title: Endogenous cardiotonic steroids in chronic renal failure.
abstract: BACKGROUND
  Previous reports demonstrated that digitalis-like cardiotonic steroids (CTS) contribute to the pathogenesis of end-stage renal disease. The goal of the present study was to define the nature of CTS in patients with chronic kidney disease (CKD) and in partially nephrectomized (PNx) rats.
  
  
  METHODS
  In patients with CKD and in healthy controls, we determined plasma levels of marinobufagenin (MBG) and endogenous ouabain (EO) and erythrocyte Na/K-ATPase activity in the absence and in the presence of 3E9 anti-MBG monoclonal antibody (mAb) and Digibind. Levels of MBG and EO were also determined in sham-operated Sprague-Dawley rats and in rats following 4 weeks of PNx.
  
  
  RESULTS
  In 25 patients with CKD plasma, MBG but not EO was increased (0.86 ± 0.07 versus 0.28 ± 0.02 nmol/L, P < 0.01) and erythrocyte Na/K-ATPase was inhibited (1.24 ± 0.10 versus 2.80 ± 0.09 μmol Pi/mL/h, P < 0.01) as compared to that in 19 healthy subjects. Ex vivo, 3E9 mAb restored Na/K-ATPase in erythrocytes from patients with CKD but did not affect Na/K-ATPase from control subjects. Following chromatographic fractionation of uremic versus normal plasma, a competitive immunoassay based on anti-MBG mAb detected a 3-fold increase in the level of endogenous material having retention time similar to that seen with MBG. A similar pattern of CTS changes was observed in uremic rats. As compared to sham-operated animals, PNx rats exhibited 3-fold elevated levels of MBG but not that of EO.
  
  
  CONCLUSIONS
  In chronic renal failure, elevated levels of a bufadienolide CTS, MBG, contribute to Na/K-ATPase inhibition and may represent a potential target for therapy.
authors.affiliation: Chronic Dialysis Division, Mechnikov Medical Academy, St. Petersburg, Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Kolmakova
authors.forename: Steven T
authors.initials: ST
authors.lastname: Haller
authors.forename: David J
authors.initials: DJ
authors.lastname: Kennedy
authors.forename: Alina N
authors.initials: AN
authors.lastname: Isachkina
authors.forename: George V
authors.initials: GV
authors.lastname: Budny
authors.forename: Elena V
authors.initials: EV
authors.lastname: Frolova
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Piecha
authors.forename: Elena R
authors.initials: ER
authors.lastname: Nikitina
authors.forename: Deepak
authors.initials: D
authors.lastname: Malhotra
authors.forename: Olga V
authors.initials: OV
authors.lastname: Fedorova
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Shapiro
authors.forename: Alexei Y
authors.initials: AY
authors.lastname: Bagrov
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002018:Bufanolides / Q000097:blood* / Q000276:immunology; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D004077:Digoxin / Q000276:immunology; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D010042:Ouabain / Q000097:blood* / Q000276:immunology; D018384:Oxidative Stress; D011379:Prognosis; D011446:Prospective Studies; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000097:blood / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D002018:Bufanolides; D007140:Immunoglobulin Fab Fragments; D014662:Vasoconstrictor Agents; C050199:digoxin antibodies Fab fragments; C093896:marinobufagenin; D010042:Ouabain; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase