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Kidney function tests
Written by Tim Sheppard MBBS BSc. Created 2/4/10; last updated 12/8/12

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What are U&Es?

U&Es (oddly spoken as 'Us and Es') is the British term for a basic blood test which is extremely useful in medicine, particularly in working out how well the kidneys are working. It's very similar to the basic metabolic panel (BMP) , chem panel, Chem 7 or SMA 7. The clearest term would be kidney function tests or renal function tests, because they give an indication of kidney function.

The very simplest form of the test includes urea, and the electrolytes sodium and potassium, usually with creatinine thrown in for good measure.

Urea is a chemical which is produced when the body is trying to get rid of proteins. It's a helpful measure of dehydration or of exposure to a large amount of protein. However, it's levels can change for other reasons. Because it is released into urine by the kidneys, it can give an indication of how the kidneys are doing. Creatinine is a chemical that is produced normally by muscle cells and is also an excellent marker of how effectively the kidneys are working.

The reason that sodium and potassium are included is that they are probably the most important two electrolytes in the blood, involved in reabsorption in the kidney, determining resting membrane potential, and creating action potentials.

What is urea?

Urea (measured in the US as blood urea nitrogen, BUN), and is a waste product made up of the spare bits from amino acids. As explained elsewhere, amino acids contain a central carbon atom with ammonia and bicarbonate groups sticking out of them. When proteins are broken down, the amino acids that are left over are either used to make up new proteins, or are broken down themselves to use each of these individual groups for something else. Ammonia is a harmful substance to have floating around in the blood, so for every two ammonium molecules and a bicarbonate molecule, you can produce a molecule of urea.

This all takes place primarily in the liver, and is the product of something called the urea cycle, or the ornithine cycle. Like the TCA cycle, it involves lots of reactions that keep recycling the main molecule, and produce helpful bi-products as a result.

While being produced in the liver, urea escapes the body through the kidney. However, it's also really important for the function of the kidney. Some of it is pumped out of the collecting ducts (just before the urine flows out of the kidney) and floats around in the fluid that surrounds the nephrons, particularly at the tip of the loop of Henle. This helps to raise the osmolarity, and is essential for making the counter-current multiplier work.

(The reason you still have some urea in urine is because some of this reabsorbed urea gets into the nephron through the thin ascending limb of the loop of Henle, and manages to get into the urine before it's pumped back out of the collecting duct.)

What causes urea to change?

Urea (or BUN) most commonly goes up because of dehydration. About a half of urea in the blood is reabsorbed in the proximal tubule, with urea being carried out of the filtrate by sodium and water. If the body reckons it needs to absorb more water, then more water will be absorbed in the proximal tubule and the urea will be absorbed more quickly.

Another really important reason is when your body has absorbed lots of protein. Of course this can happen with protein that comes into the bloodstream from any source, especially when you've eaten a meal with a lot of protein in it. Indeed, whenever the gut is exposed to a large amount of protein, the urea may go up - which means that you can get a raised urea in a high-protein meal, or if you're bleeding into your gut.

Urea also goes up when the kidneys stop working. Although a lot of urea is reabsorbed, a lot of it is also passed out in the urine. If the kidneys are not working properly, then they will not be able to filter out the the urea; instead, it will kick around in the bloodstream and slowly build up. The longer the kidney problem has been going on for, the more the urea will build up.

Because urea is made in the liver, a problem with the liver (e.g. liver failure) will lead to poor production of urea. This means that it can be hard to interpret changes in the urea levels if the liver isn't working properly. Instead of a raised urea, you may instead get a raised ammonia - which, because it is dangerous for the body, may cause confusion or even a coma.

What is creatinine?

Creatinine is a breakdown product from something called creatine phosphate (or phosphocreatine), which is found in muscle and involved in supplying energy. In many ways it is no more important in the kidney than anything else, but we talk a lot about it because it gives a good idea of how the kidneys are working.

Creatinine is pushed out (or 'excreted') at the glomerulus and the proximal tubule. Because it does not get reabsorbed, everything which gets pushed out of the glomerulus will flow out into the urine. If the glomerulus is working well, then lots of creatinine will be filtered out into the urine. If it's not working very well, then not much blood will get filtered through it and so the creatinine will stick around in the blood. Creatinine, then, has an inverse relationships with kidney function. The higher the creatinine, the worse the kidneys are functioning.

