Neuropeptide release augments serum albumin loss and reduces ultrafiltration in peritoneal dialysis

Abstract

Background: The triggers of the acute local inflammatory response to peritoneal dialysis (PD) fluid exposure remain unknown. In the present study, we investigated the effects of neurogenic inflammation and mast cell degranulation on water and solute transport in experimental PD.

Methods: Single 2-hour dwells in rats with PD catheters were studied. Histamine and the neuropeptides substance P and calcitonin gene-related peptide (CGRP) were measured in PD fluid samples by ELISA. Radiolabeled albumin ((125)I and (131)I respectively) was used as an intraperitoneal (IP) and intravascular tracer. Glucose and urea concentrations were measured in plasma and PD fluid. The effects of varying the volume and osmolarity of a lactate-buffered PD fluid were compared and related to the effects of pharmacologic intervention.

Results: Application of 20 mL 3.9% glucose PD fluid induced an IP histamine release during the first 30 minutes, blockable by the mast cell stabilizer doxantrazole and the substance P neurokinin-1 receptor (NK1R)-blocker spantide. Histamine release was also inhibited at a reduced PD volume (14 mL), but was not affected by normalizing the PD fluid osmolarity. Blockade of NK1R also reduced plasma albumin leakage to the peritoneal cavity. Inhibition of CGRP receptors by CGRP8-37 improved osmotic (transcapillary) and net ultrafiltration and reduced the dialysate urea concentration. Neuropeptide release was not clearly related to activation of the TrpV1 receptor, the classic trigger of neurogenic inflammation.

Conclusions: Neuropeptide release exaggerated albumin loss and reduced ultrafiltration in this rat PD model. Intervention aimed at the neuropeptide action substantially improved PD efficiency.

Figure 1

— Histamine release pattern in 2-hour dwells using 14 mL and 20 mL peritoneal dialysis (PD) fluid. Upper panel: In response to 20 mL of PD fluid, the intraperitoneal histamine concentration peaks within the first 30 minutes and then approaches a plateau, suggesting a steady state between the plasma space and the intraperitoneal fluid volume. Lower panel: The peak histamine concentration in response to 20 mL PD fluid reaches approximately 8% of the value induced by the mast cell degranulator C48/80, used as a positive control.

Figure 2

— Histamine release, calculated as the average quantity of histamine per kilogram body weight (b.w.) released during the first 30 minutes of dwell time. Low-volume peritoneal dialysis (PD) dwells (14 mL instead of 20 mL) significantly reduced histamine release, as did treatment with the mast cell stabilizer doxantrazole and the substance P receptor antagonist spantide at normal PD volumes (20 mL). Addition of the TrpV1 receptor blocker SB366791 did not significantly affect histamine release compared with that during control dwells with 20 mL PD fluid without additional treatment. ^* Significant at the 5% level after correction for multiple comparisons.

Figure 3

— Plasma albumin leakage, calculated as the average clearance of labeled bovine serum albumin from plasma to the intraperitoneal space during 2-hour dwells with 20 mL standard peritoneal dialysis (PD) fluid. Mast cell degranulation by C48/80 significantly increased albumin leakage, and addition of the substance P receptor antagonist spantide significantly reduced albumin leakage compared with control dwells of fluid without additional treatment. The mast cell stabilizer doxantrazole and the TrpV1 receptor blocker SB366791 had no significant effects. b.w. = body weight. ^* Significant at the 5% level after correction for multiple comparisons.

Figure 4

— Graphic representation of transperitoneal fluid transport over 120 minutes’ dwell time (presented as mean ± standard error of the mean in Table 2). Total bar height, corresponding to osmotic (transcapillary) ultrafiltration (UF), is resolved in the Net UF (net volume gain) and Redistribution (clearance of volume marker from the intraperitoneal cavity) table rows. Compared with a standard peritoneal dialysis dwell, + represents a significant increase and – represents a significant decrease of the three transport components. The CGRP receptor antagonist CGRP8-37 significantly increased osmotic UF and net UF; the TrpV1 receptor blocker SB366791 significantly reduced redistribution and osmotic UF. b.w. = body weight.