluid Study partially support and reinforce those of the earlier BalANZ Study (7), which reported that the PSTR trajectory remained stable in patients receiving biocompatible PD solutions but continued to increase in controls receiving conventional solutions. Consequently, the between-group difference in PSTR gradient over 2 years was both statistically significant and clinically meaningful (mean difference, −0.004 per month; 95% confidence interval, −0.01 to <−0.01; P<0.001) (7). However, in contrast to the Global Fluid Study, in which initial 2-month PSTR values were lower in the biocompatible group than in controls, the BalANZ Study observed that patients receiving biocompatible solutions had higher 1-month dialysate-to-plasma creatinine ratios than controls (0.67±0.10 versus 0.62±0.10; P=0.002). The apparent disparity in findings between the Global Fluid Study and the BalANZ Study may be explained by differences in study design (observational study versus RCT), patient populations (mix of incident/prevalent versus incident only), biocompatible solution type (a mix of low [82%] and ultralow [18%] GDP solutions versus solely ultralow GDP solution), and timing of PSTR measurements (variable versus prospectively scheduled). For example, the “baseline” PSTR measurement in the Global Fluid Study was approximately at 6 months (median times from PD commencement to first measure were 0.52 years [biocompatible solution] and 0.53 years [conventional solution]) compared with month 1 for the BalANZ Study. These differences could have led to inconsistent results, and one cannot directly compare outcomes from these studies. Moreover, although the Global Fluid Study was strengthened by its relatively large size, only about 20% of included patients received biocompatible solutions, which could have increased the effect of results with extreme values. Therefore, considering the results of the Global Fluid Study in the context of preexisting evidence, what implications do the findings reported by Elphick et al. (9) have for clinicians, patients, caregivers, and policymakers? Foremost, the cumulative evidence to date suggests that biocompatible and conventional PD solutions exert differential effects on peritoneal membrane structure and function on the basis of peritoneal biopsy findings and PSTR measurements. The reported effects of biocompatible solutions on the peritoneal membrane would seem to include less severe histologic changes, stabilization of PSTR (despite early differences in PSTR values), and an attenuation of the effect of peritonitis on the peritoneal membrane, which would generally be regarded by clinicians as beneficial. However, because of a paucity of well designed trials with adequate sample sizes and follow-up, it remains uncertain as to whether these effects will translate into improvements in patient-reported experiences, patient-reported outcomes, or clinical outcomes (such as peritonitis free, technique, and patient survival). This yawning evidence gap will continue to fuel debate between the biocompatible enthusiasts and critics as well as engender confusion in patients with PD and inequitable access to these solutions until high-quality evidence through international, high-quality research trial collaboration becomes available. This approach, rather than ill-informed opinion, is the only way to definitively answer patient-important questions, such as whether biocompatible solutions improve the peritoneal and overall health of patients treated with maintenance PD. Disclosures Y.C. is a current recipient of an Australian National Health and Medical Research Council Early Career Fellowship. D.W.J. has received consultancy fees, research grants, speaker’s honoraria, and travel sponsorships from Baxter Healthcare and Fresenius Medical Care. He has also received consultancy fees from Astra Zeneca and travel sponsorships from Amgen. He is a current recipient of an Australian National Health and Medical Research Council Practitioner Fellowship.

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