A Century of Creatinine and the Endless Search for Accuracy

This week on For Kidneys Sake, Prof Jeremy Levy and Dr Andrew Frankel celebrate an unlikely centenary: 100 years since creatinine was first recognised as a marker of kidney function. From the early days of serum creatinine and the Cockcroft-Gault formula to today’s eGFR reporting, the duo unpack how kidney function testing evolved and why the numbers we rely on still come with important caveats. 

The conversation explores why muscle mass can dramatically distort creatinine-based kidney estimates, when cystatin C offers a better alternative, and why gold-standard nuclear medicine tests remain impractical for routine care. 

Along the way, they tackle common misconceptions around eGFR, explain why urine ACR tells a different story entirely, and remind listeners that numbers should never replace clinical judgement. A witty, practical, and surprisingly celebratory deep dive into the science behind every kidney health check. 

Top 5 Takeaways

1. Creatinine has been used for 100 years — Serum creatinine was recognised as a marker of kidney function in 1926, making 2026 the centenary year of one of medicine’s most widely used blood tests. 

2. eGFR is helpful — but imperfect — eGFR improves on creatinine alone by incorporating age and sex into mathematical formulas, but it still struggles in people with unusually high or low muscle mass. 

3. Muscle mass matters more than many realise — A muscular person may appear to have “worse kidneys” on paper, while frail patients with low muscle mass can have deceptively normal creatinine levels despite significant kidney disease. 

4. Cystatin C is an underused alternative — Unlike creatinine, cystatin C is not heavily influenced by muscle mass and can provide a more accurate estimate of kidney function in selected patients. 

5. Kidney health is more than eGFR — Urine ACR measures kidney damage rather than filtration and can be abnormal even when kidney function appears normal. Both tests matter.

The purpose of this podcast is to inform and educate health care professionals working in the primary care and community setting. The content is evidence based and consistent with NICE guidelines and North West Guidelines available at the time of publication.

The content of this podcast does not constitute medical advice and it is not intended to function as a substitute for a healthcare practitioner’s judgement.

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Produced by award-winning media and marketing specialist Heather Pownall of Heather's Media Hub 

Transcript

Jeremy (00:00)
Hello, I'm Jeremy Levy, a consultant nephrologist at Imperial Healthcare NHS Trust.

Andrew Frankel (00:04)
And I'm Andrew Frankel, a colleague of Jeremy, also a nephrologist at Imperial College Health Care NHS Trust. So the cornerstone of kidney care in primary care is the kidney health check.

which includes the measurement of GFR or kidney function. So today we want to talk in more detail about measuring kidney function, when it might go wrong and alternatives to creatinine and the routine EGFR. But first Jeremy, I know you've got some news about this and you're going to remind us a bit about creatinine and EGFR.

Jeremy (00:42)
Yes, thanks Andrew. So this is amazing and I didn't really know this until I was doing some background work but serum creatinine, which we all use every day, was first measured properly in 1886. Amazingly! And was really first identified as a marker of kidney function, a marker of GFR, meaning how well the kidneys filter the blood, in 1926. That's a hundred years ago, exactly this year.

Nobody's out there celebrating this. We need a year of creatinine. It's a hugely important event.

Andrew Frankel (01:16)
Absolutely and at this stage this podcast is the celebration.

Jeremy (01:21)
It is. We're celebrating Andrew. We're celebrating creatinine as a mark of kidney function. We should publicize that actually all over the place. So in the 1920s, 1926, it was recognised that if you measure serum creatinine, creatinine in the blood, that was a marker of glomerular filtration rate, because as filtration declined, serum creatinine rose. But at that time, it was also recognised that creatinine essentially was a byproduct of

of muscle metabolism and therefore muscle mass. creatinine is made from muscle. And so people with a higher muscle mass will have a higher serum creatinine with the same level of kidney function. So normal kidneys, higher muscle mass, slightly higher serum creatinine And so this dilemma, which has affected us essentially since 1926, was recognised in the 1920s.

