Background
The peritoneum is composed of a monolayer of mesothelial cells resting upon a thin basement membrane [
1,
2]. Continuous exposure to conventional peritoneal dialysis (PD) solutions contributes to progressive peritoneal injury, is an important source of local inflammation that can result in adverse functional outcomes, such as higher peritoneal solute transport rate (PSTR), a widely accepted risk factor for mortality and technique failure in PD patients [
3‐
5].
Interleukin-6 (IL-6) is an immuno-modulatory cytokine that plays a critical role in many innate and acquired inflammatory processes [
6]. It is secreted in large quantities by peritoneal mesothelial cells in response to inflammatory stimuli and modulated by exposure to PD solutions [
7]. Interest in IL-6 and its role in intraperitoneal inflammation in PD patients is increasing as a result of the link from single centre studies to changes in PSTR, data that has now been corroborated by recent analysis from the large multicenter GLOBAL study [
8‐
10]. To date there are no data on the impact of biocompatible PD solution use on IL-6 levels and its relationship to PSTR. Improvement in peritoneal membrane morphology from the use of more biocompatible solutions, characterized by neutral pH with lowered glucose degradation product (GDP), has been suggested previously [
11,
12]. Therefore, its use may lead to changes in the intraperitoneal inflammatory milieu with potential benefits to peritoneal membrane function and improved host defence against peritonitis. Although a number of randomized controlled trials (RCT) have reported comparable dialysate IL-6 levels from biocompatible and standard solutions use [
13‐
16], these studies were limited by open and variable prescription, large drop out rates (>20%) [
16], cross-over study designs with the risk of carry-over effect [
14], risk of bias from including biocompatible solutions with variable GDP levels in the treatment group [
15], and a lack of accounting for the confounding effect of peritonitis [
13‐
16]. The utility of dialysate IL-6 as a potential predictor of adverse peritoneal membrane function has not been studied within an RCT setting.
The aims of the present study were to describe the trend in dialysate IL-6 concentration and IL-6 appearance rate (IL-6 AR) in incident PD patients, to explore the utility of dialysate IL-6 as a predictor of PSTR and peritonitis in this patient group and to evaluate the impact of neutral pH, low GDP PD solutions on these outcomes.
Discussion
The present investigation is the first study to examine the impact of biocompatible PD solution use on the utility of IL-6 as a predictor of higher PSTR and peritonitis in incident PD patients. A statistically significant increase in dialysate IL-6 concentrations with longer time on PD was observed whilst the type of PD solution (biocompatible vs. standard) and loss of residual renal function exerted no effect on its levels. Higher levels of dialysate IL-6 and the use of standard solutions were predictive of a greater increase in PSTR. The risk of peritonitis was associated with PD solution (biocompatible solution reduced the risk) but not baseline IL-6 levels.
An increase in dialysate IL-6 levels with a longer PD duration has been inconsistently reported by several groups [
8,
13,
23] including the recently completed GLOBAL fluid study, which did not show any association between the duration of PD and dialysate IL-6 levels in incident and prevalent PD patients [
10]. While results from the GLOBAL study were strengthened by a large number of patients (n = 959), no data were presented pertaining to a longitudinal trend in dialysate IL-6 levels nor was there a detailed examination of the impact of biocompatible PD solution use on intraperitoneal inflammatory markers. In contrast, the extension study of the Balnet trial observed a significant increase in dialysate IL-6 levels from baseline at 24 months in both biocompatible (143 ± 69.6 pg/mL vs. 57.6 ± 54.5 pg/mL;
P < 0.001) and control groups (121 ± 69 pg/mL vs. 47 ± 31.2 pg/mL;
P < 0.001) [
13]. There was no significant difference between the two groups (
P = 0.38). However, the sample size was small (n = 46), and the potential impact of peritonitis on dialysate IL-6 levels was not separately explored. The latter factor might have been important given the discrepant number of peritonitis episodes between biocompatible and control groups (19 vs. 6 episodes, respectively), with a significantly worse peritonitis-free survival in the biocompatible group (
P = 0.03). The present investigation also observed a statistically significant increase in dialysate IL-6 levels with longer PD duration with a lack of observed difference between biocompatible and standard types of PD solution. The robustness of the findings was confirmed by a sensitivity analysis performed in the peritonitis-free cohort. Nevertheless, there is conflicting information about the effect of biocompatible PD solutions on dialysate IL-6 levels. For instance, the Bicarbonate/Lactate Study group (n = 92) reported a significant decrease in dialysate IL-6 levels at six months (
P = 0.01) in the patients who received biocompatible solutions [
24]. Although the difference in results might have stemmed from examining the biocompatible solution that contained bicarbonate-buffer, another study (n = 55) examining bicarbonate-buffer based solution reported comparable dialysate IL-6 levels between biocompatible and standard solution groups [
14]. Therefore, the true effect of biocompatible solutions on the level of intraperitoneal inflammation, defined by IL-6 concentrations, remains uncertain. Furthermore, the rate of loss of residual renal function exerted no significant impact on dialysate IL-6 levels. These results are supported by findings from the GLOBAL study where urine volume had no significant impact on dialysate IL-6 levels in incident PD patients (
P = 0.2) [
10].
