Fluid and electrolyte deity, Robert Schrier, had an interesting editorial in Feburary’s Nature Reviews: Nephrology (yes, I’ve gotten a little behind in this blogging business).
Escape versus breakthrough refere to completely different and unrelated concepts related to aldosterone.
- Aldosterone breakthrough occurs following administration of an ACEi or ARB. ACEi block the conversion of angiotensin I to angiotensin II. The decrease in angiotensin II lowers aldosterone. Angiotensin receptor blockers prevent angiotensis II from from binding receptors through out the vasculature but including the adrenal gland where it prevents aldosterone release. At least that is the plan. In reality about 30-40% of patients given ACEi or ARBs have only a temporary decrease in aldosterone and then after a few weeks, aldosterone returns to pre-treatment levels.
- Aldosterone escape is a physiologic phenomenon that occurs with hyperaldosteronism. Aldosterone initially decreases urinary sodium increasing sodium retension contributing to hypertension. This does not result in edema because the sodium retention is short lived. After a short time urinary sodium returns to normal through a process called aldosterone escape. There are two processes that account for this:
- Pressure natriuresis. Increased blood pressure decreases distal sodium resorption. The exact mechanism of pressure natriuresis is unknown, it is thought to be mediated by hydrostatic forces. Increased blood pressure is transmitted to the peritubular capillaries, so the resorption of solutes must overcome an elevated hydrostatic pressure gradient. In the face of this increased gradient, sodium resorption falls.
- Decreased proximal sodium resorption. Volume expansion decreases proximal sodium reabsorption and increases sodium delivery to the distal nephron and overwelms the aldosterone induced sodium resorption.
The implications of aldosterone escape is that primary hyperaldosteronism does not cause edema. It also explains the delay in hypokalemia found with primary hyperaldosteronism. Aldosterone stimulates potassium excretion but hypokalemia is a late finding in primary hyperaldosteronism. The increased potassium excretion occurs with aldosterone escape when the increased sodium delivery (decreased proximal absorption, i.e. escape) occurs with the increased aldosterone levels.
The regulation of aldosteron is uncompletely understood and others factors than K and ATII play a role (example Aldo releasing substances produced by adipocytes). We do not know the exact regulation of AT1 receptors on the surface of the cell and the postreceptor signalling? Do we know all the locally produced ACE and their regulation and the role of the prorenin receptor in this? In others words the classical RAAS system is only a small piece of the puzzle.
In the Aldo escape venous capacity receptors in the heart and big veins and their efferent system may play a role like BNP and ANP. I bed this is also an oversimplification.
The late presence of hypokalemia in primary aldosteronism is an interesting finding. Particularly since the there is a thought for distal sodium reabsorption being inhibited. An interesting role for purinergic signaling in regulating ENaC has been found by Stockand's group in this JASN article: http://www.ncbi.nlm.nih.gov/pubmed/20813869
The late presence of hypokalemia in primary aldosteronism is particularly interesting considering the role of inhibition of distal nephron sodium reabsorption during aldosterone escape. In particularly, the key role of purinergic signaling in regulating ENaC during aldosterone escape was highlighted in a JASN article by Stockand's group: http://www.ncbi.nlm.nih.gov/pubmed/20813869