These doctors must have a low workload...

Someone didn't think this sign through. It's from the same hospital I work at...

An approach to hypernatraemia

Now that we've dealt with the commonest derangement of sodium concentration, it's time meet its rarer cousin: hypernatraemia. There are only two ways to become hypernatraemic: either you must lose water (at least in excess of sodium) or you must gain sodium (at least in excess of water).

What you'll need: serum sodium, urine sodium, urine osmolality¹, total urine daily volume.

Once again, there are three main questions to answer in working up the patient with hypernatraemia:

1. Is the hypernatraemia due to water loss or sodium gain? You can solve this riddle just by looking at the patient. If their extracellular fluid volume is expanded (e.g. oedema), then they've gained sodium, either because:

• you gave it to them (iatrogenic administration of hypertonic saline or hypertonic sodium bicarbonate) - look for a higher urine sodium concentration; or
• they have an excess or mineralocorticoid - look for hypertension, and a hypokalaemic metabolic alkalosis; urine sodium is variable.

You can now stop looking. However, if the extracellular fluid volume is anything but overloaded, then the hypernatraemia is due to water loss, and you must answer the second question.

2. Is this water loss renal or extrarenal? You judge this by looking at the urine results. If the loss is extrarenal (e.g. gastrointestinal water loss, or insensible water loss), then the kidneys will respond appropriately by excreting a small volume (~500 mls), hypertonic (more than 800 mosmol/kg) urine. Hooray! Have you found your cause of hypernatraemia yet? If not, then the kidneys must be to blame, and you must answer the third question.

3. Is the renal water loss due to a diuresis? Either an osmotic diuresis (e.g. flushing out masses of glucose after a diabetic ketoacidotic episode has been treated) or a diuretic will cause water to be lost in the urine, usually in excess of sodium. In either case, the daily urine osmole excretion rate will be high (more than 750 mosmol per day). Calculate this by multiplying the urine osmolality by the urine volume. For example, if the urine osmolality is 400 mosmol and the amount of urine passed in a day is 2.5 litres, then the daily urine osmole excretion rate will be:

400 ⨯ 2.5 = 1000 mosmol/day

If the excretion rate isn't high, then your patient sadly has diabetes insipidus. Further workup will include differentiating nephrogenic from central diabetes insipidus - for instance, by administering desmopressin.

Hopefully that wasn't too painful! In the next post, you'll have the opportunity to put your physiology to the test a bit...

Notes:

1. In hypernatraemia, unlike hyponatraemia, you don't have to worry about other osmolytes (like glucose) getting in the way of your reasoning. You can safely assume that hypernatraemia is a hyperosmotic state, and so you don't need to pull a serum osmolality.

An approach to hyponatraemia

Hyponatraemia is arguably the commonest metabolic derangement in medicine, and yet it can be tricky to pin down. There are extensive and complicated algorithms that can be worked through, but I've condensed many of them into what follows below.

What you'll need: serum sodium, serum osmolality, urine sodium, urine osmolality.

1. Look at the serum osmolality. Since sodium is the major determinant of extracellular fluid's osmolality, a low sodium should be reflected by a low serum osmolality. If the osmolality is low, go to step 2.

If the osmolality is high instead, then you need to find the extracellular osmolyte that's sucking water from the intracellular compartment (thereby decreasing the sodium concentration). There are only two important causes here - glucose and mannitol.

If the osmolality is normal, then you may be dealing with a case of pseudohyponatraemia. This occurs when a solid is present in the blood in increased amounts. This solid takes up such an amount of space that there is less sodium per volume of blood. Examples of such offending substances are massively elevated triglycerides and the excessively elevated serum proteins that occur in Waldenström's macroglobulinaemia.

2. Look at the extracellular fluid volume. If it's increased (e.g. oedema), this implies that both sodium and water are excessively high in this patient (it's just that the water's increase outnumbers the sodium's increase here). The major diseases in this category are cirrhosis, cardiac failure, renal failure, and nephrotic syndrome.

If the extracellular fluid volume is decreased (e.g. the patient is dehydrated, or hypovolaemic) then sodium is being lost somewhere. If it's being lost in the urine, the urine sodium concentration will be inappropriately high (> 20 mmol/L). This occurs with diuretics and with hypoaldosteronism. If it's being lost elsewhere, the kidneys will try their best to hang on to any sodium, and so the urine sodium concentration will generally be less than 20 mmol/L. Such conditions include vomiting, diarrhoea, burns and even excessive sweating.

