Hypoosmolar hyponatremia with concentrated urine and low urine sodium is a state where there is either an actual low extracellular volume (and water and sodium are being appropriately retained by the kidneys), or a volume overloaded state where the renal mechanisms have been fooled into retaining sodium and water by some other pathological process.
The college loves this aspect of sodium physiology, and it is well represented in the papers:
Imagine the state of sodium handling following a massive blood loss. The renin-angiotensin-aldosterone system is busy trying to retain as much water as possible. Sodium resorption is maximal, to maintain extracellular fluid volume; water retention is maximal because the hypotension has resulted in vasopressin release and the collecting duct is highly water-permeable. While the sodium resorption tries to restore the extracellular volume and extracellular sodium, there will be a hyponatremia.
This is a hyponatremia which occurs in people who have suffered an extracellular fluid loss. Crippling diarrhoea or vomiting, burns, blood loss, third-spacing into an oedematous post-laparotomy abdomen - the list is endless.
Naturally, one may want to treat this with normal saline. Both extracellular fluid and sodium will be replenished in this way.
In these situations, the renin-angiotensin-aldosterone system is activated inappropriately. Whereas in fact oedema and fluid overload may be the reality, the kidneys are convinced that there is an extracellular fluid deficit.
All of these forms of hyponatremia are treatable by ACE-inhibition and with loop diuretics.
A low output state (where the cardiac output is reduced) results in a decreased salt delivery to the macula densa, which in turn activates the renin-angiotensin-aldosterone system. Sodium and water retention are the result; this oedematous patient will have low serum sodium as well as a low urine sodium, with a decreased volume of concentrated urine. Sica (2005) describes these mechanisms very well. Basically, the decreased baroreceptor stimulation in advanced heart failure leads to an increased ADH release even while the extracellular fluid becomes more and more hypotonic, because the defence of volume trumps the defence of tonicity. The urine should be relatively sodium-poor (Weber, 2001), and though precise numbers are difficult to find, a study by Cody et al (1986) quoted daily excretion rates of 24 mmol/d of sodium for patients identified as "sodium retainers" (i.e. a random urinary sodium concentration of 12mmol/L assuming 2000ml of urine).
Cirrhosis may actually be a high-output state (with a hyperdynamic circulation) - but the arterial blood pressure is still low, owing to the systemic vasodilation. Why the vasodilation? Anybody's guess, really. It is though that nitric oxide secretion plays a role; it is thought that intestinal bacterial endotoxins cause this, as they are no longer being cleared from the portal blood by the useless wooden liver.
In any case, the arterial vasodilation activates the renin-angiotensin-aldosterone system, and again water and sodium is retained. It does not help that the liver is responsible for the metabolism of about 1/3rd of the secreted vasopressin.
Third space distribution of fluid is the key factor in the mechanism of hyponatremia due to nephrotic syndrome. Because of the low serum protein, oncotic pressure is reduced and fluid migrates out of the intravascular compartment, reducing the effective circulating volume. Again, the renin-angiotensin-aldosterone system responds by increasing sodium and water retention.
Now, Question 29 from the first paper of 2015 asked the candidates to "outline the pathophysiological mechanisms responsible for the hyponatraemia commonly seen in hepatic and renal failure", for 20% of the marks. That seemed valuable enough to merit a subheading of its own. In addition to the brief explanations offered above, one should have a short paragraph up one's sleeve which can be regurgitated if this topic ever comes up again. The answer should focus not only on the effect of apparent hypovolemia, but also on the renal tubular defects. Thus:
This is a situation of low serum sodium, in spite of which sodium losses are continuing.
The "high" urine osmolality threshold here is only 100 mOsm/Kg; this is in fact quite a low osmolality (seeing as a laboratory value for normal urine osmolality is typically about 400-700 mOsm/Kg). This threshold value has been selected because it encompasses a number of conditions where quite dilute urine is being passed (eg. post-obstructive diuresis, polyuric phase of ATN).
Thiazide diuretics do this more frequently than the others.
For some reason, the ratio of women to men is about 4:1. It usually happens in the first few weeks.
The mechanism of this hyponatremia rests on the tendency of diuretics to produce volume depletion, which in turn causes ADH secretion, which in turn causes water retention - with ongoing sodium loss (so the urine ends up being more sodium-rich than the plasma!). Unlike the loop diuretics, the thiazides do not impair the medullary osmotic gradient, and ADH can still cause the reabsorption of water into the medulla (whereas the loop diuretics interfere with the medullary gradient, rendering ADH less effective). The result is a failure to dilute urine, combined with a failure to reabsorb sodium. There is an excellent review article on this topic, available free from PubMed.
The most appropriate response to this sort of hyponatremia (apart from ceasing the thiazide) is normal isotonic saline. Both the sodium and the water usually need to be replaced. The college has explored this problem in Question 5.1 from the second paper of 2011, were they gave us a woman in a state of volume-depleted shock, obtunded and with a serum sodium of 103 mmol/L. The following suggestions for management were made in the discussion section of this question:
Sodium transport in the proximal tubule relies on the action of Na+/K+ ATPase sucking sodium out of the cell (and into the peritubular capillary), maintaining a gradient to drive the Na+/H+ antiporter which gets sodium out of the tubular lumen. Obviously, this is a hungry process. It demands vast quantities of ATP. In a state of ischaemia, this process breaks down, and sodium remains in the proximal tubule lumen. Seeing as about 85% of sodium resorption occurs here, one might expect a significant resorption problem to occur in acute tubular necrosis.
