Ep70: Zeroing in on “the renal troponin”

Ep70: Zeroing in on “the renal troponin”
Date:
11 June 2021
Category:

Fellows of the RACP can claim credit for listening to this episode and reading supporting resources via MyCPD.

Acute Kidney Injury makes a greater contribution to early mortality than acute myocardial infarction and it's been argued we should consider the concept of “kidney attack” to give it the weight that it deserves. But the presentation of kidney injury isn’t as overt or timely as a heart attack often is.

While serum creatinine is a pretty good reporter of chronic impairment in kidney function it’s very insensitive to acute injury, so for two decades there’s been a concerted search for more proximal biomarkers of AKI.

The three most promising candidates are neutrophil gelatinase‐associated lipocalin (NGAL), tissue inhibitor of metallo-proteinase 2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGBFP-7). Commercial assays for these exist that can predict moderate to severe AKI with a lead time of many hours in at-risk patients.

But many questions remains as whether these are specific enough to be useful at point of care, whether we have the interventions to respond to the information they provide, and what ‘false positives’ might indicate..

Credits

Guest
Professor Rinaldo Bellomo AO FRACP FCICM FAHMS (Director of Research Intensive Care, Austin Hospital; University of Melbourne; Monash University).
author of “Novel renal biomarkers of acute kidney injury and their implications” (2021) Internal Medicine Journal 51;3 pp316-318

Production
Written and produced by Mic Cavazzini DPhil. Music courtesy of FreeMusicArchive includes ‘Downhill Racer’, by Blue Dot Sessions, ‘Making a Change’ by Lee Rosevere, ‘Fryeri’ by Kai Engel, ‘Subscribe to the New Internationalist’ by Tzara. Image licensed from Getty Images. Recording assistance in Melbourne provided by Jon Tjhia.

Feedback on this episode was kindly provided by physicians of the RACP’s Podcast Editorial Group; Vicka Poudyal, Paul Cooper, Rhiannon Mellor, Duncan Austin Seema Radhakrishnan, Phillipa Wormald, Victoria Langton, Oliver Dillon and Loryn Einstein.

References

Novel renal biomarkers of acute kidney injury and their implications [IMJ 2021, Bellomo]

What has changed since the KDIGO guidelines in 2012? [KDIGO, 2019 webinar]
Cell cycle control in the kidney
[Nephrology Dialysis Transplantation]
Use of Biomarkers to Identify Acute Kidney Injury to Help Detect Sepsis in Patients With Infection
[Crit Care Med, 2021]
Clinical adoption of Nephrocheck® in the early detection of acute kidney injury [Ann Clin Biochem, 2020]
Biomarker-Guided Risk Assessment for Acute Kidney Injury: Time for Clinical Implementation?
[Ann Lab Med, 2021]
Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis
[Am J Kidney Disease, 2020]
Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury
[Critical Care, 2013]
Care Bundles for Acute Kidney Injury: Do They Work?
[Nephron, 2016]
Vasopressor Therapy and Blood Pressure Management in the Setting of Acute Kidney Injury
[Seminars in Nephrology, 2019] T
he Rise and Fall of NGAL in Acute Kidney Injury
[Blood Purification]

Transcript

RINALDO BELLOMO:       The fact that a subclinical or a sub-GFR derived acute kidney injury exists, is a fact.  And that these patients are at greater risk of adverse events, compared to those patients that do not release these biomarkers, is a fact. So there is a thing—it’s a biological event.  We can pretend that it doesn’t exist, but it’s probably best to pretend that it does exist, and then investigate it more clearly to understand it better.

MIC CAVAZZINI:               That’s Professor Rinaldo Bellomo, co-author of a fascinating review titled “Novel renal biomarkers of acute kidney injury and their implications”. The article was published in the March edition of the Internal Medicine Journal, which like this podcast, is a publication of the Royal Australasian College of Physicians. Welcome to Pomegranate Health. I’m Mic Cavazzini.

Even if you’re not a nephrologist, this story is a good parable on the challenge of proving utility for a new diagnostic tool. Acute Kidney Injury is dangerous because it disrupts the fluid-balance of the blood and can cause a build-up of waste products in every major organ. AKI is associated with not just with higher in-hospital morbidity and mortality, but it virtually triples the long-term risks of chronic and end-stage kidney disease.

