Aldosterone escape

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In physiology, aldosterone escape is a term that has been used to refer to two distinct phenomena involving aldosterone that are exactly opposite each other:

  1. Escape from the sodium-retaining effects of excess aldosterone (or other mineralocorticoids) in primary hyperaldosteronism, manifested by volume and/or pressure natriuresis. [1]
  2. The inability of ACE inhibitor therapy to reliably suppress aldosterone release, for example, in patients with heart failure or diabetes, usually manifested by increased salt and water retention. This latter sense may rather be termed refractory hyperaldosteronism. [1]

In patients with hyperaldosteronism, chronic exposure to excess aldosterone does not cause edema as might be expected. Aldosterone initially results in an increase in Na+ reabsorption in these patients through stimulation of ENaC channels in principal cells of the renal collecting tubules. Increased ENaC channels situated in the apical membranes of the principal cells allow for more Na+ reabsorption, which may cause a transient increase in fluid reabsorption as well. However, within a few days, Na+ reabsorption returns to normal as evidenced by normal urinary Na+ levels in these patients. This return to normal is induced by volume expansion, as escape typically occurs in humans after a weight gain of approximately 3 kg. [2]

The exact mechanism(s) underpinning aldosterone escape are an active subject of research, though several mechanisms have been proposed. [3]

Proposed mechanisms for this phenomenon do not include a reduced sensitivity of mineralocorticoid receptors to aldosterone, because low serum potassium is often seen in these patients, which is the direct result of aldosterone-induced expression of ENaC channels. Furthermore, electrolyte homeostasis is maintained in these patients, which excludes the possibility that other Na+ transporters elsewhere in the kidney are being shut down. If, in fact, other transporters such as the Na+-H+ antiporter in the proximal tubule or the Na+/K+/2Cl− symporter in the thick ascending loop of Henle were being blocked, other electrolyte disturbances would be expected, such as seen during use of diuretics.

One mechanism proposed by ES Prakash [1] suggests that pressure natriuresis underpins aldosterone escape, as Starling force backflow of Na+ and water into the tubules thus favors Na+ excretion. [4] [5] Experiments isolating the perfusion pressures seen by glomerular capillaries from heightened systemic pressures due to hyperaldosteronism have shown that Na+ excretion remains minimal until the kidney is exposed to heightened perfusion pressures. These experiments brought about the proposition that initially high perfusion pressures due to increased Na+ and water reabsorption in a high aldosterone state actually causes "backflow" of Na+ and water into the tubules.

Normally, Na+ and water are reabsorbed from the tubules and dumped into the renal interstitium. From there, Starling forces dictate the gradient for movement of water and Na+ into the peritubular capillaries. Because hydrostatic pressures in the tubules, interstitium and peritubular capillaries are normally equivalent, oncotic pressures govern flow.

Typically, oncotic pressures are higher in the peritubular capillaries, because protein composition in the interstitium is negligible; therefore, Na+ and water leave the interstitial space and enter the capillaries. However, hyperadosteronism raises pressures in the peritubular capillaries. When hydrostatic pressures are raised in the peritubular capillaries, Starling forces begin to favor "backflow" of Na+ and water from the interstitium into the tubules—thus, increasing Na+ excretion. This is a proposed mechanism of aldosterone escape for how patients with increased levels of aldosterone are able to maintain Na+ balance and avoid an edematous state. [1]

Another mechanism proposed by RW Schrier [6] suggests that aldosterone involves synergistic processes. In addition to increasing renal perfusion pressure, the resultant volume expansion decreases proximal sodium reabsorption and increases sodium delivery to the distal nephron sites of mineralocorticoid action. This increased delivery of sodium overrides the enhanced aldosterone sodium reabsorption at the site of mineralocorticoid action. Moreover, volume expansion, secondary to the action of aldosterone, increases levels of plasma natriuretic hormone and therefore its inhibitory effect on sodium reabsorption in the collecting duct. Together, these events contribute to normal aldosterone escape and the prevention of edema. [6]

