If it weren’t for your kidney’s, where would you be? You’d be in the hospital or infirmary (with apologies to Fred Dagg). The heart and kidneys are not just linked by a pipe, but the health of one is very much dependent on the health of the other. Acute Kidney Injury (AKI) is a phenomenon whereby there is a sudden loss of all or some of the kidneys’ filtration ability. This can have dire immediate consequences with a greater increased risk of mortality & longer hospital stays. It can also increase the risk of developing a chronic kidney disease or even later cardiac problems. Unfortunately, AKI is devilishly difficult to detect, and therefore there are no early treatments. It is also very common – some 4-5% of all hospital patients. Those with heart failure are particularly vulnerable.
IDENTAKIT-HF is a new project all about identifying AKI biomarkers inheart failure. Two weeks ago it enrolled its first patient. It is a collaborative project involving myself, the Christchurch Heart Institute, and a biomarker laboratory in Prince of Wales Hospital, Sydney headed by former Christchurch nephrologist Professor Zoltan Endre. Not only are blood samples being taken from patients with heart failure and potential AKI, but also urine samples. This is because various novel protein markers in the urine appear to respond much more quickly to AKI than markers in the blood. It is now recognised, that not one marker, but a panel of markers is needed to identify AKI and provide information about how to target any treatments. IDENTAKIT-HF will identify the likely members of such a panel and then test if they really do identify the disease and predict its course. This will form the platform for future intervention trials to develop treatments and improve patient outcomes.
“In ancient times the Persian philosopher Avicenna [Ibn Sina] noted that urine may be retained in crisis of fever (s393) and prescribed hot oil baths (s413)(1). Unfortunately, apart from the supportive therapy of dialysis, there has been little progress since in the treatment of acute kidney injury (AKI).”(2)
Given that getting AKI at least doubles your chance of dying in hospital “no progress” is a major health issue.
Today is World Kidney Day and I get to post quite possibly the first blog post in the world on this day. I believe Avicenna would be thrilled with the attention paid to the organ which delivers urine. He may not be so thrilled that hot oil baths have been abandoned. Of course there is the obvious safety issues of scalding and drowning. Also, as Herod the Great found out, syncope (sudden loss of consciousness) is also a possible side effect (probably just because the heat constricted his blood flow [vasoconstriction] causing too little oxygen to reach his brain [cerebral anoxaemia].(3) Nevertheless, I think Avicenna is the type of person who would have welcomed a randomised controlled trial of hot oil baths verse today’s standard treatment.
If you don’t fancy a hot oil bath this World Kidney Day, then there are other things to do to minimise the possibility of Acute Kidney Injury. Have you got high blood pressure, diabetes or Chronic Kidney Disease? Be warned, ~10% of the adult population have Chronic Kidney Disease, many of whom are not aware, and many more are at risk of developing it. All add to your risk of multiple illnesses any one of which can trigger acute kidney injury. If you happen to have a heart attack or sepsis (very serious infection) you are more likely to get AKI and more likely to die because of these underlying conditions.
So, on the assumption that readers of this blog are smarter than the average bear, I shall give you some sound advice – for the sake of yourselves and your family LOOK AFTER YOURSELF (yes, I’m shouting and therefore sinning against the internet protocol police – but this is important). Cut the sugar intake, quit smoking, take a walk around the block. It ain’t rocket science (one of the simpler sciences that involves cylinders with fins and lots of explosives) – it’s easier than that.
Everyone said it did, but how did they know and by how much? Statements like
“The development of AKI [Acute Kidney Injury] after CPB [Cardiopulmonary Bypass Surgery] is associated with a significant increase in infectious complications, an increase in length of hospital stay, and greater mortality.” (Kumar & Suneja, Anaesthesiology 2011 14(4):964)
are common place in the acute kidney injury literature. When I started to look at the references for such statements I realised that they were all to individual, normally single centre, studies and that the estimates of the increased risk associated with AKI after CPB varied considerably. Furthermore, the way AKI is defined in these studies is quite varied. This lead to two questions?
Just how deadly is getting AKI after CPB?
Does it matter how we define AKI in this case?
