Tags

Type your tag names separated by a space and hit enter

First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution: A New Candidate Therapy for Volume Overload.
Circulation. 2020 Mar 31; 141(13):1043-1053.Circ

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.

Authors+Show Affiliations

Department of Internal Medicine, Section of Cardiovascular Medicine (V.S.R., M.G., D.M., N.B., J.M. Testani), Yale University School of Medicine, New Haven, CT.Department of Medicine, Division of Nephrology (J.M. Turner, F.F.), Yale University School of Medicine, New Haven, CT.Department of Internal Medicine, Section of Cardiovascular Medicine (V.S.R., M.G., D.M., N.B., J.M. Testani), Yale University School of Medicine, New Haven, CT.Department of Internal Medicine, Section of Cardiovascular Medicine (V.S.R., M.G., D.M., N.B., J.M. Testani), Yale University School of Medicine, New Haven, CT.Department of Comparative Medicine (J.A.), Yale University School of Medicine, New Haven, CT.Yale School of Nursing, West Haven, CT (S.J.).Department of Surgery, Transplantation and Immunology (P.S.Y.), Yale University School of Medicine, New Haven, CT.Department of Internal Medicine, Section of Cardiovascular Medicine (V.S.R., M.G., D.M., N.B., J.M. Testani), Yale University School of Medicine, New Haven, CT.Department of Internal Medicine (A.F.), Yale University School of Medicine, New Haven, CT.Department of Medicine, Yale Translational Research Imaging Center, Section of Cardiovascular Medicine (A.S.), Yale University School of Medicine, New Haven, CT.Program of Applied Translational Research (F.P.W.), Yale University School of Medicine, New Haven, CT.Department of Medicine, Division of Nephrology (J.M. Turner, F.F.), Yale University School of Medicine, New Haven, CT.Department of Internal Medicine, Section of Cardiovascular Medicine (V.S.R., M.G., D.M., N.B., J.M. Testani), Yale University School of Medicine, New Haven, CT.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31910658

Citation

Rao, Veena S., et al. "First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution: a New Candidate Therapy for Volume Overload." Circulation, vol. 141, no. 13, 2020, pp. 1043-1053.
Rao VS, Turner JM, Griffin M, et al. First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution: A New Candidate Therapy for Volume Overload. Circulation. 2020;141(13):1043-1053.
Rao, V. S., Turner, J. M., Griffin, M., Mahoney, D., Asher, J., Jeon, S., Yoo, P. S., Boutagy, N., Feher, A., Sinusas, A., Wilson, F. P., Finkelstein, F., & Testani, J. M. (2020). First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution: A New Candidate Therapy for Volume Overload. Circulation, 141(13), 1043-1053. https://doi.org/10.1161/CIRCULATIONAHA.119.043062
Rao VS, et al. First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution: a New Candidate Therapy for Volume Overload. Circulation. 2020 Mar 31;141(13):1043-1053. PubMed PMID: 31910658.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution: A New Candidate Therapy for Volume Overload. AU - Rao,Veena S, AU - Turner,Jeffrey M, AU - Griffin,Matthew, AU - Mahoney,Devin, AU - Asher,Jennifer, AU - Jeon,Sangchoon, AU - Yoo,Peter S, AU - Boutagy,Nabil, AU - Feher,Attila, AU - Sinusas,Albert, AU - Wilson,F Perry, AU - Finkelstein,Fredric, AU - Testani,Jeffrey M, Y1 - 2020/01/08/ PY - 2021/03/31/pmc-release PY - 2020/1/9/pubmed PY - 2020/1/9/medline PY - 2020/1/9/entrez KW - clinical trial [publication type] KW - heart failure SP - 1043 EP - 1053 JF - Circulation JO - Circulation VL - 141 IS - 13 N2 - 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. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/31910658/First-in-Human_Experience_With_Peritoneal_Direct_Sodium_Removal_Using_a_Zero-Sodium_Solution:_A_New_Candidate_Therapy_for_Volume_Overload L2 - https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.043062?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -
Try the Free App:
Prime PubMed app for iOS iPhone iPad
Prime PubMed app for Android
Prime PubMed is provided
free to individuals by:
Unbound Medicine.