Dehydration is associated with production of organic osmolytes and predicts physical long-term symptoms after COVID-19: a multicenter cohort study
Michael Hultström, Miklos Lipcsey, Dave R Morrison, Tomoko Nakanishi, Guillaume Butler-Laporte, Yiheng Chen, Satoshi Yoshiji, Vincenzo Forgetta, Yossi Farjoun, Ewa Wallin, Ing-Marie Larsson, Anders Larsson, Adriana Marton, Jens Marc Titze, Sandra Nihlén, J Brent Richards, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Dave R Morrison, Tomoko Nakanishi, Guillaume Butler-Laporte, Yiheng Chen, Satoshi Yoshiji, Vincenzo Forgetta, Yossi Farjoun, Ewa Wallin, Ing-Marie Larsson, Anders Larsson, Adriana Marton, Jens Marc Titze, Sandra Nihlén, J Brent Richards, Robert Frithiof
Abstract
Background: We have previously shown that iatrogenic dehydration is associated with a shift to organic osmolyte production in the general ICU population. The aim of the present investigation was to determine the validity of the physiological response to dehydration known as aestivation and its relevance for long-term disease outcome in COVID-19.
Methods: The study includes 374 COVID-19 patients from the Pronmed cohort admitted to the ICU at Uppsala University Hospital. Dehydration data was available for 165 of these patients and used for the primary analysis. Validation was performed in Biobanque Québécoise de la COVID-19 (BQC19) using 1052 patients with dehydration data. Dehydration was assessed through estimated osmolality (eOSM = 2Na + 2 K + glucose + urea), and correlated to important endpoints including death, invasive mechanical ventilation, acute kidney injury, and long COVID-19 symptom score grouped by physical or mental.
Results: Increasing eOSM was correlated with increasing role of organic osmolytes for eOSM, while the proportion of sodium and potassium of eOSM were inversely correlated to eOSM. Acute outcomes were associated with pronounced dehydration, and physical long-COVID was more strongly associated with dehydration than mental long-COVID after adjustment for age, sex, and disease severity. Metabolomic analysis showed enrichment of amino acids among metabolites that showed an aestivating pattern.
Conclusions: Dehydration during acute COVID-19 infection causes an aestivation response that is associated with protein degradation and physical long-COVID.
Trial registration: The study was registered à priori (clinicaltrials.gov: NCT04316884 registered on 2020-03-13 and NCT04474249 registered on 2020-06-29).
Keywords: Acute kidney injury; Aestivation; Intensive care medicine; Long-COVID; SARS-CoV-2; Urea synthesis.
Conflict of interest statement
JBR served as an advisor to GlaxoSmithKline and Deerfield Capital, and is the founder and CEO of 5 Prime Sciences. VF and YF are employed by 5 Prime Sciences. YF consults for Fulcrum Genomics. The other authors declare that they have no conflicts of interest.
© 2022. The Author(s).
Figures
References
- Hultstrom M, von Seth M, Frithiof R. Hyperreninemia and low total body water may contribute to acute kidney injury in COVID-19 patients in intensive care. J Hypertens. 2020;38(8):1613–1614. doi: 10.1097/HJH.0000000000002531.
- Luther T, Bulow-Anderberg S, Larsson A, Rubertsson S, Lipcsey M, Frithiof R, Hultstrom M. COVID-19 patients in intensive care develop predominantly oliguric acute kidney injury. Acta Anaesthesiol Scand. 2021;65(3):364–372. doi: 10.1111/aas.13746.
- Stookey JD, Allu PKR, Chabas D, Pearce D, Lang F. Hypotheses about sub-optimal hydration in the weeks before coronavirus disease (COVID-19) as a risk factor for dying from COVID-19. Med Hypotheses. 2020;144:110237. doi: 10.1016/j.mehy.2020.110237.
- Nihlen S, Frithiof R, Titze J, Kawati R, Rasmusson J, Rylander C, Pikwer A, Castegren M, Belin A, Hultstrom M, et al. The contribution of plasma urea to total osmolality during iatrogenic fluid reduction in critically ill patients. Function (Oxf) 2022;3(1):zqab055. doi: 10.1093/function/zqab055.
- Delles C, Rossitto G. Of snails, earthworms, and men: insights into strategies to preserve water. Function (Oxf) 2022;3(1):zqab071. doi: 10.1093/function/zqab071.
- Haussinger D, Lang F, Gerok W. Regulation of cell function by the cellular hydration state. Am J Physiol. 1994;267(3 Pt 1):E343–355.
- Wild J, Jung R, Knopp T, Efentakis P, Benaki D, Grill A, Wegner J, Molitor M, Garlapati V, Rakova N, et al. Aestivation motifs explain hypertension and muscle mass loss in mice with psoriatic skin barrier defect. Acta Physiol (Oxf) 2021;232:e13628. doi: 10.1111/apha.13628.
- Kitada K, Daub S, Zhang Y, Klein JD, Nakano D, Pedchenko T, Lantier L, LaRocque LM, Marton A, Neubert P, et al. High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation. J Clin Invest. 2017;127(5):1944–1959. doi: 10.1172/JCI88532.
- Kovarik J, Morisawa N, Wild J, Marton A, Takase-Minegishi K, Minegishi S, Daub S, Sands JM, Klein JD, Bailey JL, et al. Adaptive physiological water conservation explains hypertension and muscle catabolism in experimental chronic renal failure. Acta Physiol (Oxf) 2021;232:e13629. doi: 10.1111/apha.13629.
- Mirabella S, Gomez-Paz S, Lam E, Gonzalez-Mosquera L, Fogel J, Rubinstein S. Glucose dysregulation and its association with COVID-19 mortality and hospital length of stay. Diabetes Metab Syndr. 2022;16(3):102439. doi: 10.1016/j.dsx.2022.102439.
- Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E, Oczkowski S, Levy MM, Derde L, Dzierba A, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19) Intensive Care Med. 2020;46(5):854–887. doi: 10.1007/s00134-020-06022-5.
- Moreno RP, Metnitz PG, Almeida E, Jordan B, Bauer P, Campos RA, Iapichino G, Edbrooke D, Capuzzo M, Le Gall JR, et al. SAPS 3—From evaluation of the patient to evaluation of the intensive care unit. Part 2: development of a prognostic model for hospital mortality at ICU admission. Intensive Care Med. 2005;31(10):1345–1355. doi: 10.1007/s00134-005-2763-5.
Source: PubMed