Endogenous digitalis-like factor(s), originally proposed as a vasoconstrictor natriuretic hormone, was discovered in fetal and neonatal blood accidentally because it cross-reacts with antidigoxin antibodies (ADAs). Early studies using immunoassays with ADA identified the digoxin-like immuno-reactive factor(s) (EDLF) in maternal blood as well, and suggested it originated in the feto–placental unit. Mammalian digoxin-like factors have recently been identified as at least two classes of steroid compounds, plant derived ouabain (O), and several toad derived bufodienolides, most prominent being marinobufagenin (MBG). A synthetic pathway for MBG has been identified in mammalian placental tissue. Elevated maternal and fetal EDLF, O and MBG have been demonstrated in preeclampsia (PE), and inhibition of red cell membrane sodium, potassium ATPase (Na, K ATPase (NKA)) by EDLF is reversed by ADA fragments (ADA-FAB). Accordingly, maternal administration of a commercial ADA-antibody fragment (FAB) was tested in several anecdotal cases of PE, and two, small randomized, prospective, double-blind clinical trials. In the first randomized trial, ADA-FAB was administered post-partum, in the second antepartum. In the post-partum trial, ADA-FAB reduced use of antihypertensive drugs. In the second trial, there was no effect of ADA-FAB on blood pressure, but the fall in maternal creatinine clearance (CrCl) was prevented. In a secondary analysis using the pre-treatment maternal level of circulating Na, K ATPase (NKA) inhibitory activity (NKAI), ADA-FAB reduced the incidence of pulmonary edema and, unexpectedly, that of severe neonatal intraventricular hemorrhage (IVH). The fall in CrCl in patients given placebo was proportional to the circulating level of NKAI. The implications of these findings on the pathophysiology of the clinical manifestations PE are discussed, and a new model of the respective roles of placenta derived anti-angiogenic (AAG) factors (AAGFs) and EDLF is proposed.
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June 2018
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Double immunofluorescence staining for mindin (red) and CD68 (green) in atherosclerotic plaques of HFD-treated APOE-/- mice. In Issue 11 of Clinical Science, Zhu et al. discuss mindin deficiency as a novel mediator in protecting against foam cell formation and atherosclerosis, through direct interaction with LXR-β; for details, see pages 1199–1213.
Review Article|
June 21 2018
Role of endogenous digitalis-like factors in the clinical manifestations of severe preeclampsia: a systematic review
Vardaman M. Buckalew
1Emeritus Professor of Internal Medicine (Nephrology), Wake Forest University School of Medicine, Winston Salem, NC 27157-1053, U.S.A.
Correspondence: Vardaman M. Buckalew ([email protected])
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Publisher: Portland Press Ltd
Received:
November 06 2017
Revision Received:
April 26 2018
Accepted:
May 08 2018
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Clin Sci (Lond) (2018) 132 (12): 1215–1242.
Article history
Received:
November 06 2017
Revision Received:
April 26 2018
Accepted:
May 08 2018
Citation
Vardaman M. Buckalew; Role of endogenous digitalis-like factors in the clinical manifestations of severe preeclampsia: a systematic review. Clin Sci (Lond) 29 June 2018; 132 (12): 1215–1242. doi: https://doi.org/10.1042/CS20171499
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