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.

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.

What is the Schilling Test?

The Schilling Test is an investigation, conducted in two parts, that is done to determine the cause of a vitamin B12 deficiency.

Under normal circumstances, vitamin B12 is found in animal products.  Upon ingestion, stomach acid releases the B12 from the food, and it binds to intrinsic factor, a glycoprotein that binds to and protects B12 from further degradation.  The B12-intrinsic factor then travels down the intestine as usual, and is absorbed at the terminal ileum.

A B12 deficiency can therefore result from two general categories.  Either:

• not enough is being eaten - e.g. strict vegans, or 
• not enough is being absorbed - intrinsic factor deficiency (from chronic atrophic gastritis, or stomach surgery), disease or resection of the terminal ileum (e.g. Crohn's), or bacterial overgrowth of the bowel (bacteria also like B12!)
  

The Shilling test helps to shed some light as to the B12 deficiency's aetiology.  As I mentioned, there are two parts to it.

In the first phase, the aim is to determine whether or not there is an absorption problem (i.e. one of the second category's causes).  Firstly, a B12 injection is administered intramuscularly, so that the body's stores are saturated.  Thereafter radiolabeled B12 is given orally.  Because the body's stores are full, the additional oral B12 should be absorbed but not well utilised by the tissues, and so a significant proportion (> 5%) should end up in the urine.  If this figure is less than 5%, it can be assumed that not enough of the oral B12 was absorbed.

The second part of the test seeks to determine whether this malabsorption is due to intrinsic factor deficiency.  The protocol is the same, except that intrinsic factor is administered along with the oral B12.  If the problem was a shortage of intrinsic factor, this should remedy things.  On the other hand, if B12 is still not well absorbed despite this, it implies that the malabsorption was not due to an intrinsic factor deficiency.  You obviously only need to do the second part of the Schilling test if the first one showed a pathological result.

What is the commonest cause of a metabolic alkalosis?

The answer is ... vomiting.  

In fact, if significant, this is so overwhelmingly likely to be the initial cause that secretive purging behaviours (e.g. in bulimia nervosa) should be suspected if vomiting is denied.  In a hospitalised patient, nasogastric drainage can give you the same effect.

Of course there are other causes though.

In the case of vomiting, you get a metabolic alkalosis because you are losing hydrogen ions and chloride ions from the stomach (remember, it contains hydrocholoric acid - HCl).  The hydrogen ions need replacing, and this will cause a metabolic alkalosis on its own, but chloride also contributes via a more deviantly indirect method.  Hypochloraemia means that less sodium can be absorbed proximally by the kidney (the two are absorbed together).  This means that the sodium load to the distal parts of the kidney is increased.  The body, desperate to reabsorb the sodium (to thereby reabsorb the water too), has no option but to take in the extra sodium at the cost of excreting more potassium and/or ... hydrogen.  Thus, vomiting is typically characterised by a hypochloraemic, hypokalaemic metabolic alkalosis.

What are the causes of low serum potassium?

(A.k.a. "What are the causes of 'hypokalemia', or 'hypokalaemia?" Damn this transatlantic spelling thing.)

As usual, any answer to a question beginning with "What are the causes of ... " would keep you writing to the end of time. The key is to have an approach to the problem that helps you remember more of the causes than the 'scattershot approach', and that is hopefully clinically relevant.

A general schema for causes of a low that I use is as follows:

• Too little going in.
• Too much being destroyed / used up.
• Too much hiding somewhere else.
• Too much being lost from the body.

For example, in the case of low platelets (thrombocytopenia) an example from each category would be:

• Ineffective marrow production
• Immune thrombocytopenia (autoimmune destruction of the platelets)
• Hypersplenism (platelets being sequestered in a huge spleen)
• (Hmm, there aren't really any good examples for this category, but you get the picture.)

Now let's use the schema for dealing with low potassium:

• Deficient dietary intake (a rare cause on its own, since potassium abounds in most foods; however, this can still contribute.)
• You can't very well destroy potassium (short of a nuclear explosion) since they are nice 'indivisible' atoms. This category doesn't therefore apply to any of the atoms or ions.
• On the other hand, 'hiding somewhere else' is a major cause of hypokalaemia, in the form of an intracellular shift. Anything that stimulates the sodium/potassium ATPase on cells will do this, and thus certain elevated hormones (insulin, beta-adrenergics) lower the extracellular potassium nicely by hiding some of it inside cells. Other ways to get more potassium inside cells is to make more cells (e.g. some cancers, treatment of B12 or folate deficiency) or to get a metabolic alkalosis (hydrogen ions usually compete for intracellular binding sites; the less of them around, the more potassium gets to go indoors.)
• Excreting too much potassium from the body is also a famous way to have a hypokalaemia. Broadly, the potassium may be lost by the kidney (most commonly secondary to diuretics), the gut (as in diarrhoea) or, less commonly, through sweat.

