The tao of science missed by National Science Challenges

The challenges are out. The committee has spoken. And now the critics respond.  Word on science street and in the media goes a bit like this:

Brilliant $73M more for science in New Zealand.  Well done Steven Joyce and the National Party.

Lacking in lustre.  These challenges are all a bit predictable. [eg Prof Hendy here]

Damn.  My research does not fit any of the challenges. [eg Dr Wiles here]

I sympathise with each of these opinions.  The National party has set a goal of 0.8 percent of GDP for science.  This is to be applauded. They have chosen a path of narrowing the scope of science to ensure it meets their own ideology of “government’s job is to grow the economy”.  This is reflected in the challenges and the language around them.  For example the challenge “High value nutrition: research to develop high value foods with health benefits” in the Peak Report document states:

There is enormous capacity to leverage both our primary industry and medical research to discover, validate and develop nutritional products with proven health benefits of significant market potential.

Some scientists seem to think that economic goals some how “devalue” science.  I am rather more pragmatic in suggesting that an economic return is an inevitable result of doing science.  The difficulty, though, is that any attempt to pick winners – and that is what the National Science Challenges does, fails to recognise that science at its best is not shackled but free to explore and expand.  Science by its very nature is at a frontier and a journey into lands unknown.  A pathway cannot be chosen for it and any attempt to do so will as often as not go straight past the pot of gold.

The National Science Challenges have been chosen by committee – there are “winners” and “losers” and the result is necessarily bland.  This is inevitable when science is done by committee.  Great science comes from great scientists who are driven to great discoveries.  It is driven by leadership, and leadership never comes from a committee.  On Morning Report this morning the interviewer and Prof Hendy both mentioned the US Space Program as an example of a truly exciting and great science challenge.  That challenge came from a great leader, President Kennedy, and while driven politically, the political goal was the same as the science vision.  Sadly, once the political goal had been reached the politicians turned elsewhere and the science community was left holding on to a few rocks and a vision shattered.

From my perspective what is needed for science in this country even more than challenges is vision and visionaries.  We need to fund scientists first and projects second.  Sadly, we have that priority completely around the wrong way.  Dr Wiles who ironically was one of the faces of science on the television campaign encouraging public submissions on the challenges is disappointed that her area of research, infectious diseases, is not acknowledged in a challenge.  I am disappointed that enthusiastic talented scientists like Dr Wiles are not directly receiving 3, 5, 10 year’s of salary and research cost support from this new money to pursue their vision. It’s not so much the topic of research as the researcher that counts.  I have a challenge for the New Zealand government.  And that is for their science policy to be evidence based (see Grant Jacobs’ blog post).  Part of that puzzle is whether it is best to fund researchers or to fund projects. This is why I say the Challenges have missed the tao of science – they are not in harmony with the way science is really done.  Let us run a trial.  Randomly select ten scientists and fund their salaries and $100K a year and let them pursue whatever they want.  Compare this to the results of randomly selected National Science Challenge funded projects with the same number of scientists involved.  The title of the trial could be “Is picking winners better than letting winners pick?“

Happy WKD

I love living in NZ, it enables me to be the first in the world to wish everyone a happy World Kidney Day.  May your kidneys never lack oxygen, be always filtering, and ever distant from the nephrologists biopsy needle!

Let me remind you:

 If it weren’t for your kidneys where would you be

You’d be in the hospital or mortuary

If you didn’t have functioning kidneys

(with apologies to John Clarke)

Better, take a look at this video too (from www.worldkidneyday.org):

This year’s theme for World Kidney Day is “Kidneys for Life: Stop Kidney Attack.”  If you’ve not caught up with my myriad of other posts, Kidney Attack (aka Acute Kidney Injury) is the rapid loss of kidney function and/or structural damage brought about by toxic damage to the kidneys or temporary loss of blood to the kidneys.

This week I published a blank post entitled “A list of effective treatments for Kidney Attack.”  There is no known treatment – merely acute dialysis, a support for the kidneys, not a treatment. There is no treatment because detection is delayed and difficult and because not enough research has been done.

