Endogenous Cardiotonic Steroids in Kidney Failure: A Review and an Hypothesis

Abstract

In response to progressive nephron loss, volume and humoral signals in the circulation have increasing relevance. These signals, including plasma sodium, angiotensin II and those related to volume status, activate a slow neuromodulatory pathway within the central nervous system (CNS). The slow CNS pathway includes specific receptors for angiotensin II, mineralocorticoids, and endogenous ouabain (EO). Stimulation of the pathway leads to elevated sympathetic nervous system activity (SNA) and increased circulating EO. The sustained elevation of circulating EO (or ouabain) stimulates central and peripheral mechanisms that amplify the impact of SNA on vascular tone. These include: changes in synaptic plasticity in the brain and sympathetic ganglia that increase preganglionic tone and amplify ganglionic transmission, amplification of the impact of SNA on arterial tone in the vascular wall, and the reprogramming of calcium signaling proteins in arterial myocytes. These increase SNA, raise basal and evoked arterial tone, and elevate blood pressure (BP). In the setting of chronic kidney disease, we suggest that sustained elevation of the slow CNS pathway, plasma EO and the cardiotonic steroid marinobufagenin (MBG), comprise a feed-forward system that raises BP and accelerates kidney and cardiac damage. Block of the slow CNS pathway and/or circulating EO and MBG may reduce BP and slow the progression to end stage renal disease.

Novel pathomechanisms of cardiomyocyte dysfunction in a model of heart failure with preserved ejection fraction

“…In the present CKD HFpEF model, amelioration of increased reverse mode NCX activity and Ca 2+ decay in cardiomyocytes dialysed with equal [Na + ] (Supplementary material online, Figure S6 ) corroborates a role for dysregulated [Na + ]. Potential mechanisms for increased cardiomyocyte [Na + ] in CKD include inhibition of the cardiac Na + /K + ‐ATPase by circulating digitalis‐like endogenous cardiotonic steroids as reviewed in Hamlyn and Manunta . At a later stage in our model, we observed increased expression of NCX protein, which–when in reverse mode–may have aggravated the phenotype.…”

Hemodialysis‐induced cardiovascular disease

“…Cardiotonic steroids are among many compounds that accumulate in renal failure and affect cardiovascular function . These compounds inhibit sodium‐potassium ATP‐ase, affecting intra‐ and extra‐cellular volume, electrolyte hemostasis, and myocardial contractility, elevating blood pressure.…”

Endogenous Ouabain

“…EO, which may contribute to renal failure 96 and may be linked to cardiomyopathy in chronic kidney disease, 62, 97, 98 also appears to be a valuable biomarker of heart failure. In 845 patients undergoing elective cardiac surgery, plasma EO was correlated negatively with left ventricular ejection fraction, and positively with cardiac end-diastolic diameter and plasma NT-proBNP.…”