Another important observation from the current investigation was the significant role of an individual’s baseline IL-6 levels in predicting future levels. Patients with low baseline IL-6 levels yielded the greatest increase in dialysate IL-6 concentrations over time, whereas the opposing relationship held true for those with higher baseline IL-6 levels (Additional file
1: Figure S1). This highlights the importance of performing appropriate statistical analyses to accommodate intra-individual correlation and inter-individual variation, as adopted in the present study.
Similarly, due to the presence of inter-individual variation in PSTR levels, a change in PSTR from baseline for each individual was examined. Significant associations between increasing PSTR and higher IL-6 levels, the use of standard PD solutions and longer PD duration were observed. These results are in keeping with the findings from the GLOBAL study [
10]. An association between a greater increment in IL-6 with increasing PSTR (r = 0.306,
P = 0.002) was previously reported in a prospective 12-month longitudinal observational study (n = 187) in incident PD patients [
23]. This study allowed for patients to receive either biocompatible or standard solutions, and observed an increase in PSTR in patients receiving standard solutions over time, unlike those who were treated using biocompatible solutions who maintained a stable PSTR. However, whether PD solution type and/or dialysate IL-6 levels had differing or independent effects on PSTR was not examined. Furthermore, the choice of therapy (biocompatible vs. standard) was at the discretion of each patient’s treating physician, thereby introducing the risk of selection bias. In contrast, the cohorts from the present study were participants of a RCT with well-balanced baseline characteristics, at low risk of selection bias and with longer follow-up duration (24 months). In addition, when PSTR was re-examined in those free of peritonitis, a consistent association with dialysate IL-6 levels was observed. These associations are certainly biologically plausible as higher PSTRs are considered a functional consequence of morphological alterations at the level of the peritoneal membrane (i.e. peritoneal membrane injury), which are likely to be a result of or lead to more marked intraperitoneal inflammation.
Progressive and cumulative peritoneal injury, mediated by repeated exposures to PD solutions [
2], might not only manifest with changes in the inflammatory milieu but also increase the risk of developing further problems (e.g. peritonitis) as the balance of peritoneal homeostasis and host defence are altered [
25]. In this respect the IL-6 and associated signaling cascades play a key role in controlling host defence and leukocyte trafficking during infection [
6,
26]. In fact, a retrospective observational study of incident PD patients (n = 31) receiving standard solutions reported higher baseline dialysate IL-6 concentrations in patients who developed peritonitis (58.4 ± 12.6 pg/mL) compared to those who remained peritonitis-free (20.3 ± 8.7 pg/mL,
P = 0.07) [
8]. The difference however did not reach statistical significance, and the study was limited by its small sample size and single-centre design. Similar to their findings, a median dialysate IL-6 concentration was greater in those who experienced peritonitis in the present study, but was not statistically significant when compared to those who did not develop peritonitis. Furthermore, only the use of standard PD solutions, and not baseline IL-6, was predictive of shorter time to first peritonitis. These findings support the results from pre-clinical trials where the use of biocompatible solutions has been associated with an improvement in host cell defence [
27]. The mechanisms contributing to the beneficial effect of biocompatible solutions are clearly complex but its ‘protective effect’ may extend beyond improved preservation of the peritoneal membrane. These beliefs have been challenged by findings from a recent observational study that reported a shorter time to first peritonitis with the use of biocompatible solutions [
28]. However, this study has several limitations. These include a risk of indication bias with residual confounding, relatively low usage of biocompatible solutions in the cohort suggestive of underlying selection bias, and classifying biocompatible solutions from different manufacturers with varying GDP content in the biocompatible group which could have compromised the beneficial effect from the use of solutions that are truly low in their GDP content. On the other hand, although the balANZ trial was able to clearly demonstrate a lowered risk of peritonitis with the use of biocompatible solutions, it was one of the secondary outcomes measured during the trial [
17,
20]. Therefore, in order to evaluate the true effect of biocompatible solutions on peritonitis risk, a well designed, multicenter, multinational RCT adequately powered to examine peritonitis as a primary outcome is needed.