If the extracellular fluid volume is normal, then there are three conditions to consider: SIADH, hypothyroidism and Addison's disease. These can usually be easily distinguished with a few further tests (e.g. TSH).

3. Still no luck? If none of the above categories fit, check that the patient's urine osmolality is appropriately low (it should be less than 100 mosmol/L). If this isn't the case, consider whether it's possible that the patient is drinking (or receiving via IV fluids) more than 20-30 L per day. Needless to say, this isn't a common cause of hyponatraemia! However, if it ever does manage to occur, the amount of water taken in will exceed the kidney's ability to excrete it, and the sodium concentration will drop accordingly.

I think that the above schema is quite handy, but feel free to amend it to suit your own desires. Now, if you're feeling strong, click onwards and look at an approach to hypernatraemia.

Sodium and Water (4) - The difference

OK, in the last post, I alluded to the difference between maintaining the body's water balance and maintaining the body's sodium balance. It's quite an important distinction, and it's clinically relevant too.

If you increase or decrease the total body water independently of its sodium content, then it follows that the sodium concentration will be altered. Think about it: if I have 100 mmol of sodium in one litre, but I then add 200 mls of water, I've changed the sodium concentration from 100 mmol/L to 83 mmol/L [100/1.2]. But changing the sodium concentration hasn't meant that I've changed the sodium content (amount) - which has remained the same, at 100 mmol, no matter how much water I've added.

Therefore, as a general rule, changes in sodium concentration reflect disturbed water homeostasis. The problem will lie with one of the regulators of water balance, then: water intake or AVP.

Now look what happens if I take a human body and force it to retain sodium. You might think that the sodium concentration would again be affected, but remember that sodium is highly osmotically active: it more or less drags an equal amount of water with it. Therefore, reabsorbing (or failing to excrete) sodium will not change the body's sodium concentration. Rather, it will cause there to be a rise in the total amount (content) of sodium and water in the body.

Therefore, as a general rule, changes in sodium content cause hyper- or hypovolaemia. Clinically, this manifests as oedema or dehydration/shock respectively. The problem lies with one of the regulators of sodium balance, usually the renin-angiotensin-aldosterone system.

Before this gets too theoretical, let's look at a few clinical examples.

1. Cardiac failure - in this state, the sodium concentration is often low, and the patient is oedematous. From this, we can infer that (1) water is being retained in excess of sodium, causing hyponatraemia, and (2) the body contains too much of both sodium and water, causing oedema. Sure enough, treatment involves water and salt restriction, and diuretics to promote water and salt loss.
2. Diarrhoea - the sodium level here can be low, normal or high depending on whether sodium is lost in excess of water or vice versa. For the sake of argument, let's say that in this patient the sodium is low. Regardless of the sodium level, however, the patient is certainly dehydrated. Therefore, unlike in cardiac failure, the treatment of hyponatraemic diarrhoea will include giving (not restricting) sodium and water (e.g. via intravenous normal saline).

In the next post, we'll discuss an approach to hyponatraemia.

Sodium and Water (3) - Sodium Balance

In the previous post, we discussed how the body regulates its free water content. Now we turn to sodium regulation.

We can lose a minimum of about 100 mmol per day. Therefore, this is the amount that we need to ingest on a daily basis. You lose some sodium in your sweat, and some sodium in your faeces, but these are largely unregulated losses. The place where the body does its sodium bookkeeping is in the kidneys.

Of the filtered load of sodium, about 98% is reabsorbed:

1. Two thirds is reabsorbed in the proximal convoluted tubule.
2. One quarter is reabsorbed in the thick ascending loop of Henle (via the Na⁺/K⁺/2Cl^- cotransporter)
3. About 5% is reabsorbed at the distal convoluted tubule (by the thiazide -sensitive Na⁺/Cl^- cotransporter.

These channels aren't particularly regulated from a sodium perspective. Rather it is at the last stage that the body finally turns its attention to the fate of sodium.