Actually, some of you always ask about serum urea. Urea was first identified in the 1830s as a measure of kidney function and kidney dysfunction. High blood urea, bad kidneys. But very rapidly, urea was recognised to have lots of other confounders, especially hydration. So small changes in body hydration affect urea for various reasons. So it's a really unreliable marker of kidney function. So creatinine been around 100 years. We can use it. We've known it's a marker of kidney function.

but we're always confounded by the fact that higher muscle mass, higher serum creatinine.

Andrew Frankel (02:51)
Yes, indeed, Jeremy, and indeed, as you know, we always talk about this, my career spans a little bit earlier than yours, and I remember we had many, many years where we just had creatinine, and we certainly never used urea. But I do remember something about doctors Cockroft and Gault, that they proposed something that make the creatinine a little bit more reliable. Do you want to tell us a little bit about that, Jeremy?

Jeremy (03:17)
They did. Nothing wrong with your memory, Andrew, and it's still widely used. So this was the Cockroft and Gault formula. And so this all comes from a small study that they did in Canada in 250 white Canadian men. They were in a care home, essentially. And they tried to say, can we do something to make the creatinine more reliable? And they generated the Cockroft Gault formula. And this was a little bit of mass that took the serum creatinine.

and tries to define what then was called the creatinine clearance without measuring urine. At that stage, people were doing 24-hour urine, but they said, let's avoid that. So it used sex and age and creatinine and generated a number that was meant to be essentially equivalent to a GFR called the creatinine clearance. But the study was done in these 250 white men, and there is a correction for sex, but it's not a representative sample.

It has been widely used, especially in drug dose calculations, but it has exactly the same problem as essentially using creatinine alone in the sense that if you've got more muscle mass, you tend to have a higher serum creatinine. Using the body weight in there, did try to use its body weight as well as age and sex, did try and get round that problem, but it still is actually pretty unreliable and has many of the similar problems. We now have an issue. It still is there in often.

drug companies as they measure drug dosing but that's changing as well. So yes, you're right, Andrew, Cockrock Gout formula is around, has been used, but has very similar problems to using serum creatinine

Andrew Frankel (04:52)
So it was significantly by pharmaceuticals and pharmacists provides a little bit more of information about ⁓ kidney function in the context of weight. But what you're saying, very poorly studied and really still has some problems. So that brings us to the 2000s and the appearance of eGFR or Estimated GFR.

You're going to tell us about that now.

Jeremy (05:21)
Yeah, you're right, Andrew. And we're all familiar with this now, but actually it all started in the sort of late 1990s and just loads of research groups saying, can we do something with this serum, creatinine that we're measuring? It's cheap. We can measure it everywhere around the world. Can we do something better to get a better handle of GFR of true glomerular filtration rate? And various numbers were done, various studies were done. And in the end, a sort of single formula was derived that took creatinine.

age, sex, sometimes some other markers like serum albumin, and just mathematically did produce a better estimate of true GFR than anything that had gone before. So that's where the eGFR evolved from and in those studies they were using gold standard measures, which we'll come back to in a moment, so they were really trying to compare formulas versus gold standard measures of kidney function of GFR. And overall

Andrew Frankel (06:16)
So.

Jeremy (06:17)
The formulas that have evolved over time generate this number called the eGFR, the estimated GFR. And they are almost certainly more accurate than Cockroft-Gault or using serum cratine alone. In people with either stable or slowly changing kidney function, they are not reliable in acute kidney injury where the kidney function is changing quite fast. So yes, these formulas, and doesn't matter what they are,

generate this EGFR and most labs around the world will now report serum creatinine and then an EGFR using the best available formula, sometimes tinkered for different populations, but not always. And that's where we are. It's an estimate. It's more reliable than other measures. And it tries to give us a handle of the glomerular filtration rate. But again, it's using creatinine with some of the same problems that we have recognised already around muscle mass.