Indeed it does occur. With sodium transport in the tubules being such an energy-intensive process, one cannot expect the war-ravaged post-necrosis tubules to squander their scarce resources on moving ions back and forth. They are too busy healing. Furthermore, they are resistant to aldosterone and ADH. The result is a failure to reabsorb the sodium as it travels down the tubule, as well as a failure to reabsorb water. Once the glomerulus recovers, it sends a normal amount of fluid through the tubule, but the tubule simply doesn't care.
The resulting urine is likely to be reasonably dilute (above 100mOsm/Kg is still quite dilute) but with an abnormally high urinary sodium. Replacement with normal saline seems to be the treatment of choice.
Weirdly, one cannot find any good data in the literature to discuss this process. textbooks discuss acute renal failure and ATN, throw away a line about how glomerular filtration normalises but tubular resorption doesn't, and then they move on. It is possible that nobody has a good handle on what precisely happens here. The glorious College of Intensive Care Medicine (in an exam question quite possibly written by Rinaldo Bellomo) report that polyuric ATN urine usually has an osmolality below 350-450 mosmol/kg "in almost all cases".
In acute renal failure, the urine osmolality is unpredictable. A combination of tubule dysfunction and reduced urine delivery to the distal nephron reduces its ability to reclaim sodium from the tubular lumen; however the ability to concentrate urine (i.e. ADH responsiveness of the collecting duct) may still be preserved. In chronic renal failure, the urine osmolality trends towards about 300mOsm/Kg ("isosthenuria"). Water intake in these patients is not matched by excretion, and a dilutional hyponatremia develops; the sodium loss occurs because of insufficient efforts to reclaim it from the tubules.
Fluid restriction tends to improve the situation in these patients.
Aldosterone activates the ENaC channel in the collecting duct, which causes resorption of sodium (and thus forces excretion of potassium). Loss of aldosterone, eg. Addisons disease, results in decreased sodium resoprtion, and increased potassium retention – thus the hyponatremia and hyperkalemia. Not only that - but cortisol itself acts an inhibitor of ADH secretion; less circulating cortisol means more circulating vasopressin. The result is water retention, and concentrated sodium-rich urine.
This can occur either because of primary adrenal insufficiency, or because of an aldosterone deficiency, or when exogenous steroids are withdrawn, or when aldosterone receptors are blocked (eg. by massive amounts of spironolactone). Exogenous corticosteroids tend to remedy this problem rapidly and completely.
The pathophysiology of this is incompletely understood, even though we have known about this since the 1950s. It does not seem to be a problem with inappropriate ADH hypersecretion, according to the more recent reviews. The vasopressin levels are usually high in these people but the mechanism seems to be a matter of ADH-induced water retention, in response to a decreased cardiac output which causes decreased renal blood flow. The situation is therefore analogous to the hyponatremia of cardiac failure. The college presented such a thing in Question 30.1 from the first paper of 2014, where a patient presents with amiodarone-induced myxoedema coma. The patient in that scenario is hypotensive bradycardic and cold, with a raised CK and cholesterol.
Thyroxine, predictably, is the solution. Don't forget to supplement with hydrocortisone.
The college has asked about this in Question 30.1 from the second paper of 2016, where a postpartum haemorrhage patient presents with hyponatremia, lethargy and failure to lactate. This is due to pituitary infarction which results from hypotension during postpartum haemorrhage, and is known as Sheehan's syndrome. Its an fairly uncommon complication.
As one might imagine, elevated vasopressin levels tend to result in water retention, and a dilutional hyponatremia develops. These patients have no way of increasing their water excretion in response to an increased water intake. The urinary mechanisms of solute excretion remain intact, hence the high urinary sodium. In fact, as you keep giving sodium to these people, so their urinary sodium excretion will continue to ramp up, until they look like they are "sodium wasting" They are not wasting anything: they are simply trying to maintain an even balance in the face of increased sodium intake.
SIADH has attracted a sufficuient attention from the college examiners to merit a chapter dedicated all to itself. Instead of duplicating that material here, to simplify revision. I will list some of the causes of SIADH below, as well as the widely acknowledged criteria for its diagnosis.
Diagnostic criteria for SIADH:
Natriuretic peptides such as BNP and ANP are thought to be the cause of this. One can imagine the injured brain releasing BNP as its cells decompose; however in humans there is not much BNP in brain tissue (it was first named after being discovered in porcine brains, where it for some reason exists in higher concentration). Whatever the (poorly understood) cause, a diuresis with natriuresis occurs, and the brain-injured patient dehydrates gradually as electrolyte-rich urine issues forth.
The key feature if hypovolemia. These patients are dry and they produce a high urine output; in contrast SIADH patients are normovolemic, and have low urine output. The trick to discriminating between these two conditions lies in the ability to demonstrate that the body fluid volume is decreased. In both conditions the ADH level is elevated, but in cerebral salt wasting the ADH is elevated appropriately because the patient is hypovolemic, and so it cannot possibly be SIADH by definition.
Now, this statement is not to be taken as an endorsement of CSW as a genuine disease state; many smarter people with serious endocrinology cred argue that it may not exist. The controversy is discussed in greater detail in the Required Reading chapter on cerebral salt wasting from the Neurology and Neurosurgery section.
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