4. The remaining sodium reabsorption occurs at the distal proximal tubule, and in the cortical and medullary collecting tubules. This stage is sensitive to hormonal manipulation.

And what are these sodium-controlling hormones? The most famous is aldosterone, which causes the principal cells in this area to reabsorb sodium (in exchange for potassium). Incidentally, it also performs as similar swap in the gut, although this is a less important phenomenon.

A slightly less well-known hormone is atrial natriuretic peptide, which is secreted in response to atrial stretch. It promotes sodium loss directly (by inhibiting distal tubular sodium reabsorption) and indirectly (by decreasing renin, one of the controlling hormones for aldosterone release).

In a similar class is brain natriuretic peptide, which is secreted in response to ventricular stretch and has similar properties to its atrial counterpart. (Note, it doesn't come from our brains, despite the name!)

Between them, these three hormones regulate the amount of sodium in our bodies. They don't really regulate sodium concentration though - this is the job of the body's water balance system described in the previous post. It's important not to get this mixed up. If your patient comes back with a low serum sodium concentration, he may still have a high total body sodium content.

If this last point seems a bit oblique, don't worry: we'll spend a bit of time on it next.

Sodium and Water (2) - Water balance

To maintain a steady state, your intake of a substance must equal your loss of that substance, and water is no exception. So what are you obligatory water losses - those losses that you can't help but sustain?

First up, the kidney can only concentrate substances up to a maximum of 1200 mosmol/L. Since we produce about 600 msomol of substances per day, that means that you have to urinate out about 500 ml per day, no matter how inconvenient this is.

Next, we have evaporation from the skin, which totals a minimum of about 400 ml per day. If you're exercising, or out in the hot sun, this amount can increase to a staggering 5 L.

Then there's evaporation from our respiratory tracts. The air we breathe in has a lot less water vapour in it than it ends up with as it descends into our lungs - water evaporates from our moist mucosa to join it. Under normal conditions, the amount of water lost in this way is about 350 ml, but this number will increase rapidly if you are breathing heavily or rapidly.

Lastly, there is fluid loss in our stools, which as we all know aren't perfectly dry. The body is actually quite good at retaining fluid from our gastrointestinal tracts, and so we only lose an average of about 100 ml per day via defaecation.

OK, so under optimal conditions, this means that we lose about 1400 ml per day, although usually it's a bit more than this. Therefore, this is the minimum amount if fluid we need to take in to keep in balance.

Fortunately, we don't have to do the calculation consciously: our intake of water is regulated by the sensation of thirst. Osmoreceptors, located in the anterior hypothalamus, are stimulated by the rise in osmolarity that corresponds to water depletion. As a result, we drink more and the status quo is preserved.

On the other hand, what if we've taken too much water on board, and need to excrete the excess? The kidneys come to the rescue here: they are capable of excreting urine with an osmolality of just 50 mosmol/L and so can get rid of large volumes of water (without necessarily increasing the renal losses of other substances). The principle determinant of renal water excretion is arginine vasopressin (AVP, also known as antidiuretic hormone - ADH). This polypeptide hormone is secreted by the posterior hypothalamus and acts on the V2 receptors of the kidney (mainly in the collecting tubules and ducts). Binding of the hormone causes these cells to insert water channels (aquaporins) into their luminal membrane, thereby massively increasing the permeability of these cells to water. The water can then passively move from the 'urine' side back into the cells and hence back to the body.

Between them, thirst and AVP are the two main mechanisms that preserve a constant body osmolality.

Ineffective vs effective osmoles

Here's a challenge for you. In the previous post, I said that examples of ineffective osmolytes were urea and glucose. That's because these two substances, although osmotically active, could easily distribute themselves across the various body compartments and so wouldn't cause fluid shifts from one compartment to the other. Although this is true in health, what happens in the case of diabetes?

The answer, of course, is that glucose becomes an effective osmolyte, capable for causing fluid shifts from the intracellular to the extracellular compartments. This is because diabetics have a (relative or absolute) lack of insulin, which is required for glucose entry into many cell types. Thus, for all intents and purposes, glucose becomes more confined to the extracellular compartment in diabetes.

This has serious implications, since the resultant fluid shifts are a major part of the pathogenesis of both diabetic ketoacidosis and the hyperosmolar non-ketotic state, which you've probably heard about.