Associations between dialysate interleukin-6 and Tie-2 and peritoneal solute transport rate and outcomes for patients undergoing peritoneal dialysis: A prospective cohort study

Objectives: We designed this prospective observational study to clarify the associations between dialysate IL-6, a marker of ongoing peritoneal inflammation, Tie2, an important factor in angiogenesis in the peritoneum, and a high peritoneal solute transport rate (PSTR) in patients undergoing peritoneal dialysis (PD) and to investigate their outcome predictive roles. Methods: A total of 60 stable continuous ambulatory peritoneal dialysis (CAPD) patients from a single center in China were analyzed in this prospective study. We measured dialysate levels of IL-6 and Tie-2 using ELISAs. Our primary study endpoint was all-cause mortality with 10 years’ follow-up. Results: For the evaluation of PSTR, we used the Dialysis/Plasma creatinine (D/Pcr) ratio. We subdivided the patients into two groups for statistical evaluation: low and low average D/Pcr (<0.64; L/A), and high and high average D/Pcr (≥0.65; H/A) transporters. The mean levels of dialysates IL-6 (21.71 ± 8.88 pg/mL) and Tie-2 (1.23 ± 0.43 ng/mL) were significantly higher in the H/A (high and high average, group than those in the L/A group (13.94 ± 5.43 pg/mL, p<0.001 and 0.95 ± 0.43 ng/mL, p=0.019; respectively). Moreover, IL-6 and Tie-2 were positively correlated with D/Pcr (r=0.366, p=0.004 and r=0.402, p=0.001; respectively). Both dialysates IL-6 and Tie-2 were independent determinants of a high peritoneal solute transport rate. After follow-up for 42.65±18.08 months, 30 patients (50.0%) had died. An increased D/Pcr increased the risk of all-cause mortality in patients with CAPD (p=0.018), but the dialysates IL-6 and Tie2 were not independent predictors of all-cause mortality (p>0.05). Conclusion: Our results suggest that patients undergoing CAPD have a high peritoneal solute transport status with local peritoneal inflammation and angiogenesis. Increased D/Pcr is a relative risk factor for mortality and technique failure in patients undergoing CAPD. doi: https://doi.org/10.12669/pjms.37.4.4328 How to cite this:Hang Y, Yan H, Zhang H, Li Z, Fang W. Associations between dialysate interleukin-6 and Tie-2 and peritoneal solute transport rate and outcomes for patients undergoing peritoneal dialysis: A prospective cohort study. Pak J Med Sci. 2021;37(4):---------. doi: https://doi.org/10.12669/pjms.37.4.4328 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Effluent Osteopontin levels reflect the peritoneal solute transport rate

Long-term peritoneal dialysis (PD) is accompanied by low-grade intraperitoneal inflammation and may eventually lead to peritoneal membrane injury with a high solute transport rate and ultrafiltration failure. Osteopontin (OPN) is highly expressed through the stimulation of pro-inflammatory cytokines in many cell types. This study aimed to investigate the potential of OPN as a new indicator of peritoneal deterioration. One hundred nine continuous ambulatory PD patients were analyzed. The levels of OPN and IL-6 in peritoneal effluents or serum were analyzed by ELISA kits. The mean effluent OPN concentration was 2.39 ± 1.87 ng/mL. The OPN levels in drained dialysate were correlated with D/P Cr (p < 0.0001, R = 0.54) and D/D0 glucose (p < 0.0001, R = 0.39). Logistic regression analysis showed that the OPN levels in peritoneal effluents were an independent predictive factor for the increased peritoneal solute transport rate (PSTR) obtained by the peritoneal equilibration test (p < 0.001). The area under the receiver operating characteristic curve of OPN was 0.84 (95% CI: 0.75–0.92) in predicting the increased PSTR with a sensitivity of 86% and a specificity of 67%. The joint utilization of effluent OPN with age, effluent IL-6, and serum albumin further increased the specificity (81%). Thus, OPN may be a useful indicator of peritoneal deterioration in patients with PD.

Osteopontin levels in the drained dialysate reflect the peritoneal solute transport rate

