Urinary extracellular vesicle protein profiling and endogenous lithium clearance support excessive renal sodium wasting and water reabsorption in thiazide induced hyponatremia

Channavajjhala, Sarath K.; Bramley, Roger; Peltz, Theresa; Oosthuyzen, Wilna; Jia, Wenjing; Kinnear, Sue; Sampson, Barry; Martin, Nick; Hall, Ian P.; Bailey, Matthew A.; Dear, James W.; Glover, Mark

Abstract

Introduction

Thiazide diuretics are amongst the most widely used anti-hypertensive medicines worldwide. Thiazide-Induced Hyponatremia (TIH) is one of their most clinically significant adverse effects. A priori TIH must result from excessive saliuresis and/or water reabsorption. We hypothesised that pathways regulating the thiazide-sensitive NCC and the water channel AQP2 may be involved. Our aim was to assess whether patients with TIH show evidence of altered NCC and AQP2 expression in urinary extracellular vesicles (UEVs), and also whether abnormalities of renal sodium reabsorption were evident using Endogenous Lithium Clearance (ELC).
Methods

Blood and urine samples were donated by patients admitted to hospital with acute symptomatic TIH, after recovery to normonatremia, and also from normonatremic controls on and off thiazides. UEVs were isolated and target proteins evaluated by Western blotting and by Nanoparticle Tracking Analysis (NTA). ELC was assessed by Inductively Coupled Plasma Mass Spectrometry.
Results

UEVs analysis by Western blotting showed that patients with acute TIH display reduced total NCC and increased phospho-NCC and AQP2 relative to appropriate control groups; smaller differences in NCC and AQP2 expression persisted after recovery from TIH. These findings were confirmed by NTA. Renal ELC was lower in acute TIH compared to controls and convalescent cases.
Conclusion

Reduced NCC expression and increased AQP2 expression would be expected to result in saliuresis and water reabsorption in TIH patients. This study raises the possibility that UEV analysis may be of diagnostic utility in less clear cut cases of thiazide associated hyponatremia and may help identify those at risk of TIH before thiazide initiation.

Citation

Channavajjhala, S. K., Bramley, R., Peltz, T., Oosthuyzen, W., Jia, W., Kinnear, S., Sampson, B., Martin, N., Hall, I. P., Bailey, M. A., Dear, J. W., & Glover, M. (2019). Urinary extracellular vesicle protein profiling and endogenous lithium clearance support excessive renal sodium wasting and water reabsorption in thiazide induced hyponatremia. Kidney International Reports, 4(1), 139-147. https://doi.org/10.1016/j.ekir.2018.09.011

• Journal Article Type: Article
• Acceptance Date: Sep 17, 2018
• Online Publication Date: Sep 22, 2018
• Publication Date: 2019-01
• Deposit Date: Oct 5, 2018
• Publicly Available Date: Feb 27, 2019
• Journal: Kidney International Reports
• Print ISSN: 2468-0249
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 4
• Issue: 1
• Pages: 139-147
• DOI: https://doi.org/10.1016/j.ekir.2018.09.011
• Keywords: Thiazide Diuretic; Sodium; Hyponatremia; Hypertension; Urinary extracellular vesicles
• Public URL: https://nottingham-repository.worktribe.com/output/1147782
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2468024918302110
• Contract Date: Oct 5, 2018