Systemic and Intraperitoneal Interleukin-6 System during the First Year of Peritoneal Dialysis

Abstract

Objective To investigate if intraperitoneal and systemic interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) are related to each other and to peritoneal solute transport rate (PSTR). Design Longitudinal study in retrospectively selected patients. Setting Peritoneal dialysis (PD) unit of a university-based hospital. Patients and Methods 31 PD patients on treatment with conventional glucose-based solutions participated in a longitudinal study. IL-6 and sIL-6R were measured in plasma and overnight effluent, both at baseline and after 12 ± 2 months on PD. C-reactive protein (CRP) and serum albumin were used as surrogate markers of inflammation. PSTR of small solutes was evaluated using the dialysate-to-plasma ratio (D/P) of creatinine after a 4-hour dwell; PSTR of large solutes was evaluated using the 24-hour D/P ratio of albumin. Results D/P creat increased over time (0.67 ± 0.15 vs 0.80 ± 0.11, p < 0.0001) and correlated to D/P albumin only at the baseline evaluation. Patients with plasma IL-6 ≥median had higher ( p < 0.005) D/P creat at baseline [0.74 (0.62 – 0.87)] compared to patients with IL-6 < median [0.57 (0.47 – 0.66)]. Dialysate IL-6 at baseline was also higher ( p < 0.05) in patients with plasma IL-6 ≥median [24.7 (16.5 – 38.5) pg/mL] compared to patients with IL-6 < median [14.1 (10 – 25.7) pg/mL]. Neither CRP nor albumin changed over time on PD, although they were closely linked to plasma IL-6 levels. A strong positive correlation was found between D/P creat and dialysate IL-6 (rho = 0.77, p < 0.0001) at baseline, but not at 1 year. In contrast, there was a significant correlation between D/P creat and dialysate sIL-6R (rho = 0.39, p < 0.05) at 1 year, but not at baseline. At 1 year, 17 patients with increasing PSTR had higher increases in dialysate IL-6 (28 ± 26 vs –21 ± 78 pg/mL, p < 0.05) and levels of dialysate sIL-6R (693 ± 392 vs 394 ± 274 pg/mL, p = 0.05) compared to patients with stable PSTR ( n = 11). Patients who had peritonitis presented higher baseline serum IL-6 concentration (6.8 ± 1.0 pg/mL) compared with patients without peritonitis (4.0 ± 0.6 pg/mL, p < 0.05). Finally, both at baseline and after 1 year, there were significant correlations between plasma and dialysate IL-6 (rho = 0.46, p < 0.05, and rho = 0.40, p < 0.05) respectively. Conclusions These findings indicate that, ( 1 ) intraperitoneal and systemic inflammation increase in PD patients during the first year of therapy; ( 2 ) intraperitoneal and systemic inflammation may be interrelated and the IL-6 system may be the link; ( 3 ) the IL-6 system (both intraperitoneal and systemic) is associated with PSTR, particularly in the early phase of PD treatment, in which small and large solute transport are linked. Signs of a transition between acute and chronic inflammation were observed in the follow-up evaluation. Inflammation may, at least in part, be responsible for the development of a high PSTR, and this could be one reason for the high mortality in patients with high PSTR.

Inflammatory factors for hypoalbuminemia in Japanese peritoneal dialysis patients

“…When conventional high-glucose PD solutions were used, the peritoneal transport characteristics seemed to be changed as early as one year, and the correlation between dialysate IL-6 and peritoneal small solute transport was lost. 10 In our study, however, although the patients' population included shortand long-term PD patients, the positive association of dialysate IL-6 with the peritoneal solute transport and peritoneal protein leakage was demonstrated. Furthermore, the interquartile range).…”

“…8,19 However, recent well-controlled prospective studies have shown that intra-peritoneal IL-6, but not systemic IL-6 was associated with peritoneal solute transport in the early phase of PD, 3,10 while this association between dialysate IL-6 and small solute transport tended to be lost over time. 10 This time-dependent change was considered due to the functional or morphological change to the peritoneal membrane during the course of PD, and this change in the peritoneal membrane characteristics might have depended upon such factors as age, race, original kidney disease, complications, IL-6 genetic polymorphism 7,20 and biocompatibility of the PD solutions. 14,21 The cumulative exposure to a bioincompatible PD solution would induce a persistent intraperitoneal inflammatory response and might affect the peritoneal permeability.…”

“…While systemic inflammation is not necessarily an independent determinant of the peritoneal solute transport rate, 8,9 peritoneal inflammation seems to directly induce membrane hyperpermeability, as shown by the spent dialysate IL-6 concentration being positively correlated with the peritoneal solute transport rate. [10][11][12] Both long-term PD and high-glucose PD solutions would induce chronic lowgrade peritoneal inflammation, subsequently leading to structural and functional alterations to the peritoneal membrane. 13,14 Degeneration of mesothelial cells and fibrosis are common features of morphological changes to the peritoneal membrane, and the condition of the mesothelial cell mass has been reported to affect the concentration of the peritoneal effluent marker, CA125.…”

Peritonitis as a risk factor for long‐term cardiovascular mortality in peritoneal dialysis patients: The case of a friendly fire?

“…8 It was previously described that intraperitoneal inflammation, as evaluated by dialysate levels of cytokines [particularly interleukin-6 (IL-6)] is associated with systemic inflammation and protein leakage through the peritoneum. 9 Interestingly, while dialysate IL-6 is associated with membrane functional changes, the relationship between systemic IL-6 and patient survival (similarly to other biomarkers of inflammation, such as CRP and serum albumin) has been consistent throughout published studies. 6,10 The increased levels of intraperitoneal markers of inflammation have been described during peritonitis episodes and remained elevated several weeks after the end of the antibiotic therapy, 10 suggesting that peritonitis may contribute to the chronic inflammatory state of the peritoneum.…”

Opinion: What Are the Problems with Using the Peritoneal Membrane for Long‐Term Dialysis?

“…It is likely that the predominant type of inherent fast transport status is dependent on population differences in the severity of inflammation. This is supported by the mean serum CRP concentration that was three times higher in the PD population from Sweden (22) compared to the population from the Netherlands (25).…”