Background and objectives: Long-term peritoneal dialysis (PD) is accompanied by low-grade intraperitoneal inflammation, may eventually lead to peritoneal membrane injury with high solute transport rate and ultrafiltration failure. Osteopontin(OPN) is highly expressed with the pro-inflammatory cytokines stimulation in many cell types, and evolves in the process of tissue fibrosis. This study aimed to investigate the potential of OPN as a new indicator of peritoneal injury. Methods: We analyzed a total of 125 PD patients with end-stage renal disease, including 16 patients with continuous ambulatory PD(CAPD)-related peritonitis and 109 patients without peritonitis in a single renal center. The OPN levels in the overnight peritoneal effluents or in serum were analyzed using ELISA. In HMrSV5 cells, The OPN and fibronectin(FN) protein expression were identified using western blot analysis. Results: The OPN levels in overnight drained dialysate were significantly correlated with D/P Cr (P < 0.0001, R =0.54) and D/D0 glucose (P < 0.0001 R=-0.39). Logistical regression analysis showed that the OPN levels in peritoneal effluents was an independent predictive factor for the increased peritoneal solute transport rate (PSTR) (p < 0.001). The area under the receiver operating characteristic (ROC) curve of the OPN-PSTR model for identifying PSTR was 0.88, with 95% confidence interval (CI):0.81-0.95. The OPN was more abundant in peritoneal effluents of the CAPD-related peritonitis group compared with the patients without peritonitis (18.64±13.04 vs. 2.23±1.63 ng/ml, p<0.001). In the in vitro experiment, lipopolysaccharides(LPS) increased the OPN expression in HMrSV5 cells, whereas downregulation of OPN suppressed FN induction with transforming growth factor-β1(TGF-β1)stimulation. Conclusions: The OPN levels in drained dialysate were independently correlated with peritoneal transport status in accordance with the PET results. OPN was highly expressed in effluents in patients with CAPD-related peritonitis. Peritoneal mesothelial cells displayed a high expression of OPN under inflammatory stimuli and OPN was likely to be implicated in the progression of peritoneal fibrosis. Thus, OPN may be a useful indicator of peritoneal injury in patients with PD. Keywords: peritoneal dialysis, osteopontin, peritoneal injury, peritoneal solute transport rate

Excessive salt intake increases peritoneal solute transport rate via local tonicity-responsive enhancer binding protein in subtotal nephrectomized mice

BackgroundHigh peritoneal transport is associated with high mortality and technical failure in peritoneal dialysis (PD). Baseline peritoneal solute transport rate (PSTR) as measured by the peritoneal equilibration test (PET) within 6 months after PD initiation varies between patients. Sodium is reported to be stored in the skin or muscle of dialysis patients. This study investigated whether excessive salt intake in uremic mice caused peritoneal alterations without exposure to PD fluid.MethodsSham-operated (Sham) and subtotal nephrectomized (Nx) mice were randomly given tap water or 1% sodium chloride (NaCl)-containing water for 8 weeks. PET was then performed to evaluate peritoneal function. Human mesothelial cell line Met-5A was used for in vitro studies.ResultsWe observed higher PSTR in Nx mice with 1% NaCl-containing drinking water (Nx + salt) compared with those with tap water (Nx + water), along with enhanced angiogenesis and inflammation in the peritoneum. Blockade of interleukin (IL)-6 signaling rescued peritoneal transport function in Nx + salt mice. In cultured Met-5A, additional NaCl in the medium upregulated IL-6 as well as vascular endothelial growth factor-A, associated with increased expression and nuclear translocation of tonicity-responsive enhancer binding protein (TonEBP). Knockdown of TonEBP lowered the induction caused by high tonicity. Peritoneal TonEBP expression was higher in Nx + salt mice, while removal of high-salt diet lowered TonEBP level and improved peritoneal transport function.ConclusionsExcessive dietary salt intake caused peritoneal membrane functional and structural changes under uremic status. TonEBP regulated hypertonicity-related inflammatory changes and might play a crucial role in high baseline peritoneal transport.

Associations between Peritoneal Glucose Exposure, Glucose Degradation Product Exposure, and Peritoneal Membrane Transport Characteristics in Peritoneal Dialysis Patients: Secondary Analysis of the balANZ Trial

Background Glucose is the most commonly used osmotic medium in peritoneal dialysis (PD) solutions, and its use has been associated with both local and systemic adverse effects. Previous, single-center, observational cohort studies have reported conflicting findings regarding whether a relationship exists between peritoneal glucose exposure and peritoneal small solute transport rate. Methods In this secondary analysis of the balANZ multi-center, multinational, randomized controlled trial of a neutral pH, ultra-low glucose degradation product (biocompatible) versus conventional PD solutions over a 2-year period, the relationship between time varying peritoneal glucose exposure and change in peritoneal solute transport rate, (measured as dialysate to plasma creatinine ratio at 4 hours [D:PCr4h]), was evaluated using multivariable, multilevel linear regression. Baseline peritoneal glucose exposure was also assessed as either a continuous or categorical variable. Results The study included 165 patients (age 58.1 ± 14.2 years, 55% male, 33% diabetic). Peritoneal glucose exposure increased over time (coefficient 1.49, 95% confidence interval [CI] 1.07 – 1.92 and was not significantly associated with change in D:PCr4h (coefficient 0.00004, 95% CI -0.0001 – 0.0002, p = 0.68). Similar results were found when peritoneal glucose exposure was examined as a baseline continuous or categorical variable. A significant 2-way interaction was observed with PD solution type, whereby a progressive increase in D:PCr4h was seen in the patients receiving conventional PD solution, but not in those receiving biocompatible solution. Conclusions Increases in peritoneal solute transport rate in PD patients over time were not associated with peritoneal glucose exposure, although a strong and positive association with PD solution glucose degradation product content was identified. Peritoneal glucose exposure may be a less important consideration than peritoneal glucose degradation product exposure with respect to peritoneal membrane function over time.