Andrew Frankel (07:14)
So complex maths and when I'm talking to my patients I always tell them that we measure kidney function by measuring creatinine and then I describe the fact we put it into this black box of a mathematical complex equation and that the other end comes out eGFR or estimated GFR which gives an indication of kidney function but it's still got a number of that make it a little unreliable.

most particularly in the upper end of the range between 60 and 90. And if I'm right, Jeremy, many labs certainly didn't and may still not report GFRs or AGFRs greater than 60. And that's because of the increasing unreliability at that But it is still, was still the best we had over the early part of this century.

in terms of measuring kidney function. And I should remind listeners that they may recall that the original formula, as you highlighted, did have a correction for black ethnicity. However, that's now been removed, mostly because it was actually unhelpful and unreliable.

Jeremy (08:30)
That's exactly right, Andrew. That correction for black ethnicity is gone and shouldn't be needed at all. Whatever your lab reports as the EGFR is the estimated GFR. But again, if your patient's 90 kilograms of pure muscle, their creatinine will be higher and their EGFR will be lower when they've still got normal kidney function and normal true GFR. So it is still creatinine based and often particularly in older patients, let's say you've got a 45 year old, 45 kilogram person.

with a normal creatinine, but yet they've got no muscle mass, that might represent actually very bad kidneys because they're not generating creatinine. So, EGFR is there, use the number you reported, but always remember the patient in front of you.

Andrew Frankel (09:13)
quick question then, Jeremy. What about children?

Jeremy (09:16)
So children, very good question. ⁓ The labs either use a child specific formula or they won't report EGFR if the labs only set up to use the adult formula. And they'll just write because the patient is under the age of 18, no EGFR is estimated. There are formulas that have been done for children, but they're not the same as adults, not surprisingly. And given that children are going through stages of growth, it can be harder to generate an EGFR.

but there are child-specific equations out there, but they are not the same as the adult ones.

Andrew Frankel (09:49)
So you talked a little bit Jeremy about the comparison of the eGFR estimated GFR with gold standards. So there are gold standard measurements out there. Perhaps we better tell the audience a little bit about them and why they're not as accessible perhaps as eGFR or available to primary care.

Jeremy (10:10)
So you're right, there are gold standards out there, but they're not available in primary care. So the best gold standard would be to measure how well the kidneys clear something from the blood that you've introduced from outside, an exogenous substance that does not come from muscle. And that's what can be done in the hospital centers, in radiology departments. And you can either inject somebody with something called IOhexol or a radioisotope such as EDTA.

You inject a known amount into the patient and then you wait a period of time, sometimes two hours, sometimes four hours, and then you measure how much is left in the body. And the one's a radioisotope, the other is an easily measured chemical. And in that way, you can work out how well the kidneys have got rid of the amount that you introduced by seeing how much is left. So these are highly accurate tests. They do tell you exactly how well the kidneys are filtering the blood.

Both are expensive. They require the patient to be at least four hours in a radiology department. And they might use radioisotopes, so need a nuclear medicine department. So these are really tricky tests to do, expensive and just not available in primary care. And actually many hospitals may not be able to do them around the country. So these are the gold standards, but these are often quite difficult to undertake.

Andrew Frankel (11:31)
So from a public health perspective, given that we're trying to get millions of patients having their kidney function checked as part of a kidney health check, this is simply not practical. Is there something in between?

Jeremy (11:46)
So there is, yes. And it's not that new, but lots of people haven't heard of it. It's a blood test called a Cystatin C Cystatin C. In fact, it's been around since the mid 1980s and was shown to be an accurate marker of kidney function of GFR from the mid 1990s. And it's not affected by age or by sex or by muscle mass. It's not a muscle protein. And it should be widely available.

in secondary care, certainly sadly not yet in primary care, but even locally to us in West London, as you know, it's taken us until this year, sadly, 2026 to get this routinely available. yes, Cystatin C as a blood test is a good marker of kidney function and has been very well validated in lots of populations.

Andrew Frankel (12:38)
And just like creatinine, you can go online to on the internet and you can find a GFR calculators that use both cystatin and or creatinine to give you an estimated GFR. So it is available, but it is more expensive. So when should we be considering using cystatin C and is this something for primary care?

