First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution: A New Candidate Therapy for Volume Overload

Abstract

Background: Loop diuretics have well-described toxicities, and loss of response to these agents is common. Alternative strategies are needed for the maintenance of euvolemia in heart failure (HF). Nonrenal removal of sodium directly across the peritoneal membrane (direct sodium removal [DSR]) with a sodium-free osmotic solution should result in extraction of large quantities of sodium with limited off-target solute removal.

Methods: This article describes the preclinical development and first-in-human proof of concept for DSR. Sodium-free 10% dextrose was used as the DSR solution. Porcine experiments were conducted to investigate the optimal dwell time, safety, and scalability and to determine the effect of experimental heart failure. In the human study, participants with end-stage renal disease on peritoneal dialysis (PD) underwent randomization and crossover to either a 2-hour dwell with 1 L DSR solution or standard PD solution (Dianeal 4.25% dextrose, Baxter). The primary end point was completion of the 2-hour dwell without significant discomfort or adverse events, and the secondary end point was difference in sodium removal between DSR and standard PD solution.

Results: Porcine experiments revealed that 1 L DSR solution removed 4.1±0.4 g sodium in 2 hours with negligible off-target solute removal and overall stable serum electrolytes. Increasing the volume of DSR solution cycled across the peritoneum increased sodium removal and substantially decreased plasma volume (P=0.005). In the setting of experimental heart failure with elevated right atrial pressure, sodium removal was ≈4 times greater than in healthy animals (P<0.001). In the human proof-of-concept study, DSR solution was well tolerated and not associated with significant discomfort or adverse events. Plasma electrolyte concentrations were stable, and off-target solute removal was negligible. Sodium removal was substantially higher with DSR (4.5±0.4 g) compared with standard PD solution (1.0±0.3 g; P<0.0001).

Conclusions: DSR was well tolerated in both animals and human subjects and produced substantially greater sodium removal than standard PD solution. Additional research evaluating the use of DSR as a method to prevent and treat hypervolemia in heart failure is warranted. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03801226.

Keywords: clinical trial [publication type]; heart failure.

Figures

Figure 1:

Ultrafiltration volume, sodium content of peritoneal fluid, and peritoneal fluid osmolarity in 5 pigs during a 6-hour dwell with sodium-free 10% dextrose.

Figure 2:

Total blood volume, plasma volume, and red blood cell volume in n=4 pigs before and after cycling 10L of sodium free 10% dextrose across the peritoneal membrane. Post cycling the hematocrit had increased from 23.8 ± 1.0% to 54.3 ± 7.2%. Degrees of freedom = 3 for all comparisons and t value = 7.41 for blood volume, 10.27 for plasma volume and 0.43 for RBC volume. RBC: red blood cell.

Figure 3:

Hemodynamic parameters of the cardiac tamponade acute heart failure model After fluid loading (marked “post-fluid”), pigs underwent pressurization of the pericardium (marked “post tamponade”). CO: cardiac output, SBP: systolic blood pressure, MAP: mean arterial pressure, PCWP: pulmonary capillary wedge pressure, CVP: central venous pressure, Pericardial: pericardial pressure.

Figure 4:

Ultrafiltration volume and sodium removal during a 2-hour dwell in healthy animals and animals with experimental heart failure with elevated right sided filling pressures. Degrees of freedom=4.2 t =9.25. HF: Heart failure.

Figure 5:

Plasma glucose and glucose-corrected plasma sodium levels for individual human participants and aggregate data over a 2-hour dwell with direct sodium removal (DSR) or standard peritoneal dialysis (PD) solution. Plasma glucose was higher with DSR at all timepoints during the dwell compared to standard PD solution (F(4;76)=5.3, p=0.008). Glucose corrected plasma sodium was not different between groups (F(4;76)=1.07, p=0.38). DSR: direct sodium removal, PD: peritoneal dialysis.

Figure 6:

Volume of ultrafiltration and sodium removal in human subjects during a 2-hour dwell with DSR or standard PD solution. Ultrafiltration volume (top left) and sodium content of peritoneal fluid (top right) over time in the aggregate population determined using I-131 indicator dilution. Ultrafiltration volume (bottom left) and sodium removal (bottom right) in individual patients at two hours determined from the physically drained volume. F(1;9) test statistics were =158 for ultrafiltration and 694 for sodium removal. DSR: direct sodium removal, PD: peritoneal dialysis.