Biocompatible Solutions and Long-Term Changes in Peritoneal Solute Transport

Background and objectivesThe inflammation-driven increase in peritoneal solute transport rate that occurs during long-term peritoneal dialysis is associated with higher mortality, hospitalization, and encapsulating peritoneal sclerosis. Because biocompatible solutions were developed to mitigate these effects, we examined the association with their use and longitudinal peritoneal solute transport rate.Design, setting, participants, & measurementsWe analyzed subjects from the multinational prospective Global Fluid Study with three or more peritoneal solute transport rate measurements >2 months from the start of peritoneal dialysis. Follow-up was for 7.5 years (median, 2.3 years; interquartile range, 1.8–3.6) in biocompatible solutions and 12.8 years (median, 3.2 years; interquartile range, 1.9–4.3) for standard solutions. Using a random intercept/slopes multilevel model, we examined the association of patients using biocompatible solutions and peritoneal solute transport rate over time, adjusting for center effects, dialysate dextrose concentration, baseline dialysate IL-6 concentration, icodextrin use, residual kidney function, and peritonitis.ResultsOf 366 patients, the 71 receiving biocompatible solutions throughout their time on peritoneal dialysis had a mean adjusted dialysate-to-plasma creatinine ratio of 0.67 compared with 0.72 for standard solutions (P=0.02). With duration of treatment, there was a continuous increase in peritoneal solute transport rate in patients using standard solutions (range, 2 months to 4 years). In contrast, patients using biocompatible solutions had peritoneal solute transport rates that plateaued after 2 years of therapy. These changes in peritoneal solute transport rate were independent of baseline inflammation and time-varying predictors of faster peritoneal solute transport rate. In patients suffering episodes of peritonitis while using standard solutions, there was an associated increase in peritoneal solute transport rate of 0.020 (95% confidence interval, 0.01 to 0.03) per episode, whereas in patients using biocompatible solutions, there was no change in this parameter (−0.014; 95% confidence interval, −0.03 to <0.01).ConclusionsThese data suggest that a different temporal pattern in changes in peritoneal solute transport rate occurs during the course of peritoneal dialysis according to solution type and that patients using biocompatible solutions may avoid the increase in solute transport associated with peritonitis.

Higher Dialysate Matrix Metalloproteinase-2 Levels are Associated with Peritoneal Membrane Dysfunction

♦ Background Peritoneal dialysis (PD) patients develop progressive and cumulative peritoneal injury with longer time spent on PD. The present study aimed to a) describe the trend of peritoneal injury biomarkers, matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1), in incident PD patients, b) to explore the capacity of dialysate MMP-2 to predict peritoneal solute transport rate (PSTR) and peritonitis, and c) to evaluate the influence of neutral pH, low glucose degradation product (GDP) PD solution on these outcomes. ♦ Methods The study included 178 participants from the balANZ trial who had at least 1 stored dialysate sample. Changes in PSTR and peritonitis were primary outcome measures, and the utility of MMP-2 in predicting these outcomes was analyzed using multilevel linear regression and multilevel Poisson regression, respectively. ♦Results Significant linear increases in dialysate MMP-2 and TIMP-1 concentrations were observed ( p < 0.001), but neither was affected by the type of PD solutions received (MMP-2: p = 0.07; TIMP-1: p = 0.63). An increase in PSTR from baseline was associated with higher levels of MMP-2 ( p = 0.02), and the use of standard solutions over longer PD duration ( p = 0.001). The risk of peritonitis was independently predicted by higher dialysate MMP-2 levels (incidence rate ratio [IRR] per ng/mL 1.01, 95% confidence interval [CI] 1.005 – 1.02, p = 0.002) and use of standard solutions (Biocompatible solution: IRR 0.45, 95% CI 0.24 – 0.85, p = 0.01). ♦ Conclusion Dialysate MMP-2 and TIMP-1 concentrations increased with longer PD duration. Higher MMP-2 levels were associated with faster PSTR and future peritonitis risk. Administration of biocompatible solutions exerted no significant effect on dialysate levels of MMP-2 or TIMP-1, but did counteract the increase in PSTR and the risk of peritonitis associated with the use of standard PD solutions. This is the first longitudinal study to examine the clinical utility of MMP-2 as a predictor of patient-level outcomes.