The present study is strengthened by its long follow-up duration in comprehensively described participants of an RCT. It is one of the largest longitudinal studies to date exploring the utility of IL-6 in predicting important patient-level clinical outcomes and the influence of biocompatible PD solution use. Also, given the cause-and-effect relationship between peritonitis and IL-6 levels, a sensitivity analysis including only peritonitis-free patients was performed to confirm the robustness of the findings.
However, the conclusions that can be drawn from the study are challenged by several limitations. First, the balANZ trial was a RCT with primary outcome measure of residual renal function decline, rather than a biomarker study. Therefore, the study design did not account for potential biological and pre-analytical sources of variations of IL-6, which could have affected the measured results. Second, the baseline PSTRs were not true baseline values as they were obtained at one month after study commencement. Thirdly, by selecting patients who had completed the 24-month follow-up, this might have introduced the risk of selection bias. Fourthly, some of the risk factors associated with a shorter time to peritonitis, such as educational level, [
29] were not available and could not be adjusted for in the relevant analyses. And lastly, although it is one of the largest studies to date, the size is relatively small and may have increased the chance of Type II statistical error especially when comparing the outcomes between biocompatible and control groups.
Appendix
Collaborators (balANZ Investigators)
Australian Centres: G Rangan, L Liew, Blacktown Hospital, Sydney (NSW); H Kulkarni, U Steinwandel, Fremantle Hospital, Fremantle (WA); B Jones, L Garvey, John Hunter Hospital, Newcastle (NSW); M G Suranyi, M Gilbert, Liverpool Hospital, Sydney (NSW); F G Brown, I Abraham, J Nandkumar Monash Medical Centre, Melbourne (VIC); A Coburn, V Bali, Princess Alexandra Hospital, Brisbane (QLD); S McDonald, S Frasca, M Hockley, C Russ, The Queen Elizabeth Hospital, Adelaide (SA); T J Elias, K Bannister, M Hockley, K Pirone, Royal Adelaide Hospital (SA); D Ranganathan, L Williams, Royal Brisbane Hospital, Brisbane (QLD); K Warr, G Smith, Perth (WA); N Boudville, S Pellicano, Sir Charles Gairdner Hospital, Perth (WA); R Langham, E O’Flaherty, St Vincents Hospital, Melbourne (VIC).
New Zealand Centres: J Schollum, L Reed, L Anderson Dunedin Hospital, Dunedin; D Voss, B Jagannathan, P Nicholls Middlemore Hospital, Auckland.
Singapore Centres- M WY Foo, CK Tam, Singapore General Hospital, Singapore; R Lee, Tang Tock Seng Hospital, Changi General Hospital, Singapore; SH Tan Kidney and Medical Clinic, Gleneagles Medical Centre, Singapore.
Competing interests
David Johnson is a consultant for Baxter Healthcare Pty Ltd and has previously received research funds from this company. He has also received speakers’ honoraria and research grants from Fresenius Medical Care. He has previously been a consultant to Gambro Pty Ltd. He is an International Society of Peritoneal Dialysis Councillor and is a current recipient of a Queensland Government Health Research Fellowship. Yeoungjee Cho is a current recipient of Australian Postgraduate Award and is a recipient of 2012 Jacquot Research Entry Scholarship. Carmel Hawley has received research grants from Baxter Healthcare Pty Ltd and Gambro Pty Ltd, and has been a consultant to Fresenius Medical care. Margaret Clarke is an employee of Fresenius Medical Care. Remaining authors declare no conflicts of interest.
Authors’ contributions
The study was conceived, designed, and supervised by authors YC, DWJ, CH, NT, DV (non-Fresenius employee). MC was involved in the acquisition of the data. YC wrote the first draft of the manuscript, subsequent drafts were reviewed and approved by YC, DWJ, DV, CH, EP, MC, and NT.