There you go. Now, into this schema you can insert as many causes as you need. It also suggests a way to work up a person with hypokalaemia too, if you think about it.

What are the symptoms of hypokalemia?

(That's 'hypokalaemia' if you're outside of North America!)

Physiologically, hypokalaemia's dominant effect is the hyperpolarisation of cells. Remember that there is an electrochemical gradient across our cells: the complicated arrangement of the various ions on either side of our cells ends up making the interior of the cells negative, relative to their outsides. Sometimes this is referred to as the resting membrane potential, and this fact is exploited by excitable cells like neurones and muscle cells - the right signal causes rapid changes in the membrane potential, setting off a chain reaction that culminates in something useful (like the muscle contracting).

With less positively charged potassium ions on the outside of the cell (the definition of hypokalaemia), potassium ions from within the cell leave to replace them, causing the inside of the cell to become even more negatively charged than before. The result is that the cells become 'hyperpolarised' - less likely to fire off action potentials.

From this fact, most of the symptoms can be deduced:

• Cardiac arrhythmias can be induced by hypokalaemia. Also, certain ECG changes are typical: increased PR interval (slowed atrio-venticular conduction) and flattened or inverted T-waves (delayed repolarisation) are seen.
• Skeletal muscle weakness may exist, and occasionally be profound (anybody unlucky enough to see a hypokalaemic kwashiorkor child will attest to this). It usually involves the peripheral muscles, sparing the facial and respiratory muscles. At the final end of the continuum, rhabdomyolysis (destruction of skeletal muscle) may ensue.
• Smooth muscle weakness usually manifests clinically as constipation and paralytic ileus.
• Glucose intolerance is also sometimes found, and it is due to the fact that hypokalaemia impairs insulin release: the pancreas' beta cells also need to depolarise before the agree to give up their insulin.
• Polyuria and dehydration is the main symptom complex not directly caused by hyperpolarisation of cells. Potassium is the 'rate limiting' element to the thick ascending loop of Henle's Na+/K+/2Cl- pump (the others are usually present in abundance). A lack of potassium means that the pump can't absorb all the sodium it needs to, and since sodium carries water with it, you get both polyuria and dehydration.
• Metabolic alkalosis requires some expaining too, since it also isn't directly due to hyperpolarisation. At the distal parts of the kidney's nephrons, it is helpful to think of sodium being reabsorbed in exchange for either potassium or hydrogen. The situation is a little more complicated than this, but that doesn't matter. The point is that if potassium is low, more hydrogen must be booted out the cells to get enough sodium in. The result of this is, of course, a metabolic alkalosis (which is fortunately usually quite mild).

EDIT: I forgot the last point off the original version of this post!

Is a high phosphate level (hyperphosphataemia) dangerous?

The commonest cause of hyperphosphataemia is renal insufficiency, but there are several other potential aetiologies. Mildly elevated serum phosphate levels probably aren't of much consequence, but they should prompt a search for the underlying diagnosis.

There are two side-effects of hyperphosphataemia:

• Inhibition of vitamin D 'activation' in the kidney: The production of Vitamin D is complex, but in its final stage, if you must know, 25-hydroxycholecalciferol is α1-hydroxylated, to form 1,25-dihydroxycholecaliferol. This latter substance more handily called 'calcitriol', or the active form of vitamin D. The above chemical reaction is inhibited by high phosphate levels. Why? Calcitriol stimulates calcium and phosphate absorption from the gut, and so it makes sense that phosphate should inhibit calcitriol synthesis, to prevent its levels from getting too high. Nonetheless, a lack of active vitamin D also therefore leads to lower calcium levels, which has its own set of attendant problems.



• Calcium precipitations: Calcium readily binds with phosphate if either one of them is too high. This compound is then deposited in vessels and tissue, where it may cause damage. It is actually possible to quantify this risk, although this is obviously only an approximation: the danger is real once the product of the serum calcium and phosphate levels (both in mmol/L) is greater than 4.4.