The good news is that I and many others around the world are engaged in finding new ways of detecting this disease.  Before I list some of the good news I want you all to repeat after me “30,000 kidney attacks a year in New Zealand, 1300 deaths.”  If you live out of New Zealand you may say “Two million die of Kidney Attack each year.”  Now tell someone else … anyone … the next person you see (not your boss if you read this at work).  Well done, thank you.

So, for some good news:

Hooray – we have for the first time means of measuring structural damage to the kidneys.  For us, this is the X-ray moment.  Imagine life before the X-ray – all that could be said is that you could no longer bowl a bouncer (throw a curve ball), play the piano, or dance a jig (whatever that is).  In other words, all that could be said was function was lost.  With the X-ray actual injury to the bone could be observed.  Importantly, it could be observed before function was lost permanently.  The measurement of various molecules we make in the urine are to us like the X-ray – they are measures of injury to the kidney (we call them biomarkers).

We are busy investigating how best to use these biomarkers and have been discovering:

• which are best after Cardiac surgery, Contrast procedures or in the ICU (all risk factors for Kidney Attack),
• what the optimal timing is for measurement of each biomarker,
• how to use the biomarkers in Randomised Controlled Trials aimed at testing new treatments,
• which biomarkers are best for detecting Kidney Attack when someone has additional co-morbidities like sepsis, and
• which biomarkers add the most value to what we already know and enable the best assessment of risk of poor outcomes.

In the meantime, some of my work has shown how we can better utilise the information we already have with urine output and the mainstay of nephrology, the plasma creatinine measure:

• the discovery that even when creatinine does not change after Cardiac Arrest there is likely to be Kidney Attack (it had been thought that it was only when creatinine was elevated there was a problem),
• a combined measurement of plasma & urine creatinine and urine flow rate (called creatinine clearance) over a short period of time in the ICU helps identify Kidney Attack patients otherwise missed,
• how best to estimate someone’s “normal renal function” so that a judgment can be made if it has recently changed, and
• how best to utilise creatinine in Randomised Controlled Trials to tell if an intervention is improving kidney function.

All these add up to progress.  My own and my group’s work over the last 6 years has received funding from a number of funders (see logos attached) some of which originate with your tax dollar – hence my commitment to keep the tax payers informed. I am indebted to my boss, Professor Zoltan Endre, not only did her hire me (I think he mistook Physicist to mean Physician!), he has taught me heaps and consequently we have formed a strong collaboration. Our work has also depended on the good staff of Dunedin and Christchurch Hospital ICU’s, Christchurch Emergency Department, and the Canterbury Health Laboratories.  Without the commitment to research these people make, progress would not have been made.  Most important are the patients or their families who have consented for us to take extra samples or enroll them in a trial. The decision to participate is often made at a difficult time – families wrestling with issues of possible death or long term health issues of their loved ones.  I salute them.  I thank them.  New hope, new medicines, new tests, and new procedures are built on the courage and generosity of the patients and families who participate in research.

Sponsors who have provided grants (top row), or run assays (middle row), or provided free accommodation (me!) for the Christchurch Kidney Research Group, University of Otago.

2 years on the Papanui campus remembers and celebrates

This post is published at 12:51 February 22 2013 – exactly 2 years to the day from the deadly Christchurch quake and 5.5km from where I was on that day.  This morning I met with a PhD student as she prepares the penultimate version of her thesis.  Two years ago she, I, another PhD student and several others from my research group occupied the “clip on” on the University of Otago Christchurch building above the main entrance of Christchurch Hospital. Less than 24 hours later the Papanui campus was established.  First PhD student was within one month of submission of her thesis.  The first task was to rescue as much of the thesis as we could from USB sticks etc.  Fortunately we managed to put together enough to get on with, and her thesis eventually had a successful outcome.

When I reflect now, I just got on with what I knew I could do. I left my medical colleagues in the hospital to get on with what they knew best.  I stood outside the hospital main entrance and saw the first casualties being brought in. Once I was sure that my students and colleagues were OK to find their way home, like thousands of others I started walking home to check on my own family.  In the meantime, others worked.  Yesterday I heard Prof Michael Ardagh, head of the Emergency Department, talk about the response of the hospital staff and medical students.  It is a remarkable story – it worked, and lives were saved, because plans were in place.  It worked because the staff put others ahead of themselves.  This was not just the doctors and nurses.  It was the med students who ran errands, the maintenance staff her with ingenuity (story of a truck and syphoning diesel) kept generators running, of blood bank staff in the bowels of the hospital ankle deep in water with intermittent power processing requests from the ED and ICU, of the Canterbury Health Labs who picked up their equipment, recalibrated, and were back on line within 20 minutes.