In fact AKI makes a greater contribution to early mortality than acute myocardial infarction and it's been argued we should consider the concept of “kidney attack” to give it the weight that it deserves. But the signs and symptoms of kidney injury aren’t as overt or timely as those from a heart attack often are.

Subtle giveaways of AKI are swelling in the legs and around the eyes, fatigue or tiredness, shortness of breath, and even confusion and nausea. The first diagnostic criterion is significantly reduced urine output over 6 hours, and then a workup will include tests for serum creatinine. Increased concentrations indicate that glomerular filtration has been impaired, and there are three diagnostic thresholds defined in the AKI staging model.

While serum creatinine is a pretty good reporter of chronic impairment in kidney function, a lot of renal damage has already occurred by the time before you observe this signal. Also, creatinine readout is confounded by changes in blood volume or muscle mass, and for two decades there’s been a concerted search for more proximal biomarkers of kidney injury. This hasn’t been straightforward, however. In the seminal SAPPHIRE study of 2013 researchers started with over three hundred candidate proteins and then had to decide which patients to test these in. I’ll let Professor Bellomo tell the rest of the story.

RINALDO BELLOMO:       I am Rinaldo Bellomo.  I’m an intensive care specialist.  And I’m the Director of Research in the Intensive Care Unit at the Austin Hospital.  And I also am Professor of Intensive Care at the University of Melbourne.  And Professor of Medicine at Monash University in Melbourne, Australia.

MIC CAVAZZINI:               I want to start – before we get into the details of your article – I want to start with a quick impression of what the hunt for a biomarker looks like.  Out of the 340 candidates that John Kellum and colleagues looked at, one of those with strong associations to acute kidney injury was neutrophil gelatinase‐associated lipocalin.  So

RINALDO BELLOMO:       So the hunt for biomarkers has been dependent on the technology available to perform the hunt.  So you would have animal work.  You would identify a particular molecule in animal research over several years, that appeared to be expressed by cells under experimental situations of kidney injury.  Then you developed antibodies against that particular molecule. Then you use the antibodies to develop assays to look for that particular molecule.  And then you apply those assays to either urine, or plasma, to see how much of that molecule was expressed. And that is the way that NGAL – neutrophil gelatinase-associated lipocalin – was initially identified and studied.

MIC CAVAZZINI:               That’s interesting.  So the animal models were actually very deliberate insults created–

RINALDO BELLOMO:       Yes, that’s correct.

MIC CAVAZZINI:               And what kind of insults are we talking about when we’re thinking about –

RINALDO BELLOMO:       So there are different models of kidney insults.  There are drugs that are toxic to the kidney cells, that can be given to animals to induce injury to the kidney cells.  There are insults related to lack of blood flow.  So, for example, the experimental studies might include clamping the kidney artery so that there will be decreased blood flow to the kidney for maybe 30 minutes.  And you have what we call re-perfusion injury.

Or you can obstruct the urinary pathway by blocking the ureter and then letting go, causing obstruction to flow for a period of time.  Or you can give other substances that replicate what might happen during a serious infection, such as the administration of bacterial toxic products, like lipopolysaccharide.  So all the different models, they’ve got different characteristics.  But they can be used to induce injury to the kidney cells, and then isolate and identify molecules that would be expressed after such insults.

MIC CAVAZZINI:               NGAL is involved in the control of free iron and its concentrations in urine peak around six hours after injury to renal tubules. So now when we’re trying to validate NGAL in humans, what does the design of such a study look like?  How you’d select a group of patients, separate them into cohorts, et cetera?

RINALDO BELLOMO:       Yes, so how do you select patients to validate these animal studies?  Well, you select patients where it is known that there is a risk of kidney failure from epidemiologic studies.  For example, we know that people that have major cardiac surgery are at risk of developing acute kidney failure.  We know that people having, for example, liver transplantation are at risk of developing acute kidney failure, or kidney injury.  We know that people with sepsis or septic shock are at particular risk of developing acute kidney failure. So you take a population where the question is relevant, you can draw either a blood sample, or in the particular case a urine sample, and then you can measure the concentration of neutrophil gelatinase-associated lipocalin and then relate that to what happens subsequently – its positive predicted value, it’s sensitivity, its specificity in predicting whether somebody will or will not develop acute kidney injury – and you compare that with predictive models not including this biomarker.

MIC CAVAZZINI:               Yes, I’m going to get into the numbers a bit later, but I’m going to stick with the pathology now.

