Endogenous cardiotonic steroids in chronic renal failure

Nephrol Dial Transplant. 2011 Sep;26(9):2912-9. doi: 10.1093/ndt/gfq772. Epub 2011 Feb 3.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Bufanolides / blood*
  • Bufanolides / immunology
  • Case-Control Studies
  • Chromatography, High Pressure Liquid
  • Cohort Studies
  • Digoxin / immunology
  • Erythrocytes / enzymology
  • Female
  • Follow-Up Studies
  • Glomerular Filtration Rate
  • Humans
  • Immunoglobulin Fab Fragments / immunology
  • Kidney Failure, Chronic / blood*
  • Kidney Failure, Chronic / immunology
  • Kidney Failure, Chronic / pathology*
  • Male
  • Middle Aged
  • Nephrectomy
  • Ouabain / blood*
  • Ouabain / immunology
  • Oxidative Stress
  • Prognosis
  • Prospective Studies
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Vasoconstrictor Agents / blood
  • Vasoconstrictor Agents / immunology

Substances

  • Antibodies, Monoclonal
  • Bufanolides
  • Immunoglobulin Fab Fragments
  • Vasoconstrictor Agents
  • digoxin antibodies Fab fragments
  • marinobufagenin
  • Ouabain
  • Digoxin
  • Sodium-Potassium-Exchanging ATPase