These questions are important as the answer to them helps a surgeon and patient to better assess the risk associated with choosing to have cardiopulmonary bypass surgery and what the importance is in monitoring kidney function after such a surgery. To answer these questions required a meta-analysis the results of which I have just published (a.k.a earned a cheesecake). A meta-analysis involves systematically searching through the literature, a sentence which takes seconds to write but months to serve, for all articles reporting an association between AKI and mortality after CPB. Then there is learning how to put all the, sometimes disparate, data together (I had to learn a lot of R for this one) and to report on it. As this was my first meta-analysis, I was fortunate to have the assistance of two highly competent scientists & nephrologists with meta-analysis experience, namely Dr’s Matt James of Calgary, and Suetonia Palmer of my own department in the University of Otago Christchurch.
So – what did we find?
If you get AKI after CPB you about 4 time more likely to die compared to if you do not get AKI after CPB even after accounting for things like age, diabetes, and other risk factors.
Somewhere between 37 and 118 lives per 10,000 CPB operations could be saved if we could find a way to eliminate AKI.
How AKI was measured did not make any difference to the results.
AKI after CPB was also associated with increased risk of stroke.
A teaser of a figure from Pickering et al, AJKD 2014
In the case of dialysis dependent acute kidney injury patients this is a question which Dr Dinna Cruz and colleagues (University of California San Diego) are asking and seeking opinions from both nephrologists and non-nephrologist doctors and nurses involved in care of dialysis patients. It was a question which arose out of discussions at this year’s Continuous Renal Replacement Therapies conference (CRRT 2014). Personally, I think it is a brilliant starting point for research to go out and seek the opinion of those “at the coal face” actually treating patients. If that includes you, please take a moment to complete the survey. If it includes someone you know, please pass this request to participate on. Here is Dr Cruz’s request:
Currently there is much interest regarding the recovery aspect of AKI. A specific area of interest is how to enhance recovery in patients who remain dialysis-dependent at the time of discharge. It is hypothesized that patients with potential for renal recovery may require a different care plan than the “usual” ESRD patient.
Therefore we are asking your opinion regarding the post-discharge care of such patients, using this short survey. It will take only a few minutes of your time, and represents a starting point for developing potential strategies for these patients. We think it is very important to have the input of specialists from different healthcare settings and countries to give a more balanced view.
Kindly complete the survey appropriate for your specialty, then please share both these links with other colleagues so we get more responses from around the world
As we’ve been enjoying the World Cup and the Commonwealth Games my latest cheesecake appeared in print online. The topic once more is Kidney Attack biomarkers – those pesky little proteins in the urine that appear when your kidney is injured. This time I have been getting stuck into some math (sorry) to try and understand what it is that affects when these biomarkers appear in the urine after injury. I call this a biomarker time-course. A “Pee Profile” may be a better term but it would never get past the editor. What I care about is whether the type of biomarker and/or extent of injury, affects the pee profiles.
There are three basic types of biomarkers. First are those that are filtered from the blood by the two million odd filters in the kidney. Often they are then reabsorbed back into the blood in the little tubules where the pee is produced – that is, they don’t appear in the urine. Think of it like a stadium with many entrances. People (biomarkers) come in and sit down (are reabsorbed). If, though, a section of the stadium has been fenced off because of broken seating from the previous game (the injury), then some of those entering the stadium may end up exiting it again (the pee biomarkers). The numbers being reabsorbed and exiting will also depend on whether all the entrances are open – if some are closed then this will have a flow on affect on the rate of people leaving the stadium.
The second are preformed biomarkers. If we change the analogy slightly, imagine these as people already in the stadium (if the analogy was accurate they would have been born there!). If some terrible injury happens (like the 4th, 5th, 6th and 7th goals of a now famous football match) some of those people would get up and exit quickly. The overall rate of exit would reflect on the extent of the injury.
The third, are induced biomarkers. These are ones that don’t already exist, but are produced in response to an “injury.” Instead of being biomarkers, let us think of the spectators as produces of these biomarkers and let noise be the biomarker. There is some background noise of course, but when an “injury” (goal, gold medal performance etc) occurs there is a sudden increase in noise which slowly dies down. Depending on the team and the number of supporters this will be softer or loader and will carry on for shorter or longer periods (Goooooooooooaaaaaaaaaaaa……lllllllllllll).
The upshot of it all were many coloured graphs and a step towards understanding how we may better make use of the various types of novel biomarkers of kidney injury that have been recently discovered.