The Papanui Campus at age 730 days

The University of Otago Christchurch building is now open again.  The students are back, and the labs up and running.  I hope to get an office back sometime in the next month or two.  The scientific community from the universities of Lincoln and Canterbury, and private enterprises like Canterbury Scientific have been fantastic at opening their doors and hosting labs and staff.  Others, like myself, established themselves where they could and got on with what they could.  While there are casualties of the disruption – staff moved on (I no longer have a lab group to work with), studies interrupted (I had a study going in the ED and ICU at the time which was inevitably suspended), and grants not able to be written for lack of staff, pilot data etc, there has also been much success to celebrate.  Not least are two years of teaching which happened at various odd venues around the city including several sporting club rooms.  Prof Christine Winterbourne was awarded the highest scientific award in New Zealand in 2011 – the Rutherford Medal, and there were other awards for Uni Otago Christchurch staff too.  Just this past month some colleagues have received promotions to Professorships – deserved.  Some new research areas have begun, particularly over the health effects of a major disaster. Students have graduated, and many papers have been published (12 & a book chapter for me in the last 2 years ).  Plenty to celebrate.

Across the front of the University of Otago Christchurch building are the words “Research Saves Lives.”  Decades of research saved lives on 22 February 2011.  The research in the years since will save lives in the years to come.  Well done colleagues.  Thank you Canterbury for the support.

Lives to be saved on March 14th 2013

Kidney’s are being attacked every day.  Yours could be next.  So common and deadly are kidney attacks that the theme for this year’s World Kidney Day is “Kidneys for Life: Stop Kidney Attack!“

Kidney Attack, or as Physicians and scientists call it “Acute Kidney Injury,” is a syndrome which affects several thousand people a year here in New Zealand.  It is notoriously difficult to detect and can be deadly.  For more than 5 years now I have been researching how better to detect, and ultimately to treat, Kidney Attack.  Over the past 12 months I have posted several times about this – here are links to just a few of the previous posts:

• I am a pee scientist.
• Kidney Attack
• Deadly ignorance.

There will be more as we lead up to World Kidney Day 2013.

The Hunting of the SNARF

Some of you may know Lewis Carroll’s classic nonsense poem “The hunting of the Snark”.  Eight men set off with a blank map to find the mythical Snark.

 And the Banker, inspired with a courage so new

          It was matter for general remark,

     Rushed madly ahead and was lost to their view

          In his zeal to discover the Snark

Snarks were dangerous creatures, however

 ”For, although common Snarks do no manner of harm,

          Yet, I feel it my duty to say,

     Some are Boojums—”

I dwell in a world where inspired by the new many have rushed on ahead to discover the SNARF (SigNals of Acute Renal Failure).  The hunting of the SNARF has followed contours familiarly trodden and graphically illustrated by a Hype cycle(1).

The Hunting of the SNARF: A Hype Cycle of the hunt for the perfect biomarker of Acute Kidney Injury

It was kickstarted by new technologies called proteomics and genomics which gave the hope that soon would be discovered a rapid, accurate, and, most importantly, early biomarker of Acute Renal Failure (later renamed Acute Kidney Injury, AKI).  This was the beginning of the hype that was driven in no small part by some fantastic early results.  A paper published in the Lancet in 2005 was an important driver in the hype that followed(2).  As with many early studies this involved children and cardiac surgery.  Importantly the biomarker involved almost perfectly distinguished between those who had the disease and those who didn’t (ie not false negatives or false positives).  As the field progressed and more and more studies were investigated across a more diverse range of patient groups and potential AKI causes the ability to discriminate between those with and without the disease became much more modest.  It became apparent that one biomarker to rule them all was not going to be the solution – rather a panel of biomarkers whereby the clinician would choose which biomarkers, if any, to use according to the timing and suspected etiology of the renal injury, the baseline renal function and specific illness of the patient.  We do not yet have such a panel, nor have we conducted sufficient investigations to find if an AKI biomarker(s) adds value to what the clinician can already deduce.  That is partly my job and these are the greater challenges that must drive us up the slope of enlightenment to reach the plateau of productivity where finally we may capture the SNARF.