Notice that creatinine is different from creatine. Creatine is a chemical which the body is able to make out of certain amino acids, which is combined with phosphate to make phosphocreatine and used to help recycle ADP into ATP for use in cells with high energy usage. Creatinine is the breakdown product.

Let's think a bit more about what changes creatinine levels.

What causes creatinine to change?

Your basic levels of creatinine vary depending on how much muscle you have. The more muscle you have, the more creatine phosphate you have hanging around the place, and consequently the more waste creatinine you're likely to produce and throw into the blood stream.

Of course, this means that lots of factors are going to play into creatinine levels. A body-builder will have a higher creatinine level because he's building lots of muscle. Age and weight will also have an important impact on how much muscle you have. Men tend to have a higher creatinine level than women because they usually have more muscle mass. Race is also a significant factor.

A rise in creatinine usually means that the kidneys are not working properly. However, it's important to remember that this is a late sign. Remember that creatinine is filtered out by the kidneys, but the whole of the kidney is doing this at any one time. Because there are so many glomeruli (and proximal tubules) working on this single job, it's pretty easy to get rid of the creatinine that needs to be removed. If it's struggling to achieve this, it's because too many of the glomeruli aren't working.

Because values vary so much between individuals depending on factors such as age, changes in creatinine levels tend to be much more important than absolute values. In other words, saying that Mr Smith's creatinine today is 95 doesn't tell you very much. Normal creatinine is around 50-100 micromol/litre. But if I tell you that Mr Smith's normal creatinine is 49, you know that today's result reflects something bad happening to his kidneys.

What are GFR and eGFR?

The glomerular filtration rate (GFR) is a way of describing how well the kidneys are working by giving a number to describe how much blood is being filtered by the glomeruli of the kidney. A normal glomerular filtration rate is above 60ml per minute. This basically means that if you total all of the fluid which is being squeezed through all of the kidneys' glomeruli into each Bowman's capsule every minute, you'd get at least 60ml. Less than this means that less fluid is getting through the glomeruli - which might mean it's not getting to the kidneys, or that the kidneys aren't working properly.

In order to calculate GFR, we want to look only at that period in the kidney filtration process which happens at the glomerulus. In other words, we want to ignore reabsorption and secretion - we only want to see how much is filtered to begin with. So any chemical which is freely filtered and which isn't changed by reabsorption or secretion will do. Classically inulin (or a similar chemical, sinistrin) fits the bill.

When you've picked your chemical, the GFR is calculated by looking at the proportion of the chemical in the urine compared to the blood, and multiplying by the rate of urine production (or urine flow).

This is all well and good if you've got the luxury of injecting fairly inert chemicals into people. But most of us would rather avoid having extra substances passing through our blood streams. Fortunately we can estimate the glomerular filtration rate by looking at the U&Es and factoring in a few demographics: age, race, and gender.The eGFR is therefore the estimated glomerular filtration rate, and is a way of providing a guess of how well the kidney is working without directly measuring it.

The eGFR is useful for its simplicity (once you've done the calculation!) but it has its disadvantages. While it can be useful for looking at long-term (chronic) kidney disease, we don't know if it's any good for determining the extent of sudden (acute) kidney damage - it's probably more of an indication, rather than a completely specific value. There are several ways of estimating the GFR on the basis of creatinine concentration; the pictured calculation is the Modification of Diet in Renal Disease (MDRD) formula; others include the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Mayo Quadratic formulae. If you know a patient's weight, an estimated creatinine clearance can be used. Detailed knowledge of these estimates isn't needed for most people, but it may be important to check that you're getting all your estimates using the same formula to avoid getting confused by different results.

Why are U&Es a good measurement of kidney function?

What makes U&Es good is not just that they tell you when there's something wrong with the kidneys, but that they tell you some of the most important things. For example, there are lots of things that the kidneys do which U&Es don't tell you anything about. However, I'm not really interested in the short term whether or not the kidneys are producing erythropoietin, or how vitamin D metabolism has been affected. True, these are important - but in the short term, I'm much more interested in the things which will have an effect in the next couple of days.

The great thing about U&Es, then, is that they show me important things. A change in the electrolytes can be catastrophic; if the kidneys stop controlling how much of the salts there is in the blood, the potassium levels could quickly become life-threatening.