How do you treat hyperphosphataemia? There are several strategies, but first line therapy usually exploits phosphate's keenness to bind to cations: calcium or aluminium salts are given orally, and they bind phosphate in the gut, preventing it from being absorbed. Calcium salts are especially handy, since in renal insufficiency there will often be a concomitantly low serum calcium level [why? see here], and any left over calcium can contribute towards making up this deficit.

Why does vomiting produce hypokalaemia?

Recall that the stomach's chief acid is hydochloric acid - HCl. Therefore, it stands to reason that losing stomach contents causes low levels of both H⁺ and Cl^- ions in the blood. (Note: indirectly, of course. Blood levels of these ions drop because these ions are taken from the blood to make more stomach acid as a replacement.)

But why the hypokalaemia? You do lose a little potassium with the gastric fluid, but so little that it would take 30 to 80 L of vomitus to achieve the level of hypokalaemia seen in these patients! Clearly there is some other process going on, and as it turns out, the guilty organ is the kidney.

Recall that in the distal convoluted tubule, sodium may be absorbed in exchange for either potassium excretion or hydrogen ion excretion. (Actually, this is a two step process: first sodium is absorbed in exchange for potassium secretion, and then potassium can be reabsorbed in exchange for hydrogen ion secretion.) In cases of low H⁺, there are less hydrogen ions available to swap with sodium, and so more potassium ions must be excreted in their place. (Note that this cuts both ways - even if the primary insult were low potassium levels, as it is in other conditions, the end result would be the same: hypokalaemic alkalosis).

This may seem like a bizarre thing for the body to do - why not just reabsorb less sodium and thereby avoid this entire debacle? You may have a point, but the body has bigger fish to fry. Firstly, it needs the sodium to be reabsorbed, because significant vomiting often implies hypovolaemia. When ever you are short of water, your kidneys should reabsorb sodium, since it drags water with it by osmosis. Reabsorption of sodium is even more crucial at the distal convoluted tubule site, since the concurrent hypochloraemia makes it hard to reabsorb it proximally (where the two are reabsorbed together). Secondly, it is really important in an alkalosis to be absorbing as many hydrogen ions as possible, even if it means you have to swap them for a few potassium ions.

Hope that all made sense!

Can constipation ever lead to hyperkalaemia?

Actually, it can, but only really in the situation of chronic renal failure (now more properly called 'chronic kidney disease').

The kidney usually excretes a portion of potassium each day, and obviously in renal failure this isn't possible. In that case, the body relies on the gut to get rid of some of the potassium load - up to 30% of the potassium may be excreted in this fashion.

This is all ruined in the case of constipation, where slow transit time prevents this.

So yes, constipation can lead to hyperkalaemia, in a way. However, it will generally only do so when the kidneys are too hypo-functional to excrete enough potassium.

What is beta-2 microglobulin?

β2 microglobulin is a part of the Major Histocompatibility Complex Class 1 (!) molecules that our cells use as I.D. badges. As a cell dies or gets damaged there is a certain chance that this molecule will float off in the blood stream. Since the MHC 1 molecule (and thus β2 microglobulin) is part of almost every cell, there is always some β2 microglobulin detectable in the blood stream. And even though the kidney normally hates to filter proteins, it can't help but filter small ones like β2 microglobulin (and creatinine for that matter). However, it is normally totally reabsorbed and catabolised by the renal tubular cells, so that you don't lose precious protein into your urine.

This is where it gets interesting. If there were a tubular problem in the kidneys (e.g. acute tubular necrosis), β2 microglobulin would still be filtered by the glomeruli, but its reabsorption and catabolism would be impaired. Thus, finding it in the urine is indicative of tubular dysfunction.

On the other hand, finding an elevated level of β2 microglobulin in the blood tells us roughly the same thing as finding an elevated creatinine level in the blood - namely that you are likely to be dealing with renal dysfunction (e.g. chronic kidney disease) that involves (at least) the glomeruli, since you aren't filtering enough of it.

What's the cause of elevated HbA1c in hyperglycaemia?

One of the many dangers of having a chronically high blood glucose level is that proteins get glycoylated (a glucose gets 'added' to them). This can affect the protein's function, and this glycosylation is believed to be a major factor in explaining why uncontrolled diabetes is so bad for you.