(1)    Jackie Fenn, “When to Leap on the Hype Cycle,” Gartner Group, January 1, 1995

(2)   Mishra J, Dent CL, Tarabishi R, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365(9466):1231–8.

Deserved

Colleague Dr Suetonia Palmer just won a prestigious L’Oreal for Women in Science award.  She’s one of my “go to people” for nephrological type questions (ie all the stuff I don’t know).  This award is very well deserved!  The press release on scoop gives all the salient details.  Just let me add my bit.

What impresses me about Suetonia and her work is her attention to detail and her dedication to dig for the truth.  Her work is focussed on systemic reviews with the Cochrane Collaboration.  Quite simply, this is about as good as it gets for evidence based medicne.  Her mission is to gather evidence from multiple trials for a particular treatment or clinical practice and to analyse that evidence in detail to answer the age old question “Does it really work?”  Her focus, of course, is kidney disease.  An example is a meta-analysis of Vitamin D supplementation in Chronic Kidney Disease (1).  Suetonia and colleagues trawled through data from 76 trials, assessed them for quality, and combined the data.  Apparently Vitamin D had been widely used to prevent and treat secondary hyperparathyroidism – a consequence of the failure of the kidney to handle Vitamin D properly. The result was that despite its wide use, the beneficial effects of Vitamin D compounds on patient-level outcomes were unproven.  We all want our doctors to use the best available treatment with the least side-effects, and we don’t want unnecessary (or expensive) treatments.  Suetonia’s work enables that to happen.

Well done Suetonia.

Our Suetonia

1. Palmer SC, McGregor DO, Macaskill P, Craig JC, Elder GJ, Strippoli GFM. Meta-analysis: vitamin D compounds in chronic kidney disease. Ann Intern Med 2007;147(12):840–53.

See more of  Suetonia’s publications at http://www.otago.ac.nz/christchurch/research/ckrg/ourpeople/index.html.

$6,126,820

$6,126,820 has been sitting on my fridge for the last two years. I aim to raise this over 20 years so as to continue my research.  Yes – I confess, I am the Six million dollar man (Historical reference for those over 40).  Sounds a lot of money, but let’s put this in context.  Because I am “research only” staff, I must raise all my salary and expenses, so the calculation was the sum of my salary, a salary for a part-time research assistant (2 days a week), overheads on both our salaries at a rate of 108% (the rate my university expects from me) and about $20,000 a year for a few research expenses.  In other words, about $300,000 p.a.

A few comparisons from government funding

Teacher: $164,000 p.a.   New Zealand spends about $7000 per secondary school pupil.  Apparently there are 23.5 pupils per year 9 student.

 Olympic athlete:  $150,000 p.a.  According to Prime TV, the NZ government spent $108,000,000 sending ~180 athletes to the current Olympics.  Assuming this was spread over 4 years, then this is about $150,000 p.a per athlete.  Of course, many also have corporate sponsorship.

I wonder what a mid level manager with a part-time secretary in the ministry of housing costs?  I can well imagine it passing $300,000.

The Six Million Dollar Fridge

Is what I do worth two athlete’s olympic performance?  Is it worth more than an average year nine teacher.  Perhaps not for me to say. This is not to say the government should not put money into the athletes or teachers, merely to point out that if I were to raise the money from government science funding such as the HRC or Marsden, then this would be my relative value to NZ according to the politicians who divide up the budget.  The reality is that I am very unlikely to raise this money from government sources.  In the last two years I have raised about $420,000 dollars of which $300,000 is from governement funds via the Marsden fund (thank you) and a little from the University of Otago Research Grants. The rest is from the Australia and New Zealand Society of Nephrologists. Unfortunately, it is about $200,000 under budget, so I no longer have a research assistant (she was very good and is sadly missed). If I were to reach my goal via governement funding I will need to get a gold medal (an HRC grant or Marsden grant) every two to three years.  As these have success rates of about 7 and 12% respectively, this is a very big ask.  So, how shall I raise the dollars?