Others have suggested the involvement of decreased abundance of the thiazide-sensitive sodium-chloride cotransporter which mediates sodium reabsorption in the distal tubule. [3] [7]

Related Research Articles

<span class="mw-page-title-main">Nephron</span> Microscopic structural and functional unit of the kidney

The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure called Bowman's capsule. The renal tubule extends from the capsule. The capsule and tubule are connected and are composed of epithelial cells with a lumen. A healthy adult has 1 to 1.5 million nephrons in each kidney. Blood is filtered as it passes through three layers: the endothelial cells of the capillary wall, its basement membrane, and between the podocyte foot processes of the lining of the capsule. The tubule has adjacent peritubular capillaries that run between the descending and ascending portions of the tubule. As the fluid from the capsule flows down into the tubule, it is processed by the epithelial cells lining the tubule: water is reabsorbed and substances are exchanged ; first with the interstitial fluid outside the tubules, and then into the plasma in the adjacent peritubular capillaries through the endothelial cells lining that capillary. This process regulates the volume of body fluid as well as levels of many body substances. At the end of the tubule, the remaining fluid—urine—exits: it is composed of water, metabolic waste, and toxins.

<span class="mw-page-title-main">Renin–angiotensin system</span> Hormone system

The renin-angiotensin system (RAS), or renin-angiotensin-aldosterone system (RAAS), is a hormone system that regulates blood pressure, fluid, and electrolyte balance, and systemic vascular resistance.

<span class="mw-page-title-main">Aldosterone</span> Mineralocorticoid steroid hormone

Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a central role in the homeostatic regulation of blood pressure, plasma sodium (Na+), and potassium (K+) levels. It does so primarily by acting on the mineralocorticoid receptors in the distal tubules and collecting ducts of the nephron. It influences the reabsorption of sodium and excretion of potassium (from and into the tubular fluids, respectively) of the kidney, thereby indirectly influencing water retention or loss, blood pressure, and blood volume. When dysregulated, aldosterone is pathogenic and contributes to the development and progression of cardiovascular and kidney disease. Aldosterone has exactly the opposite function of the atrial natriuretic hormone secreted by the heart.

<span class="mw-page-title-main">Collecting duct system</span> Kidney system

The collecting duct system of the kidney consists of a series of tubules and ducts that physically connect nephrons to a minor calyx or directly to the renal pelvis. The collecting duct participates in electrolyte and fluid balance through reabsorption and excretion, processes regulated by the hormones aldosterone and vasopressin.

<span class="mw-page-title-main">Renal physiology</span> Study of the physiology of the kidney

Renal physiology is the study of the physiology of the kidney. This encompasses all functions of the kidney, including maintenance of acid-base balance; regulation of fluid balance; regulation of sodium, potassium, and other electrolytes; clearance of toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.

<span class="mw-page-title-main">Mineralocorticoid</span> Group of corticosteroids

Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances. The primary mineralocorticoid is aldosterone.

<span class="mw-page-title-main">Loop of Henle</span> Part of kidney tissue

In the kidney, the loop of Henle is the portion of a nephron that leads from the proximal convoluted tubule to the distal convoluted tubule. Named after its discoverer, the German anatomist Friedrich Gustav Jakob Henle, the loop of Henle's main function is to create a concentration gradient in the medulla of the kidney.

<span class="mw-page-title-main">Potassium-sparing diuretic</span> Drugs that cause diuresis without causing potassium loss in the urine and leading to hyperkalemia

Potassium-sparing diuretics or antikaliuretics refer to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The steroidal aldosterone antagonists can also be used for treatment of primary hyperaldosteronism. Spironolactone, a steroidal aldosterone antagonist, is also used in management of female hirsutism and acne from PCOS or other causes.