HbA1c is just one of these many glycosylated proteins - it's actually your haemoglobin molecule that's had glucose added to it. The higher the blood glucose level, the more proteins are glycosylated, and so the higher the HbA1c. Since the process is irreversible, and since haemoglobin hangs around inside a red blood cell for about 120 days, the HbA1c is a good measure of CHRONIC (over the last 2-3 months) glucose control.

What is the fractional excretion of sodium?

The above-named test is one of several that help clinicians decide whether a case of acute renal failure (ARF) is due to a pre-renal cause or an intra-renal cause. Acute renal failure can also obviously be due to a post-renal cause, but this test doesn't help much with this distinction - and it better to rule such a cause out clinically anyway.

The test takes advantage of the fact that pre-renal causes of ARF are all due to renal hypoperfusion. The kidneys take this to imply (usually accurately) that the systemic blood pressure is low, and so they start shutting down to avoid you losing too much water courtesy of your urine. Also, in prerenal dysfunction, the renal tubules are intact, and they reabsorb as much filtered sodium as possible - sodium is highly osmotically active, and so this is one method of reabsorbing as much filtered water as possible.

On the other hand, the vast majority of intra-renal causes of ARF are due to acute tubular necrosis, where insults such as hypoperfusion and toxins cause the tubular cells to die. When this happens, the tubules will be unable to reabsorb the sodium appropriately.

So, the fractional excretion of sodium basically looks at what proportion of the plasma sodium finds itself in the urine. With pre-renal dysfunction, this figure will be low (most of the sodium is reabsorbed long before it gets to your bladder), whereas in acute tubular necrosis, the figure will be higher (less sodium reabsorption).

A clear consensus for normal values is sorely lacking, but most people agree that a fractional excretion of sodium (FE_Na) of > 3 indicates ATN.

The FE_Na can be calculated by the following formula:

(FE_Na) = (U_Na x P_Cr) / (P_Na x U_Cr) x 100

(where U stands for urinary and P stands for plasma)

What is creatinine clearance? (Part 2)

Hmm, I've been getting a lot of follow-up questions about my last post on this topic. On reflection, I don't think I answered it that well - I concentrated on deriving the formula from first principles, and neglected to give you a bird's eye view.

So, here's basically what it's about:

• 'Creatinine clearance' is the amount of creatinine filtered by the kidneys per minute.


• Since creatinine is freely filtered and not reabsorbed by the kidneys, the creatinine clearance is an estimate of the glomerular filtration rate (GFR), which is the amount of blood filtered by the kidneys every minute.


• The glomerular filtration rate is a useful number to know, since it provides us with a measure of renal function that precedes changes in the serum values of certain markers for renal dysfunction. For instance, in end-stage chronic renal failure, the serum creatinine will be raised, and this is all we need to assess renal function. However, at least 50% of the nephrons must be destroyed before the serum creatinine will rise, and so if we want to know about renal function before this point, we need to estimate the glomerular filtration rate, usually by measuring the creatinine clearance.


• Since creatinine is actively secreted by the renal tubules (in addition to being filtered), creatinine clearance overestimates the GFR by about 10-20%. In particular, when the GFR is very low, this secretion is proportionately very high, and so creatinine clearance isn't a good way to estimate GFR then. There are other things that can be measured instead of creatinine (e.g. inulin) that avoid this problem, but they are usually far less convenient or simple to administer.


• The formula for calculating the creatinine clearance is:




• Nomal values for this figure are 120 ± 25 for men, and 95 ± 20 for women. There are ways of increasing the accuracy of this figure by taking into account one's muscle bulk (from which creatinine is derived). See the Wikipedia entry on this for more detail on this point, but also bear in mind that this will alter the normal values.


• Finally, there are also formulae for estimating the creatinine clearance without collecting urine. These are less accurate, but much more convenient. One such common formula is:

where the constant is 1.23 for males and 1.04 for females. Note that this formula assumes that the creatinine is being measured in µmol/L. If it's being measured in mg/dL, use a different formula.

There, that's better!

What is creatinine clearance?

Let's approach the answer to this question in stages. I've chosen to work from first principles here, but if you get bored, never fear. You can safely skip from wherever you get up to until the nice pretty equation near the end!

The kidneys filter a truly enormous amount of blood each day (see below!). However, things like diabetes and hypertension can damage and destroy them, and so it's important to know how they are doing. How do we tell?

We can't very well look at the kidneys, since they're obviously hidden from sight. We could, I suppose, perform either surgery or a biopsy in order to bring a piece of kidney to us, but this seems a little extreme, to put it mildly.