The Plan

First and foremost I shall continue to put the bulk of my time into being the best scientist I can, otherwise there is no point! My skills are in science not fund raising.

Second, and despite what I just said, I shall look for innovative ways to raise money.  Siouxsie Wiles sojourn into the world of crowd source funding was inspiring, if not a little daunting. Perhaps this sort of innovation on a larger scale?  For that I need to find the right people – entrepreneurs and fund raises who will help me find the people looking to donate to a good cause.  Maybe I will write Apps or ebooks? No stone shall be left unturned.

Third, expand my connections to other research groups here and overseas.  I’ve already begun this – I now have an honorary position with UNSW in Sydney.  So far, no money has come with the extra work, but it is worthwhile work and I certainly would like to contribute to more such projects.  As I am a data analysis person the mantra is –give me your data and I shall massage it into a story worth telling.

Fourth, corporate sponsorship.  Yes, I will wear their jacket and paint my car if they so desire.  In medicine corporate funding is a tricky business.  It is important not to be seen to be biased.  As I am not a medical doctor, I have the advantage that any sponsorship could not influence my clinical practice (I don’t think it does for most medical people anyway). However, because I am not a medic, pharmaceutical companies and the like are probably less likely to sponsor me. But if I don’t ask I won’t know!  So far I have had a good relationship with three biomarker companies who have measured specific protein concentrations for myself and my colleagues using their own assays – no strings attached.  Essentially, I contribute to their knowledge base and they contribute to my research.  Unfortunately, there is no cash flowing for salaries yet.

Fifth, I shall remind the university that my contribution to their PBRF funding is substantial and some kind of retainer wouldn’t go amiss.

Sixth, I shall continue to talk with politicians about the lack of public funding for science.  I began this in 2008 and have had several good discussions.

Finally, I shall not totally give up on grants just yet, but I shall be judicious about which ones I spend time applying for.

Health Research Council is broke

Do you want your health care professionals to be the well informed?  Do you want them to make decisions using the most accurate diagnostic tools? Do you want them to consider all alternatives?  – It’s a no brainer, of course the answers are “yes”, “yes”, and “yes.”  However, it will only happen in these professionals are in an environment where cutting edge research is taking place.  Sadly, that is New Zealand no longer.  Our health has been sadly compromised by successive governments’ failure to invest in health care research.  Last week the Health Research Council (HRC) announced the successful applicants for the latest annual grant funding round.  Only 7% of all applications were funded. HRC chief executive Robin Old stated

“It’s really low. When I talk to my colleagues from all round the world they all think it is a crisis if the success rate falls below 20 per cent. Once it gets to 7 per cent I don’t care who you are or how famous you are, it’s incredibly challenging.” http://www.stuff.co.nz/national/health/7032969/Research-falters-as-funds-tighten

 Challenging is spin for munted.

Here’s what 7% looks like

Let’s look at a few numbers

• Total grants awarded $65.7Million
• Total salaries $24.3Million (37%)

Here are some back of the envelope calculations which give a ballpark idea of why the system is munted: If the average salary is $90K then funding is for 270 scientists (FTE) or an average of 5.2 scientists per grant (1).  Assuming the average number of scientists per grant is the same in grants that were not successful, then ~3900 FTE scientists applied (note some applied on more than one grant, they are counted more than once).

If each scientist put in 1 week’s work on each application then each $6.7M of work was done.  That is, the cost of applying was 28% of the salaries granted!

Add in HRC’s admin costs ~5% of total expenditure(1) or 13% of Salaries granted! Making the cost of the HRC grant round to be ~40% of salaries funded.  The system is broke.

Here’s another way of looking at it.

• HRC annual contracts $90 Million.
• Vote health budget $14 Billion.
• Health Research Grants= 0.64%.