<span class="mw-page-title-main">Metabolic alkalosis</span> Abnormally high tissue pH due to metabolic dysfunction

Metabolic alkalosis is an acid-base disorder in which the pH of tissue is elevated beyond the normal range (7.35–7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct result of increased bicarbonate concentrations. The condition typically cannot last long if the kidneys are functioning properly.

<span class="mw-page-title-main">Hyperaldosteronism</span> Excess aldosterone in the body

Hyperaldosteronism is a medical condition wherein too much aldosterone is produced. High aldosterone levels can lead to lowered levels of potassium in the blood (hypokalemia) and increased hydrogen ion excretion (alkalosis). Aldosterone is normally produced in the adrenal glands.

<span class="mw-page-title-main">Mineralocorticoid receptor antagonist</span> Drug class

A mineralocorticoid receptor antagonist or aldosterone antagonist, is a diuretic drug which antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is often used as adjunctive therapy, in combination with other drugs, for the management of chronic heart failure. Spironolactone, the first member of the class, is also used in the management of hyperaldosteronism and female hirsutism. Most antimineralocorticoids, including spironolactone, are steroidal spirolactones. Finerenone is a nonsteroidal antimineralocorticoid.

<span class="mw-page-title-main">Liddle's syndrome</span> Medical condition

Liddle's syndrome, also called Liddle syndrome, is a genetic disorder inherited in an autosomal dominant manner that is characterized by early, and frequently severe, high blood pressure associated with low plasma renin activity, metabolic alkalosis, low blood potassium, and normal to low levels of aldosterone. Liddle syndrome involves abnormal kidney function, with excess reabsorption of sodium and loss of potassium from the renal tubule, and is treated with a combination of low sodium diet and potassium-sparing diuretics. It is extremely rare, with fewer than 30 pedigrees or isolated cases having been reported worldwide as of 2008.

<span class="mw-page-title-main">Bartter syndrome</span> Medical condition

Bartter syndrome (BS) is a rare inherited disease characterised by a defect in the thick ascending limb of the loop of Henle, which results in low potassium levels (hypokalemia), increased blood pH (alkalosis), and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic. A closely associated disorder, Gitelman syndrome, is milder than both subtypes of Bartter syndrome.

<span class="mw-page-title-main">Afferent arterioles</span> Blood vessels supplying nephrons of kidneys

The afferent arterioles are a group of blood vessels that supply the nephrons in many excretory systems. They play an important role in the regulation of blood pressure as a part of the tubuloglomerular feedback mechanism.

<span class="mw-page-title-main">Reabsorption</span> Part of the function of the kidney

In renal physiology, reabsorption, more specifically tubular reabsorption, is the process by which the nephron removes water and solutes from the tubular fluid (pre-urine) and returns them to the circulating blood. It is called reabsorption (and not absorption) because these substances have already been absorbed once (particularly in the intestines) and the body is reclaiming them from a postglomerular fluid stream that is on its way to becoming urine (that is, they will soon be lost to the urine unless they are reabsorbed from the tubule into the peritubular capillaries. This happens as a result of sodium transport from the lumen into the blood by the Na+/K+ATPase in the basolateral membrane of the epithelial cells. Thus, the glomerular filtrate becomes more concentrated, which is one of the steps in forming urine. Nephrons are divided into five segments, with different segments responsible for reabsorbing different substances. Reabsorption allows many useful solutes (primarily glucose and amino acids), salts and water that have passed through Bowman's capsule, to return to the circulation. These solutes are reabsorbed isotonically, in that the osmotic potential of the fluid leaving the proximal convoluted tubule is the same as that of the initial glomerular filtrate. However, glucose, amino acids, inorganic phosphate, and some other solutes are reabsorbed via secondary active transport through cotransport channels driven by the sodium gradient.