RINALDO BELLOMO:       Sure.

MIC CAVAZZINI:               So you write in your review that NGAL is secreted into the tubular lumen in a monomeric form, there are also dimeric forms released by activated neutrophils. And NGAL can be released by the liver in conditions of inflammation.

RINALDO BELLOMO:       It is all true, yes.

MIC CAVAZZINI:               So I presume all these processes have different aetiologies.  Is that what we mean, in a literal sense, when we say that NGAL doesn’t have great specificity as a marker for acute kidney injury?

RINALDO BELLOMO:       That is what we mean.  That is, it comes around in three different forms, as you’ve said. And the three of them have got different kinetics and they’ve got different triggers.  But all three of them, in variable quantities, can be found in the urine.  And so when you’re using a test to measure NGAL in the urine, you don’t really know which one you’re getting, and what the source is; is whether something that the tubules have secreted in response to stress to the kidney, or whether it is something that was in the plasma because there had been activation of inflammation of the neutrophils or activation of liver-related metabolic changes, and some of that has led to the filtration of the NGAL through the glomerulus in the kidney.  It’s then gone into the urine, but it actually never came from the kidney itself.

MIC CAVAZZINI:               And you write how its reabsorption in the glomeruli is also reduced –

RINALDO BELLOMO:       Yes, so life is a lot more complicated, as you say, because a quantity which is incredibly variable, will be reabsorbed by the tubules through the megalin-mediated small protein reabsorption pathway. Will also be conditioned by the expression/release of the other small proteins in the urine at the same time, that are competing with its absorption via the megalin receptor. And you have no way of knowing how much of that process has actually taken place.  You only know the final product, what’s in the bucket. 

MIC CAVAZZINI:               Yeah, so that reabsorption is important because it adds a level of nonlinearity to the readout of concentration against degree of injury.

RINALDO BELLOMO:       Totally correct.

MIC CAVAZZINI:               So there are two other urinary proteins associated with tubular injury that may have more potential as biomarkers of AKI.  They are tissue inhibitor of metallo-proteinase 2 and insulin-like growth factor binding protein-7.  Both TIMP2 and IGFBP7 are cell-cycle arrest proteins.  They turn on during cell division when mistakes in chromosome replication occur, pausing the process so that these errors to be repaired or killed off.

RINALDO BELLOMO:       That’s right, yes.

MIC CAVAZZINI:               Now, cell-cycle arrest is typically observed in fast dividing tissues, and in fact renal tubule cells divide at a very low rate most of the time. But the point is that that changes dramatically when there’s an injury?

RINALDO BELLOMO:       You’re absolutely right.  So using proteomics , investigators were able to identify a particularly strong expression of these two small proteins, and that their function is to stop the cell-cycle.  Now, why would that happen?  Well, first of all, the correct answer to it – no one knows.  But, a logical series of thoughts is that the cell-cycle is an energy intense activity and it may be that under a situation of lack of blood flow or physiological stress, the kidney cells will say, “Ah, I’m not going to undergo proliferation, however limited it may be.  I’m not going to do it now because this will be then leading to cell death.  We don’t want to do that, thank you very much.  We’re just going to hibernate.” And then when the insult has gone away – maybe tomorrow or in six or eight hours – then the cells can say, “OK, the energy status is better. I can now restart the cell-cycle and maintain cell replacement as I had it before the injury.”  Now whether that’s true or not, we don’t really know.  But it is a story that carries some logic and rationale.

MIC CAVAZZINI:               There will be a physiological reason the cell cycle arrest biomarkers are more closely linked than NGAL to the timing and location of kidney injury. But how do you demonstrate in a quantitative way that they are better predictors clinical AKI?

Just to recap; researchers draw participants from a defined at-risk group, such as patients undergoing cardiac bypass surgery. On leaving theatre, their urine is assayed for these biomarkers. Some of those patients will end up with an acute kidney injury, and for validation purposes this cohort has been defined by a stage 2 or 3 diagnosis in the classic model, which means anything above a twofold elevation in serum creatinine.

Now to decide how sensitive a biomarker is for acute kidney injury, we need to figure out how many cases were preceded by a positive signal. If out of 100 confirmed cases of AKI, our assay had been positive for 90 of them, the true positive rate or sensitivity is 90%. Meanwhile any positives from the non-case cohort are called false-positives.