My quantitative analysis is very much ad hoc and easy to criticize.  However, the fact remains that an awful lot of time of many highly skilled individuals is spent chasing a diminishing pot of money. Some of my colleagues are so disillusioned won’t even bother applying to HRC now.  Many of the medical professionals stick to teaching and healing only.  Specialists won’t come to work in New Zealand because the academic positions they are offered come with little hope of research funding.  Then there are those scientists who have no teaching position and so live by the axiom – “granted or perish.”  Note – it’s no longer “publish or perish.”  Publications are no longer enough to justify your existence.  I face the “granted or perish” situation every year myself, despite an excellent publication record.

I don’t like writing negative posts, but it is hard to find a light at the end of the tunnel that isn’t a train coming the other way.  As a nation we need to make difficult choices about our health spend, one of them is do we become a “consumer” nation (some would say parasite) and just hope that others make the breakthroughs and we can afford to buy their technology, or do we become a “contributor” nation pulling our weight or better?  If we want the latter then nothing less than a four of five fold increase in health research grant funding will do.

___________________________________________

(1) Based on the 2011 annual report:

• Total Contracts awarded: $89.9M
• Total Running costs $4.35M
• (HRC costs:  $3.92 M,Fees: $0.42M)
• http://www.hrc.govt.nz/sites/default/files/Annual%20Report%202011%20Web%20version.pdf

A positive STD

The doc said it was an STD.  I laughed.  Why?

The answer my friends lies in the numbers.

Of course the doctor wanted me to have an awkward conversation and prescribed some anti-bs.  I, on the other hand, was very confident, so took a different line – “Do the test again,” I said.

And the rest is history…

Any blood or urine test has a reference range – that is a range of concentrations  at which it is negative and above (or below) at which it is positive (some tests are just shown as a “+” or a “-“ as in home pregnancy kits rather than a number).  It is up to the doctor when they receive a positive test result how they interpret them.  They may chose to believe the test has diagnosed a disease, they may choose to do more tests in order to “confirm a diagnosis”, or they may choose to think that the results are erroneous.  I really don’t know how often they choose any course.  What I do know, is that every school child should be taught about false positives and false negatives.

A false positive is simply a test which says that you do have the disease when you don’t. 

A false negative is simply a test which says that you do not have the disease when you do.

What we want is a test with as few false positives and false negatives as possible (the “narrow” ellipse in the diagram).  In reality, tests vary a lot.

Ideally every test result will lie in the dark blue (true negative) or dark red (true positive). In reality, there is always a few false positives and false negatives [A good test would have few (the narrow ellipse), a poor test would have many (broader ellipse)].

How often do false negatives and false positives occur?  I don’t know the exact number, but the answer is “frequently.”  The more tests done, the more false negatives and false positives there are.  For a test like chlamydia which is ordered by doctors even when it is not asked for by patients (grrrr!) my guess is that it is very frequent.  Consider this – if the boffins who developed the test for chlamydia decide on the threshold for positivity (eg the concentration above which the test is called “positive”) such that the test correctly identifies as having the disease 99% of those that have it (ie only 1% of the “positives” are False positives) then for every 100 people diagnosed with the disease, 1 does not have it.  If it identifies correctly 99% of those who do not have the disease as not having the disease then 1 out of every 100 people who are told they do not have the disease actually have it.

If, on any given day, 1000 people in New Zealand have the test.  For a moment, let us assume that of those 1000 people, 100 actually have chlamydia.  With the numbers above it means 1 person will be told they have chlamydia when they don’t and 9 will be told that they don’t when they do!

Telling someone they have a disease when they don’t matters most if the treatment for the disease is dangerous and/or expensive, or the psychological or social consequences for the individual are serious (eg divorce!).

Telling someone they don’t have a disease when they do matters most if the failing to treat could lead to more serous healthy problems and/or costs for the person or their community (as with an STD).

All these factors have to be weighed up when deciding on test thresholds and on whether a test should be made available in the first place.  It is why, for example, we don’t routinely screen for prostrate cancer – the test has too high a likelihood of false positives.

Recently in the media there was concern over screening for breast cancer in Southland.  Some women had received negative readings of mammograms, yet later were found to have breast cancer.  Was this because of poor reading of mammograms?  The answer appears to be “No”, the “False negatives” were at the rate expected (See  http://www.health.govt.nz/news-media/media-releases/confidence-southern-screening-programme).