<span class="mw-page-title-main">Peritubular capillaries</span> Blood vessel

In the renal system, peritubular capillaries are tiny blood vessels, supplied by the efferent arteriole, that travel alongside nephrons allowing reabsorption and secretion between blood and the inner lumen of the nephron. Peritubular capillaries surround the cortical parts of the proximal and distal tubules, while the vasa recta go into the medulla to approach the loop of Henle.

In the physiology of the kidney, tubuloglomerular feedback (TGF) is a feedback system inside the kidneys. Within each nephron, information from the renal tubules is signaled to the glomerulus. Tubuloglomerular feedback is one of several mechanisms the kidney uses to regulate glomerular filtration rate (GFR). It involves the concept of purinergic signaling, in which an increased distal tubular sodium chloride concentration causes a basolateral release of adenosine from the macula densa cells. This initiates a cascade of events that ultimately brings GFR to an appropriate level.

<span class="mw-page-title-main">11-Deoxycorticosterone</span> Chemical compound

11-Deoxycorticosterone (DOC), or simply deoxycorticosterone, also known as 21-hydroxyprogesterone, as well as desoxycortone (INN), deoxycortone, and cortexone, is a steroid hormone produced by the adrenal gland that possesses mineralocorticoid activity and acts as a precursor to aldosterone. It is an active (Na+-retaining) mineralocorticoid. As its names indicate, 11-deoxycorticosterone can be understood as the 21-hydroxy-variant of progesterone or as the 11-deoxy-variant of corticosterone.

Pseudohypoaldosteronism (PHA) is a condition that mimics hypoaldosteronism. Two major types of primary pseudohypoaldosteronism are recognized and these have major differences in etiology and presentation.

<span class="mw-page-title-main">Diuretic</span> Substance that promotes the production of urine

A diuretic is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics increase the excretion of water from the body, through the kidneys. There exist several classes of diuretic, and each works in a distinct way. Alternatively, an antidiuretic, such as vasopressin, is an agent or drug which reduces the excretion of water in urine.

References

  1. 1 2 3 4 Prakash ES (2005). ""Aldosterone escape" or refractory hyperaldosteronism?". MedGenMed. 7 (3): 25. PMC   1681639 . PMID   16369251.
  2. ↑ August, J. Thomas; Nelson, Don H.; Thorn, George W. (1958-11-01). "Response of Normal Subjects to Large Amounts of Aldosterone1". Journal of Clinical Investigation. 37 (11): 1549–1555. doi:10.1172/JCI103747. ISSN   0021-9738. PMC   1062837 .
  3. 1 2 Young, WF (May 2024). Connor, RF (ed.). "Pathophysiology and clinical features of primary aldosteronism". UpToDate. Wolters Kluwer.
  4. ↑ Baek, Eun Ji; Kim, Sejoong (2021). "Current Understanding of Pressure Natriuresis". Electrolytes & Blood Pressure. 19 (2): 38. doi:10.5049/EBP.2021.19.2.38. ISSN   1738-5997. PMC   8715224 .
  5. ↑ Hall, J E; Granger, J P; Smith, M J; Premen, A J (March 1984). "Role of renal hemodynamics and arterial pressure in aldosterone "escape"". Hypertension. 6 (2_pt_2). doi:10.1161/01.HYP.6.2_Pt_2.I183. ISSN   0194-911X.
  6. 1 2 Schrier, R (Feb 2010). "Aldosterone 'escape' vs 'breakthrough'". Nature Reviews Nephrology.
  7. ↑ Wang, Xiao-Yan; Masilamani, Shyama; Nielsen, Jakob; Kwon, Tae-Hwan; Brooks, Heddwen L.; Nielsen, Søren; Knepper, Mark A. (2001-07-15). "The renal thiazide-sensitive Na-Cl cotransporter as mediator of the aldosterone-escape phenomenon". Journal of Clinical Investigation. 108 (2): 215–222. doi:10.1172/JCI10366. ISSN   0021-9738. PMC   203017 .
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