I’d always had this simplistic notion that sensitivity was just a reflection of how good your immunochemistry was at pulling down the protein of interest. This reasoning does explain why modern troponin assays are more sensitive for myocardial damage than those of a decade ago, but it’s only part of the story.

Even if your assay were perfect, and it could pull down every target molecule without a single cross-reaction, the output isn’t binary. The biomarker isn’t simply present or absent. Even in healthy individuals, baseline
NGAL is found over an interquartile range of about 20 to 150 ng per mL of urine. It varies from person to person and even with time of day.

To calibrate your test you have to pick a concentration value over which a result is considered positive. If you set that threshold very high at 600ng per mL, then the patients returning a positive result would be only the sickest ones. This test would be 100% specific for acute kidney injury, but you’d have missed out close to half of the real cases that just happen to have slightly lower NGAL values.

To increase sensitivity, you could lower the threshold concentration. As you keep lowering the bar, you mark more and more samples as positive to the point where you’ve captured every single true case of disease. The test has now reached 100% sensitivity, but you’ve also let some false positives through that have particularly high baseline concentrations of NGAL. So now specificity has gone down.

To hone in on the threshold that gives the best trade-off of sensitivity and specificity, researchers plot what are known as Receiver Operator Characteristic curves. The name comes from the World War Two military personnel who screened air surveillance radar. The US Army was baffled that they’d completely missed the Japanese air squadrons that bombed Pearl Harbour, and began to model this problem; How sensitive should receiver operators be without them raising a false alarm at every spurious signal?

An ROC curve is generated by plotting true positives on the y axis and false positives on the axis for every possible threshold concentration. The curves should look a bit like a lower case r, with the inflection point being the threshold value that has the greatest discriminating power.

The more that this r looks like a right angle, the better, and the closer the area under the curve will be to the impossibly perfect score of 1. If the curve looks like diagonal line, the test is no better than a coin toss and the area is 0.5. Using this shorthand measure of performance, how do our urinary biomarkers stack up as predictors of acute kidney injury?

Well NGAL has an area under the curve of 0.72, TIMP-2 is at 0.75 and IGFBFP-7 leads the way with an area of 0.77. The cell-cycle arrest biomarkers do better because there’s less overlap between concentrations found in healthy people and in AKI cases. And when you combine their scores into a single test value, that has an area under the curve of about 0.83. This integrated value probably captures more of the variation in tubular pathology between different patients.

A commercial assay for the combined cell cycle arrest proteins was approved for use in Australia in 2014 and goes by the name Nephrocheck. Like the American and European researchers behind the SAPPHIRE study, Professor Bellomo has been supported in his investigations through an academic partnership with the distributors of this assay.

RINALDO BELLOMO:       Yes.  I’ve had academic relationship with them, and we’ve done some work supported by them where they’ve actually provided the assay for free, so that we could study the performance of the Nephrocheck in an Australian population, because that’s never been done, compared to the performance of the Nephrocheck in an American, European population.

MIC CAVAZZINI:               The Nephrocheck assay can detect TIMP2 and IGBF7 in as little as 100 microlitres of urine, and the results come back in 20 minutes.  In the early validation studies it was found, retrospectively, that patients with an integrated assay score above 0.3 ng per mL squared over 1000 were at seven times more risk of developing a concerning AKI injury than those that didn’t.

RINALDO BELLOMO:       Yes, that’s right.

MIC CAVAZZINI:               And now that threshold – that 0.3 threshold from the early studies – has since been refined to match the stages of the classic AKI diagnostic model.  Can you elaborate on these for us?

RINALDO BELLOMO:       Yes, I think that at the moment the thresholds that were described in the SAPPHIRE study for different levels of severity of injury, and different levels of prediction for acute kidney injury they still are being worked on.  And what we will use in the future may have to be adjusted to different populations.  Because, at the moment, you’re looking at a broad brush population as that recruited in SAPPHIRE, but these thresholds would logically not apply to cardiac surgery patients the way they might apply to septic patients.

MIC CAVAZZINI:               Right. It’s all very well and good to have this information – this readout of biomarkers – but the real question is, what do you do with it?  How does it change practice?  The international guidelines for managing classically diagnosed kidney injury have been put together almost a decade ago by KDIGO, which is an elegant acronym of the Kidney Disease-Improving Global Outcomes consensus.  And they describe a “care bundle” for AKI that’s supposed to help standardise practice.  Is there anything in this care bundle that would surprise the generalists listening?  Or anything they need reminding of?

