Perturbed body fluid distribution and osmoregulation in response to high salt intake in patients with hereditary multiple exostoses

Jetta J Oppelaar; Nienke M G Rorije; Rik H G Olde Engberink; Youssef Chahid; Naomi van Vlies; Hein J Verberne; Bert-Jan H van den Born; Liffert Vogt

doi:10.1016/j.ymgmr.2021.100797

Perturbed body fluid distribution and osmoregulation in response to high salt intake in patients with hereditary multiple exostoses

Mol Genet Metab Rep. 2021 Nov 5:29:100797. doi: 10.1016/j.ymgmr.2021.100797. eCollection 2021 Dec.

Authors

Jetta J Oppelaar¹, Nienke M G Rorije¹, Rik H G Olde Engberink¹, Youssef Chahid², Naomi van Vlies³, Hein J Verberne², Bert-Jan H van den Born⁴, Liffert Vogt¹

Affiliations

¹ Amsterdam UMC, University of Amsterdam, Department of Internal Medicine, Section of Nephrology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, the Netherlands.
² Amsterdam UMC, University of Amsterdam, Department of Radiology and Nuclear Medicine, Meibergdreef 9, Amsterdam, the Netherlands.
³ Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, Amsterdam, the Netherlands.
⁴ Amsterdam UMC, University of Amsterdam, Department of Internal Medicine, Section of Vascular Medicine, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, the Netherlands.

Abstract

Background: Hereditary Multiple Exostoses (HME) is a rare autosomal disorder characterized by the presence of multiple exostoses (osteochondromas) caused by a heterozygous loss of function mutation in EXT1 or EXT2; genes involved in heparan sulfate (HS) chain elongation. Considering that HS and other glycosaminoglycans play an important role in sodium and water homeostasis, we hypothesized that HME patients have perturbed whole body volume regulation and osmolality in response to high sodium conditions.

Methods: We performed a randomized cross-over study in 7 male HME patients and 12 healthy controls, matched for age, BMI, blood pressure and renal function. All subjects followed both an 8-day low sodium diet (LSD, <50 mmol/d) and high sodium diet (HSD, >200 mmol/d) in randomized order. After each diet, blood and urine samples were collected. Body fluid compartment measurements were performed by using the distribution curve of iohexol and ¹²⁵I-albumin.

Results: In HME patients, HSD resulted in significant increase of intracellular fluid volume (ICFV) (1.2 L, p = 0.01). In this group, solute-mediated water clearance was significantly lower after HSD, and no changes in interstitial fluid volume (IFV), plasma sodium, and effective osmolality were observed. In healthy controls, HSD did not influence ICFV, but expanded IFV (1.8 L, p = 0.058) and increased plasma sodium and effective osmolality.

Conclusion: HME patients show altered body fluid distribution and osmoregulation after HSD compared to controls. Our results might indicate reduced interstitial sodium accumulation capacity in HME, leading to ICFV increase. Therefore, this study provides additional support that HS is crucial for maintaining constancy of the internal environment.

Keywords: BMI, Body mass index; BP, Blood pressure; ECFV, Extracellular fluid volume; EXT1/EXT2, Extosin-1 / Extosin-2; GAG, Glycosaminoglycan; Glycosaminoglycans; HME, Hereditary Multiple Exostoses; HSD, High sodium diet; Heparan sulfate; Hereditary Multiple Exostoses; ICFV, Intracellular fluid volume; IFV, Interstital fluid volume; LSD, Low sodium diet; Osmoregulation; PV, Plasma volume; Sodium; TBW, Total body water; Water balance.