Jeremy (13:04)
So, as you say, gets converted through a calculator into an estimated GFR as well. So when should you use it? Well, you use it when you really think the serum cracknein is likely to be abnormal. Exactly as we've discussed already. So people with lots of muscle mass or very little muscle mass. In people who are using creatine supplements, it can be helpful to unpick that issue. And most of those people, of course, have got more muscle mass, but not all. And then there are some drugs that affect

creatinine handling and in general practice mostly that will be lots of the HIV antiretrovirals. So in those circumstances high or very low muscle mass some drugs and using a cystatin will allow you to get a measure of EGFR independent of blood creatinine and therefore muscle mass and the confounding factors.

Andrew Frankel (13:56)
Okay, so we've got serum creatinine, creatinine-based EGFR, serum cystatin C and its estimated GFR equations and nuclear medicine tests. I know there's another way that we measure kidney function and that relates to the urine.

Jeremy (14:16)
Yeah, and those are the 24-hour measures of urine of creatinine clearance. So you're measuring the blood creatinine, you're measuring how much is excreted in the urine in 24 hours, and then you can get a measure of how well the kidneys get rid of creatinine, and that is a marker of glomerular filtration rate. The problems with it are, well, twofold really, the one is it still is based on serum creatinine, though it gives you a better measure of how well the kidneys actually get rid of your creatinine from your blood.

So it is better than creatinine alone in the one sense, but it involves a 24 hour urine collection.

Andrew Frankel (14:50)
Yes, and as you probably know, I very rarely, in fact, I never order creatinine clearances anymore because of the unreliability. In my experience, many patients, even if you go over this in detail, find it difficult to follow the instructions and get a complete or they get an overfilled 24-hour urine. There are little ways you can adjust it to estimate what a 24-hour would look like.

that really it is so unreliable, it's so difficult to do. I very rarely organise 24 hour urine unless I'm looking at people with kidney stones and looking at calcium but even there you can use different tests.

Jeremy (15:36)
right, Andrew. And I agree. I haven't done a 24 hour year in collection in ages. I have acted in years, I think in decades almost. Other other things to mark is what we're going to talk about other ways of looking at kidney function in different ways. So don't forget that measuring urine albumin creatinine ratio, the ACR, that's critical. It's not measuring kidney function.

Andrew Frankel (15:35)
don't forget.

Jeremy (15:59)
but it is telling us about kidney health and kidney damage and those are really, really important factors. So they are markers of kidney health and they're really important. And actually explaining to patients the difference between the GFR number and the ACR number, that these are two separate markers of the kidney and the way it functions is really important. And people can have normal GFRs and abnormal ACRs.

and normal ACRs and abnormal GFRs. They're not necessarily going together. And even lots of our primary care colleagues get confused sometimes about that. So you can have a completely normal GFR, but your kid is leaking protein, but it's cleaning the blood normally. So these are critically important factors to measure with the kidney function as measured by a GFR or something else.

Andrew Frankel (16:46)
So Jeremy, I think that's been very useful. My key takeaways are the following, that the validated way to measure kidney function remains estimated or EGFR, which is a calculation based on creatinine and is reported automatically by our labs. However, in people with either high or low muscle mass, or in individuals taking supplements such as creatinine

which is increasingly commonly being used, this eGFR may not be reliable because creatinine is a waste product of muscle activity. In the event of concerns, the alternatives are either cystatin C, which is a blood test, or nuclear medicine GFR. However, these are usually only available through secondary care. And a fourth, I normally only give three, is of course that we must celebrate

the fact that we are now at 100 years of the recognition of creatinine and EGFR.

Jeremy (17:50)
You're right Andrew, 100 years, happy birthday, creatinine as a measure of kidney function. And it's been a great chat, I hope people have learnt something about kidney function testing and you and I are not going to sing happy birthday because that will put everybody off listening to any future episodes of For Kidney Sake! But we have a great back-hatlog and they should go and listen to all our other episodes unless you really want to sing happy birthday Andrew.

Andrew Frankel (18:10)
I would not put the audience through it but I wish creatinine very very happy. Do they get a telegram from the King? Should do. Anyway, goodbye everybody. See you at the next podcast.