RINALDO BELLOMO:       No.  I think the consensus was in 2012, and I think it was a very important putting together of the literature at that time.  And the consensus interventions promoted by KDIGO is what, I guess, most intensive care doctors will call “motherhood and apple pie”.  It may be that in some circumstances they’re not being applied.  But we would think that will be unlikely to be the case in Australia and New Zealand. 

And so when they prescribe, or they identify those interventions, which is maintaining adequate blood pressure, maintaining adequate hydration, avoiding nephrotoxins, ensuring that cardiac output is OK, ensuring that infection is treated, you know the reply would be, “Of course we’re doing all of those things.” The point is, is there anything else we should or could be doing to decrease the likelihood of developing acute kidney injury?  And at the moment, beyond those obvious interventions that we would think everyone would apply, nothing has yet emerged.

MIC CAVAZZINI:               I think you’ve already answered my next question then.  So in 2018 there was a German study that looked at delivery of this care bundle in response to a Nephrocheck classification of kidney injury.  And this was patients admitted to ICU after major surgical procedures.  In those that had received the diagnostic intervention, there was a significant reduction in the emergence of bona fide AKI, in the length of stay in ICU, and in length of stay in hospital overall.  However, there was no change in rates of renal replacement therapy or mortality of patients while in hospital, or in the rates of adverse kidney events after they were discharged.  So is that sort of underwhelming response more –

RINALDO BELLOMO:       Well this was received with a degree of cynicism by a lot of Australians, because, when you go and – the Devil is in the detail – and you start reading through the paper and you look at, for example, they use a radio contrast in this particular population which was remarkable, from memory, at about 17 percent.  You’re just thinking, “Ah, what?  Why is this happening?  This is not what would happen in Australia.  That’s very unusual.”  And they use a variety of other potentially nephrotoxic drugs in this population.  Very strange, very unusual, typically outside of Australian practice. So, yes, I think that’s an interesting study, and potentially something that can be replicated in other places.  But, here, it was seen as very underwhelming, as you say.

MIC CAVAZZINI:               By contrast, Claudio Ronco and colleagues – the researchers in Vicenza –have been trialling a protocol they call the nephrology rapid response team.

RINALDO BELLOMO:       That’s right.

MIC CAVAZZINI:               They were more selective in their use of Nephrocheck – restricting it to higher risk patients as they were transferred to the ICU.  And those patients with assay scores above that 0.3 threshold were given a full nephrology consultation, while those under 0.3 received standard AKI prophylaxis.  And comparing data in the year before and after this intervention, the number of patients with acute kidney injury decreased from 314 to 281, a decline of 10 percent.  And the number of patients requiring renal replacement therapy decreased by almost 18 percent.  So does this tell us that it’s more about defining the context for use of this tool, than it is about improving the assay itself, or validating it further?

RINALDO BELLOMO:       I think it tells us that there is a potential for exploration of this kind of assay outside the ICU, and in all patients that are potentially at risk out on the wards.  But it also, again, was seen as a relatively weak evidence level, because it’s a single centre study and it’s unblinded, of course.  And so the doctors are particularly exposed to the risk of a Hawthorne effect, where you’ve got a before period where there wasn’t the level of commitment to the care of these patients, and interest in these patients. And then you change over to something that demands a higher level of intervention, and time, and dedication, and you see a difference. Whether it’s related to the biomarker or whether it’s just related to the Hawthorne effect remains unclear.  And, of course, this is a single centre study.  Whether it’s applicable across the board, more broadly, also remains to be tested. 

Even though you might think that the management of patients that are at risk of acute kidney injury within the ICU would be equivalent, whether you were in the United States or in Europe, or Australia, it is actually not true. And the style of management, the style of care, the manipulation of fluids, the manipulation of vasopressor drugs, and multiple aspects of the way we look after patients in Australia, are not at all identical

MIC CAVAZZINI:               It’s good that you make that point because sometimes people complain that the TGA or PBAC are asking us to reinvent the wheel to prove things that have already been proven.  But the point is not just that you’ve got this tool, but that this tool actually works in the settings that – in our settings, and with our idiosyncrasies.