Furthermore, I get more information by having several different results to look at. Looking at both urea and creatinine is a helpful way of working out whether or not a change in urea is due to kidney function or something else - if only urea rises (and creatinine is normal or not raised as much), this shows that the kidneys are still working.

Urea and creatinine are also good indicators of how well the kidney is doing its filtering work. Creatinine won't be removed from the blood stream if the filter isn't working, so the levels will rise. Of all the roles that the kidney has, its function in filtering the blood and controlling salt levels is probably the one that will most quickly cause life-threatening problems, so the results of the U&Es focus on the right thing.

Since U&Es are so regularly used, it's vital that people working in healthcare understand them. They're cheap, quick, and give important information. But, as mentioned already, there are other tests around.

What other tests of kidney function are there?

Creatinine isn't conventionally used in specific calculations of GFR because as well as being filtered at the glomerulus, it's also actively secreted in the tubule; you're going to overestimate the GFR. This secretion makes up only a small proportion of the creatinine found in the urine, however, so it can still be useful. Creatinine clearance is therefore worked out in the same way that GFR is calculated using inulin - by multiplying urine flow rate by the urinary creatinine divided by the plasma concentration. It will often be based on a 24 hour collection, and corrected for body surface area.

Problems with the glomeruli might start to show up when the filter breaks down. If it stops doing it's job properly, then big molecules that wouldn't normally fit through will start to leak out. Protein is a particularly important example of this - in extreme situations, so much protein leaks out that it starts to cause a problem. In most cases, protein simply acts as a marker that the filter has broken down. Proteinuria (that is, protein - especially albumin - in the urine) can be picked up by a urine dipstick. Even low levels of albumin in the urine (known as microalbuminuria) can be important, but lower levels might not be spotted, so collections of urine over 24 hours may be necessary. Since albumin and creatinine concentrations in the urine are often compared, you may see albumin expressed as a concentration in terms of mg/g (i.e. milligrams per gram of creatinine in the urine). Concentrations above 30mg/g are diagnostic of chronic kidney disease.

A DMSA scan uses a chemical called dimercaptosuccinic acid in order to look at which parts of the kidney are working. It's a kind of radionucleotide scan, so it uses light radiation, and the scan gives a picture of the kidneys - making it particularly useful to show up kidneys that are the wrong size, the wrong shape, or which have a scar, and showing which parts of the kidney are working. A kidney ultrasound scan can also be useful at showing structural changes.

Because the kidney has an endocrine function, looking at the hormones it is supposed to throw out into the blood stream can indicate whether or not it's working properly. These will usually be a late sign of problems with the kidney - something else will show up first. But if you know that the kidneys aren't working, you'd want to keep an eye on Vitamin D. Additionally, erythropoietin is produced in the kidney, which means spotting a low haemoglobin concentration may show if the hormone has stopped being produced.

Why does pH affect urea production?

If you're asking this question, you're obviously a step beyond the basics and so I shall be unashamed of explaining this complicated topic. If you're not asking this question, don't worry about it. What is about to follow is quite tough to understand, and requires an understanding of amino acid structure, the carbonic acid equilibrium, and interpretation of an arterial blood gas result.

Ammonium is a chemical which is dangerous to the body, and needs to be combined with something else while it's circulating around the bloodstream. This can either be done with urea or with glutamine.The pH will affect which one of these the body uses to move the ammonium around.

When amino acids are broken down, the carboxyl and amino groups produce bicarbonate and ammonium respectively. If it is only the ammonium is taken, then loads of bicarbonate will be left over and the carbonic acid equilibrium will shift to mop up the hydrogen and make the blood more alkaline.

Since urea production uses both bicarbonate and ammonium, this means you're not leaving any extra bicarbonate hanging around. This makes is a better option in an alkalosis, because you're not making the alkalosis any worse.

If there's an acidosis, it's better to use glutamine; instead of taking out any bicarbonate, this just combines ammonia to glutamate, leaving the bicarbonate around to mop up the hydrogen.

Those with some clinical experience would ask why urea is often up in metabolic acidosis. Surely the urea should be low because glutamine is being produced? This highlights a really important question in medicine - if you see a pattern, is it a cause, an affect, or a coincidence? In the case of high urea and metabolic acidosis, both may be caused by the same thing (e.g. kidney failure, or a serious infection). In fact, urea is less important in controlling blood acidity than lots of other things.

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