Sitting in the bathtub you notice that there is a slow leak around the plug. You adjust the taps to maintain a flow of water that exactly counteracts the loss due to the leak; the water level stays constant. This is called a steady state and the same thing happens with out kidneys and the molecule used to assess their function. Our bodies generate creatinine at a constant rate which finds its way into the blood. Under normal circumstances our kidneys excrete that creatinine into the urine at the same constant
rate. The creatinine concentration in the blood, therefore, stays constant. When our kidneys get injured (as they very often do in hospitalised patients) this is like plugging the leak. Just as the water level in the bathtub would rise slowly – undetectable at first – so too does the creatinine concentration rise slowly. It normally takes a couple of days to be noticed. Most of my work has been about trying to detect this injury to the kidney early. However, if the kidneys start to recover then excess creatinine is only slowly cleared from the blood by the kidney – a process that similarly can take a day or two before it is detected. Just as not knowing if the kidneys have been harmed makes treatment and drug dosing difficult for the nephrologists and intensivists, so too is not knowing if they have recovered. My latest publication (aka a cheesecake file) that has appeared in press presents a simple tool for the physicians to try and determine if kidney function has recovered after having been compromised.
This particular piece of work began when a St Louis Nephrologists (a kidney doc), Dr John Mellas, contacted me to say that although a manuscript of his had been rejected by reviewers, he thought there was merit and could I help him (he found me through a search of the literature). I confessed to being one of the reviewers who had rejected the manuscript! Fortunately, John was forgiving. His problem was that he was called in to the intensive care unit to look at a patient with high blood creatinine concentration. Should he put the patient on dialysis or should he wait? If he knew if the kidney was already recovering, then he would be less likely to put on dialysis. We talked about the issue for a while and eventually settled on a possible tool which we could test by looking at the behaviour of creatinine over time in abut 500 patients in the ICU. The tool is quite simple. It is the ratio of the creatinine that is excreted to the creatinine that is generated. If more creatinine is being generated than excreted then probably the kidney function is still below normal, however, if more is excreted than generated then probably the kidney is recovering. The difficulty is that there is no way to measure in an individual what the creatinine generation is. We ended up using equations based on age, sex, and weight to estimate creatinine generation. This is a bit like using an equation which takes into account pipe diameter, mains water pressure, and how many turns of the screw the tap has had to determine the rate of water flow. Creatinine excretion, though, can be easily measured by recording total urine production over several hours (we suggest 4h) and multiplying this by the concentration of creatinine in the urine.
We discovered that by using the ratio between estimated creatinine generation and creatinine excretion we were able to tell in most patients if the kidney was recovering or not. My hope is that physicians will test this out for themselves. The good thing is that it requires only minimal additional measurements (and costs) beyond what are already made in ICUs, yet may save many from expensive and invasive dialysis.
While I understand Auckland Women’s Health Council co-ordinator Lynda Williams unease, I also detected a failure to understand the process of how progress in medicine is made.
First, all research in such cases is approved by ethics committees which include lay people and patient advocates. That is clear in the article. In my experience they are very very thorough at ensuring the best interests of patients are highest priority. Family or whanau consent is almost always required (especially if the research involves an intervention*). These are the same family or whanau who are talking with medical staff and, at times, providing consent for medical interventions. When a person is vulnerable it is up to all around them to treat them with respect and care. Offering them, through their family, the opportunity to participate in research is showing respect for them as a valued member of society who is prepared to give in the interests of others. Indeed, it is a right of the patient, through their family, to be offered such research.
Second, without such research there can be no progress in medical treatment of unconscious critically ill patients. In order to save lives interventions must be made at critical junctures during the progress of a disease, normally at the earliest possible time. It is in the best interests of us all that such research take place. The alternative is to give up hope and allow current mortality rates to remain as they are. I research a disease (Acute Kidney Injury) which affects 1 in 3 people in the Intensive Care Unit and increases their chances of dying about 4 times. There is no treatment and it is devilishly difficult to detect in the early stages. An estimated 2 million a year die because of Acute Kidney Disease. Without the generosity of family and friends allowing trialling of an intervention (always based on years of prior research and judged to be possibly efficacious) there will be no progress and the death toll will remain high. I salute family and patients around the world who have participated in such studies in the past, and will do so in the future.
Disclaimers: 1. I have no knowledge or understanding of the antiobiotic trial under discussion. 2. I have been involved in an intervention study where participants were unconscious at the time consent was obtained.
*Note, there are some circumstances where when minutes count an intervention is required. Research in these areas is ethically more difficult, but no less necessary. I welcome public debate in this area. While ethics committees can deal with ensuring minimisation of harm in such circumstances, we do need to decide as a society what sacrifices of individual rights we should make for the greater good.