RINALDO BELLOMO:       Yeah, so there are a lot of confounders in clinical care, and clinical practice.  Medicine is not a science.  It’s a science-informed practice.  It’s not like physics where you can create standardised experiments.  It is confounded by the type of patients who present, and the treatments that we deliver as part of patient management.  And I will just go onto a brief story – recently we conducted a very large multicentre international trial called the STARRT-AKI Study.  And this was a 3,000 or so patients, in more than 170 ICUs around the world, and randomly allocated to early intervention versus late intervention with renal replacement therapy.

That’s fine.  But what we did recently, we looked at the fluid balance that was not controlled by the trial, that was allowed to happen according to clinician preferences.  And so when you compare people that are randomised in the same trial, with the same characteristics, for the same reasons, equivalent in every other way that we can tell, and you look at the fluid balance in North America, over the first two weeks these patients end up with a positive fluid balance of about 7 litres.  If they are in Europe, it’s about 6 litres.  If they’re in Australia, it’s about zero.

And so there are really significant differences in style of practice, in choices of management characteristics, approaches, that make it necessary for us to assess these biomarkers in the local context before we “buy” what the SAPPHIRE study has reported in a North American, European population.  We are just different.  We practice medicine differently. That’s reality

MIC CAVAZZINI:               This observation really captures one of the unifying themes of the Pomegranate Health podcasts. That medicine is as much about the about the human factors in delivery as it is about the tools and the science. For acute kidney management, there are still many such factors that need to be constrained.

In an assessment last year the UK’s National Institute of Health Excellence concluded “There is not enough evidence to recommend the routine use of… [commercial] NGAL assays… or [the] NephroCheck test to help assess the risk of acute kidney injury for people being considered for critical care admission.”

The KDIGO consensus group have not officially pinned their flag to the mast either but in 2019 webinar for KDIGO Professors Marlies Ostermann and John Kellum sounded confident that these biomarkers would eventually provide information about intensity of tubular injury, as well as predicting responsiveness to therapy and prognosis.

One of the critiques of the Nephrocheck assay, is that 20% of patients with a positive result don’t actually go on to develop acute kidney injury. Strictly speaking these would be called false positives, but in fact they have worse outcomes than biomarker-negative patients, even without an AKI diagnosis; higher risk of renal replacement therapy, higher rates of hospitalization and ICU and moderately higher mortality over the short term and long term. Professor Bellomo expands on this idea of subclinical kidney injury.

RINALDO BELLOMO:       That is absolutely correct.  It’s a marker of illness severity.  And what’s particularly interesting that in cardiac surgery patients, if you don’t have a change of serum creatinine but if you have a change in Nephrocheck, and you bring the patients back three months later, they have diminished functional reserve to the kidneys.  And so that tells you that these biomarkers can identify some kind of population, that may or may not have a creatinine change acutely, but somehow has had some kind of injury to the kidney that, three months later, can still play out in terms of functional reserve.

So it’s a fascinating area that we – yes, we’re just beginning to get an inkling of, because of course the kidney is really difficult to study.  You know it’s not accessible like the heart may be through the vessels very easily.  You cannot measure the flow to it.  You cannot really easily study the function of its cells.  You’re looking at the urine as a sort of a smokescreen mirror what’s happening in the kidney.  It’s really, really difficult.  Really, really difficult.  And so the tools that we have available to study it in human beings are very, very limited. And so these biomarkers are exciting in the sense that it might also allow us to understand the biology of what’s going on in a way that we couldn’t do before.

MIC CAVAZZINI:               Yes.  And just to spell out this definition problem of the classic definition of acute injury based on serum creatinine.  Well, serum creatinine rises because blood filtration by the kidney has declined, but by the time you’re getting this signal, at least half the kidney tissue has already been compromised.

RINALDO BELLOMO:       Absolutely right.  That’s a real conundrum and real problem. 

MIC CAVAZZINI:               Is that where the concept of renal functional reserve makes sense?  That even though some nephrons are injured, the remaining healthy ones take up the slack for some time.  So then you’re not seeing it reported as –

RINALDO BELLOMO:       Yes, that’s right.  And so it’s a really complex thing.  The kidney at rest in some people after injury, may look exactly the same.  But if you put it under stress by giving it a protein load, it cannot perform.  And so that’s another story.  It’s like saying, “Oh I’m not short of breath when I’m sitting in a chair watching television, but if you get me to run up the stairs I can’t do it.”  And it’s the same situation for the kidney. 