No, let's rather try a more indirect method. The kidney is supposed to do certain jobs, so what if we checked on the outcomes of these jobs to see if the kidney was doing them adequately. This is analogous to me seeing if you're packing enough of my boxes by, rather than watching you, merely counting the number of boxes packed at the end of the day. A little indirect, granted, but it avoids the bloodshed of the biopsy option.

Great all, set then. We could choose urea, say, or creatinine - two things normally excreted by the kidney. We could measure their blood concentrations, and if these measurements were normal, we could presume that the kidneys were doing OK. On the other hand, elevated levels of either urea or creatinine would suggest to us that the kidneys weren't excreting enough of them (although we would have to exclude other causes).

But there's a snag. The kidneys are massively redundant - that is, they have lots of reserve. In fact, you have to kill off more than 50% of the glomeruli before the levels of things like urea and creatinine will rise at all. This is why it's reasonably safe (but not a good idea, all things being equal) to donate one kidney to someone else. Although this redundancy is a good idea overall, it does rather bugger up our plan. This is because urea and creatinine (and anything similar) will only start to change in their blood concentrations once more than 50% of the kidneys are destroyed. So our original idea only tells us something is wrong with the kidneys once something is very wrong, which might be too late.

Hmm - what we really need to be asking is how much blood is being filtered per minute, isn't it? This is much more sensitive as far as damage detection goes, since if you lob off 10% of the kidneys, the amount of filtrate per minute must go down accordingly, even if the remaining 90% of the kidneys are able to take up the slack with regards to urea and creatinine.

Ok, but how do we measure this glomerular filtration rate then? Once again, let's start with a few instructive mistakes and work our way forwards.

If the kidney did no reabsorption at all, calculating the rate of filtration would be easy - we could just collect all the urine formed in a certain amount of time. For instance, if I produced 60 ml of urine in an hour, I could say that my filtration rate was 1 ml/min.

But, alas for us, the kidney reabsorbs more than 99% of what it filters. Together they filter a staggering 180 litres per day, and this allows for the biggest possible chance at excreting unwanted things. However, it is clear that you can't simply excrete this amount - or we would all be drinking the whole day long, having to take in the 180L that we're excreting. We would also have to do this drinking from the toilet, of course, since most of our day would be simultaneously spent urinating. Instead, the kidneys choose to reabsorb the good stuff (water, certain electrolytes, etc.) to save us from this undignified fate.

So we can't trust the total amount of urine formed, because reabsoption of water and other stuff after it has been filtered leaves us with much less urine than was initially filtered.

Hold on, though, what about some substance that isn't reabsorbed by the kidney? For instance, there is something called inulin (not insulin) that is freely filtered by the kidney but not reabsorbed at all. So we could measure how much inulin is found in the urine per minute, and that would reflect how much fluid was initially filtered, even if most of the latter has been reabsorbed subsequently.

So have we done it yet? No, but we are getting close. The first complication is that the amount of inulin filtered will depend on the blood concentration of inulin. For example, even if the glomerular filtration rate was the same in each case, more inulin would be filtered per minute if there was buckets of it in the blood than if there was one lonely molecule of it in the whole body. It's logical, but it does mean that our calculations have to factor this in.

Let's derive an intuitive equation for this, by the following experiment. Say I detect 10 units of inulin in the urine produced over a 10 minute period. That would mean that the kidney was filtering 1 unit of inulin per minute, right?

inulin formation rate = (amount of inulin) ÷ (time taken)

OK, so how much blood (plasma, technically) is it filtering per minute? As we said, for that we need to know the blood concentration, which happens to be 100 units of inulin per litre.

Are you keeping up? If we know that we are filtering 1U of inulin per minute and that there are 100U of inulin per litre in the blood, how much blood (plasma) are we filtering per minute? That's easy:

(amount of inulin ÷ time taken) ÷ (blood concentration)

= 1U/min ÷ 100U/L

= 0.01 litres

Yay - done now? Well, we have got the right answer, so we could start there. But it wouldn't hurt to factor in some actual world considerations - it'll make our lives easier, I promise.

For instance, instead of taking the patient's entire urine sample and measuring every single molecule of inulin in it, we could just take a small sample of it and measure the concentration of inulin. It's really much, much easier. We do need a slight alteration of our equation though:

Since:

'concentration' = number of molecules ÷ volume of liquid

we'll have to multiply the concentration by the volume in order to get back the number of molecules of inulin required in our formula. In other words, we can use 'concentration' instead of 'amount' of inulin, provided we modify our formula thus:

[(urinary inulin concentration) × (volume of urine) ÷ (time taken)] ÷ [blood concentration]

But by luck, the (volume of urine) ÷ (time taken) is equal to the urinary flow rate.