For the record – the second test was negative.

Keeping a promise 1

I believe in open access and the right of the public to know what I am doing.  Putting my money where my mouth is, is another story.  When I started this blog in January I promised myself to write something every time an article of mine appeared in print. That’s happened three times already this year and I’ve yet to fulfill that promise…so this is the first of several posts (promise).

Ideally all my research would be freely available online as soon as it has been through the peer review process.  Unfortunately, that costs a lot of money which few research budgets can meet (in the journals I publish it typically costs an extra US$3000 above and beyond normal page charges of around $70 per page and $500 per colour figure).  Nevertheless, this year I have managed to make two articles “Open Access” and another is on the way.   The one I have chosen today is my first book chapter in the field of Acute Kidney Injury.  I received an invite to contribute to a book  and responded positively for a change – for a reasonable cost (US$1000) it was an opportunity to produce a longer treatise on an important area of my work and to make it freely available to anyone and everyone.

 Pickering JW, Endre ZH. The Metamorphosis of Acute Renal Failure to Acute Kidney Injury [Internet]. In: Sahay M, editor. Basic Nephrology and Acute Kidney Injury. Rijeka: InTech; 2012. p. 125–49.

Freely downloadable from: http://www.intechopen.com/books/basic-nephrology-and-acute-kidney-injury/the-metamorphosis-of-acute-renal-failure-to-acute-kidney-injury

The story begins with a lament as to the repeated failure of clinical trials to discover any effective therapy for Acute Kidney Injury (AKI).  We then discuss the history of how the thinking has changed from Acute Renal Failure – the idea that the kidney filtration function is suddenly reduced – to Acute Kidney Injury – the idea that the kidney tissue is injured which often results in a reduction in function.  For the mathematically minded there is a section on how to determine the function of the kidney on the basis of the concentrations of a marker (plasma creatinine) in the blood.  Those who prefer words to symbols, though, can skip this.  We discuss the current definitions of Acute Kidney Injury (still based on function!  – That is soon to change…watch this space), then I introduce three things important to clinical trials.

1. Although AKI is associated with higher mortality rates it is financially ruinous to run a trial with mortality as an outcome because of the very high numbers of patients needed.  For that reason, a surrogate for kidney function is used.  Often this has been a definition of Acute Kidney Injury that is categorical – ie the plasma creatinine concentration increases by more than 50% you have AKI, if it doesn’t, you don’t.  A trial will then compare the proportions of patients in the placebo and treatment groups with AKI.  A couple of years ago I published an article in which I demonstrated that such a categorical trial outcome was not the best idea – better was to use a continuous measure of the change of creatinine that takes into account the duration as well as the extent of that change (I called this the RAVC). I explain this in the chapter.
2. When we use plasma creatinine to judge kidney function, we need to know what the concentration was prior to someone ending up in intensive care (ie we are interested in the change from a baseline).  About half of patients have a suitable measurement on record.  What do we do about the other half?  I present a way of dealing with the problem from a clinical trial perspective.  Previously I had shown that the first recommendations given to solve this problem were no better than using a random number generator.  There are some more clinically relevant (and less mathematical!) ways of determining baseline creatinine.
3. Finally I deal, a little (for this is an ongoing saga) with how to use the new injury biomarkers (often little enzymes measured in the urine – see “I am a pee scientist”).  Ideally, we would initiate therapy (or placebo) on the basis of measured injury even before we were able to detect a change in function.  My colleague (Prof Zoltan Endre) was the first to attempt a randomized control trial based on just such a measurement.  I was brought in to manage the numbers and since then have managed to show that it isn’t quite as easy as we hoped…hence the ongoing saga

I hope that wasn’t too boring.  I think the chapter is pretty accessible to most, and what’s more anyone can download it.  If you do do that, let me me know just if it was understandable at all.

Addendum: One of the nice things about Open Access is that people from all over the world get access to your article – according to http://www.intechopen.com/statistics/29478  one person from the Dominican Republic, 2 from Macedonia, 8 from Poland, and 9 from New Zealand have downloaded this book chapter…cool.