But finally I think the more important issue is that these biomarkers are biomarkers of tubular stress, tubular wellbeing.  They’re not biomarkers of glomerular filtration rate.  And so to use creatinine to validate or study whether these biomarkers have a particular meaning, many people have argued is pointless.  Because you cannot validate a biomarker by looking at an imperfect biomarker of another process, you cannot properly measure of which the biomarker’s creatinine is a very poor representation, that may have nothing to do with what’s happening to the tubules.

And I think, you know if serum creatinine – just if you swap the story and the logic of it – if we only had cell-cycle biomarkers and NGAL and they’d been present for the last 80 years of medicine, and then somebody discovered serum creatinine, we wouldn’t give it a second look.  We wouldn’t give it a second look.  And so what we’re the prisoners of history.  So we’ve got these biomarkers called urinary output and serum creatinine – which are historically determined by the fact that we didn’t have anything else before – and we define everything on the basis of them.  And the only reason we use serum creatinine, is it costs only about 30 cents a pop.

MIC CAVAZZINI:               Yeah I think of it as the absurdity of the US saying that, “What we’re doing in Guantanamo Bay can’t, by definition, be described as torture because the US Military, out of principle, doesn’t do torture.” It’s a definitional

RINALDO BELLOMO:       Quite right. Yes, there’s a problem there.  It’s a tautology.  Yes, I complete agree.

MIC CAVAZZINI:               But as Donald Rumsfeld said, “There are things we don’t know we don’t know.”

RINALDO BELLOMO:       Or things that we don’t want to know that we know.

MIC CAVAZZINI:               Less famous than Donald Rumsfeld, are Claudio Ronco’s words that, “Subclinical AKI is still AKI.”

RINALDO BELLOMO:       That’s right and I think it is.

MIC CAVAZZINI:               Yet in your review, there is a proposed Stage 1 threshold for biomarker concentrations.  Are you confident that that definition of subclinical AKI will become useful?

RINALDO BELLOMO:       I think there’ll be a lot of debate.  I think there is very little doubt that, whether it’s NGAL or whether it’s a cell-cycle arrest biomarkers, something is happening to the kidney that is not normal.  Now what you want to call it, it’s just a matter of nomenclature.  You can call it subclinical AKI, you can call it tubular stress, you can call biomarker release syndrome.  These are matters of nomenclature.  But there’s no question that something is happening biologically to the kidney that we couldn’t measure before, and that we can measure now with biomarkers. It’s just that we don’t know yet fully what the processes are, its meaning, and what it portends, and whether the diagnostic tools that we have allow us to then implement therapies that can stop this subclinical AKI, and thereby stop more serious patient-centred outcomes.

MIC CAVAZZINI:               In another review in the – very recent review in the Annals of Laboratory Medicine, Christian Albert and colleagues write that, “Nephrologists should not consider current kidney tubular injury biomarkers as substitutes for measuring serum creatinine and urine output, but understand their autonomous utility for predicting patient prognosis.” And I guess one example is that in ICU patients with a confirmed diagnosis of AKI – so definitely not subclinical – the cell-cycle arrest biomarkers even there predict a high risk of Rental Replacement Therapy and death.

RINALDO BELLOMO:       That’s correct.

MIC CAVAZZINI:               So it’s telling you something in addition. And conversely, there’s also evidence that kidney dysfunction can occur quite apart from tubular pathology, for example, I think you’ve mentioned, sometimes you get a creatinine rise in response to ACE inhibitors or chemotherapy but no corresponding biomarker signal or signal of tubular pathology?

RINALDO BELLOMO:       That is correct.  That’s absolutely correct, yes.  So it’s quite a complex series of interactions.  And there is a complex relationship between acute kidney injury and patient outcomes, which includes the fact that acute kidney injury is an expression of illness severity.  Simultaneously though, the presence of acute kidney injury is likely to contribute to poor outcomes because it makes the care of patients more complex, because it makes the management of fluids more difficult, because it makes the dosage of drugs more complicated, because it creates a biologic environment that is more prone to inflammation and toxicity. And that interaction between acute kidney injury being a marker of illness severity overall, and contributing to illness severity, is very difficult to unravel. 

And finally there is another backstory to all of this which is the fact that acute kidney injury is a major risk factor for chronic kidney disease.  There appears to be a variety of biological changes, a variety of processes in the kidney, after it’s recovered from acute kidney injury, that somehow might place that particular person at a greater risk of, over time, evolving a loss of kidney function.  And that’s another story in of itself.