So, in all it's grandeur, our equation is thus:

One last comment. You may have noticed we haven't mentioned 'creatinine clearance' much. The reason we used inulin is because it was freely filtered by the kidneys and not reabsorbed. The only disadvantage to inulin is that it has to be specially administered and monitored. Most clinicians use creatinine instead of inulin, since creatinine is present in the blood (plasma) and urine anyway. Like inulin, it is freely filtered, but it is also active secreted by the cells lining the renal tubule too. This extra urinary creatinine means we overestimate the glomerular filtration rate (GFR) by about 10-20% when using creatinine, but it is still a much more practical option.

(Edit: in my opinion, this post is perhaps too long and not focused enough. I've tried to remedy this with a follow-on overview post, here.)

What is the likely effect of aldosterone hyposecretion on body pH?

In terms of acid-base balance, aldosterone stimulates a pump in the kidney (technically, on the intercalated cells of the collecting duct) that normally pushes out H+ ions into the urine. In other words, under normal circumstances this pump has the effect of causing H+ loss by the body, making it more alkaline (higher pH).

From this it's easy to work out what happens in aldosterone hyposecretion: the pump is understimulated, resulting in H+ retention and acidosis. (It's usually mild, however.)

Aldosterone also has some interesting effects on other electrolytes - sodium and potassium in particular - but we'll have to cover that on some other occassion.

What does vitamin K do?

Technically, vitamin K is a fat-soluble class of compounds that are involved in a unique biological reaction - the carboxylation (adding of a CO₂) to glutamic acid residues of certain "vitamin K-dependent" proteins. (Glutamic acid is one of the amino acids in proteins.) Once these residues are carboxylated, they can bind to calcium, which they need to do in order to work properly.

The only undisputed function of these vitamin K-dependent proteins is to assist in the coagulation cascade. Clotting factors II, VII, IX and X (which promote clotting) and Protein S and Protein C (which both inhibit coagulation) are dependent on the above modification in order to become active.

Other vitamin K-dependent proteins have been discovered too. For instance, osteocalcin (in bones) and an extracellular matrix protein are both carboxylated with the help of the above vitamin. However, it is unclear what function they have.

After it's been used up in the above reaction, vitamin K is recycled by the body. Warfarin, a common anticoagulant used by us doctors, works by inhibiting this recycling process.

Why are patients with chronic kidney disease anaemic?

(For those who are a little confused, the term "chronic kidney disease" (CKD) is the favoured term for what used to be known as "chronic renal failure".)

Anaemia is common in chronic renal impairment, but not in acute renal failure, and so its presence can help distinguish between the two (although, taken in isolation, it isn't reliable).

The pathogenesis is meant to be a combination of:

• Decreased erythropoietin secretion - the kidney is responsible for this hormone's production, remember? Without adequate secretion, the bone marrow doesn't get the message to make more red blood cells.
• Bone marrow insensitivity to erythropoietin - it seems that amongst the miscellaneous "toxins" that build up when the kidneys aren't working are substances the depress bone marrow production.

Clearly the first mechanism is more easy (if expensive) to correct than the second. Simply by giving patients with chronic kidney disease some erythropoeitin, one can alleviate much of the anaemia. This is often employed in such patients.

What are paraproteins?

Paraproteins are an immunoglobulin (or part thereof) produced by a single type of clone from B lymphocytes. Because only one type of original cell is cloned many, many times, all of the clones will produce the same immunoglobulin. When plasma is then electrophoresed, the paraprotein shows up as a discreet, single, dark band. You could represent it graphically like this:



Paraproteins are common in multiple myeloma, solitary plasmacytoma and Waldenstrom's macroglobulinaemia, but they are found in other conditions too (e.g. some types of leukaemias and lymphomas).

In multiple myeloma, the light chain of the immunoglobulin is usually (75% of cases) secreted without the usual heavy chain. In around one fifth of cases, in fact, no full immunoglobulins are secreted at all, and only the light chain (called the Bence Jones protein) is secreted. The problem is that the light chain is rapidly cleared from the plasma, and so it doesn't show up in tests. Thus, if you're looking for multiple myeloma, always test the urine for Bence Jones protein, where it accumulates.