MIC CAVAZZINI:               So is there still a lot of basic physiology we need to understand before we can fully interpret these figures?

RINALDO BELLOMO:       I think so.  I think there is still a lot of work to be done, in the sense that we don’t yet really know if they’ve got different kinetics in different types of kidney injuries.  So that they might behave differently if you have kidney injury after cardiac surgery versus kidney injury after sepsis versus kidney injury due to toxic drugs. May be it’s expressed very quickly and go down very quickly.  So we don’t have that information yet.  And the important thing is also whether interventions that are applied by doctors faced with a patient who is unwell, also modify their expression.So those things remain unaddressed, and the story of the cell-cycle arrest biomarkers has just begun. 

MIC CAVAZZINI:               I think I know the answer to this question but, there are some people who’ve suggested that the cell-cycle arrest biomarkers might become “the renal troponin”.  But let’s put it into context.  In patients admitted with chest pains and typical symptoms of a heart attack, contemporary troponin assays are a very sensitive and very specific predictor that MI will be confirmed by ECG and angiography.  The area under the ROC curve ends up at around 0.96, which is in a different league to the score of 0.83 that we’re talking about here.  What does that mean for the way that Nephrocheck should be viewed as a point of care tool?

RINALDO BELLOMO:       Look, you’re absolutely right.  Troponin is in a league of its own.  And also it is associated with therapies that are clearly beneficial.  We’re nowhere around that.  On the other hand, the argument has been made – and it’s got some validity – that the availability of biomarkers may open the door to such therapies. Imagine, for example, not having chest pain when you have a heart attack, and having a test that tells you that there’s been a heart attack when half of your heart muscle is gone.  And so you lose the ability to develop a therapy, because everything’s already happened and it’s already finished. 

Giving an intervention late is like closing the stable after the horses have bolted. On the other hand, if you knew the horses were going to run out the stable, then you can close the door very quickly and you’ll be successful.  If you don’t have biomarkers, you can’t test the hypothesis that if you change the course of acute kidney injury, you change the course of the patient’s outcomes.  You’re never really in a position to test the therapy in a way that gives it a real chance of showing whether it’s efficacious or not.

MIC CAVAZZINI:               So as a parting comment, should our listeners go into work tomorrow and order a box of these assays in?  And, if so, which listeners are going to find it most useful, the intensivists, or –

RINALDO BELLOMO:       Yes, that’s a good question.  I think, at the moment, these remain research tools.  And I think that these biomarkers as research tools, as they get understood more, probably belong to both the Emergency Department, the intensive care environment, and the nephrology environment.  But how, in what patients, and specifically when and so on, is still a matter of research.

But irrespective of this research, the fact that a subclinical or a sub-GFR-derived acute kidney injury exists, is a fact.  There is a biological phenomenon where people with a variety of conditions release biomarkers in the urine, in a way that is normally not done by human beings, is a fact.  And that these patients are at greater risk of adverse events, compared to those patients that do not release these biomarkers, irrespective of whether creatinine increases do or do not take place, is a fact.  Proven, like, over multiple biomarkers, under multiple circumstances, more than – God, hundreds of papers. So there is a thing—it’s a biological event.  We can pretend that it doesn’t exist, but it’s probably best to pretend that it does exist, and then investigate it more clearly to understand it better.

MIC CAVAZZINI:         Many thanks to Rinaldo Bellomo for bringing his expertise to this complicated story. His article in the Internal Medicine Journal with Dr Emily See is a clear and informative read. For even more on this topic, I want to flag a series of ten lectures on renal physiology and disease recently published on the College Learning Series. The CLS is a library of over 450 lectures mapped to the trainee curriculum and recorded by expert clinicians.

You’ll find them at the address elearning.racp.edu.au. Another recent addition to the Online Learning Resources is a 5 part min-doco called The Advocate’s Journey. Perth paediatrician Dr Rob Lethbridge interviews other physicians about their experiences of getting advocacy issues in front of politicians and the media.
I want to thank also the members of the podcast editorial group who gave me feedback on drafts of this story, and to the artists whose music you heard. You can find all their names in the show notes.

I hope you enjoyed this episode of Pomegranate Health. Please subscribe via any podcasting app, and encourage your friends to do the same. You can post a comment at our web page racp.edu.au/podcast, or you’re always welcome send me an email. I’m Mic Cavazzini. Catch you next time.

 

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23 Oct 2021
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