#NephMadness 2018: Mark’s Bracketology for Trial Outcomes

Patrick Mark, MB, ChB, FRCP, PhD

Dr. Mark is Reader in Nephrology at the University of Glasgow and an Honorary Consultant Nephrologist at the Queen Elizabeth University Hospital Glasgow. Whilst he is somewhat of a dabbler in a number of aspects of clinical research in nephrology, he is genuinely passionate about improving clinical outcomes for patients with kidney disease. He doesn’t understand how Nephmadness works but is fairly keen on Irish rugby. Follow him @drpaddymark.

Competitors for the Trial Outcomes Region

Doubling of Creatinine vs 40% Reduction in eGFR

Proteinuria vs Patient-Reported Outcomes

The choice of four different clinical trial outcomes in nephrology is a window into the essential soul of what type of nephrologist you are (or at least want to portray to the world). We’ve heard it time and again that nephrology is the poor man of medicine when it comes to undertaking clinical trials to inform clinical practice. Is it the trials themselves? Do we choose incorrect interventions or wrong duration of follow up? Or is it that we fundamentally fail to pick the right outcome as the primary endpoint for the study? Selection of the correct primary outcome to test the efficacy of our interventions is the holy grail of clinical trials. To the best of my knowledge, there was only one grail (though I haven’t done much searching), whilst there are at least four ways of measuring eGFR that I can easily think of and a cornucopia of methods for quantifying proteinuria.

Let’s look at our contenders: doubling of creatinine versus 40% reduction in eGFR. Doubling of creatinine is a fairly robust endpoint in studies of progression of CKD. In truth, it is still just a biomarker, as the patient may perceive no difference between having a creatinine of 100 micromol/L and 200 micromol/L (I refuse to use US units). A hard outcome is commencement of dialysis, which the patient and clinician knows all about.

So, in selecting between biomarkers of doubling creatinine and 40% reduction in eGFR, you have to decide if you are purist or a pragmatist. Purists brought up on RENAAL and similar will go for old school doubling of creatinine. Pragmatists will look at the beautiful primer on trial endpoints by Perry Wilson and note that we could have MEANINGFUL CLINICAL TRIALS LESS LIKELY TO FAIL with fewer patients if we pick 40% reduction in eGFR. OK, there are some details on Type I errors but you can read that and make your mind up for yourself. For me, pragmatism wins, and I’m picking 40% reduction in eGFR.

Next up is Proteinuria versus Patient-Reported Outcomes. What are you? Did you become a nephrologist because you love difficult equations and multiple ways of measuring the same thing to bamboozle other physicians? Proteinuria is for you. Or was your calling the option to provide long-term care for patients with chronic diseases, establishing a physician-patient relationship where you have the rapport and time to find out about more than symptoms but also learn about their family and job, caring during pregnancy, commencement of dialysis, maybe a transplant and longer thereafter? Then pick Patient-Reported Outcomes.

In truth, being a caring physician and loving equations are not mutually exclusive, but here you have to pick a winner. I’m torn. As a nephrologist, I love proteinuria, but in my one attempt to perform a meta-analysis in this area, we found out that in trials we have managed to quantify proteinuria at least four different ways (urinary albumin or protein excretion, then as ratios to creatinine or spot or 24-hour collections). And then it varies a lot.

Everyone loves Patient Reported Outcome Measures (PROMs). We all want patients to feel better. I’m not sure it’s ready for adoption as the definitive outcome for trials. Like proteinuria, we haven’t quite standardized the best way to quantify these. Furthermore, we need to look at the long game. We need to clearly communicate with patients and listen to what they want as the most important outcomes for them in the short- and long-term. And then work out together how we get there.

Most people would want to spend less time attached to a dialysis machine. However, if staying healthy by increasing dialysis hours means that you are in good shape for the transplant that frees one from dialysis permanently, then that may well be an acceptable compromise. How does one quantify these outcomes using PROMs in a clinical trial? It can be done, but I’m confused. Clinical trials run alongside life itself, but different endpoints might win in life compared to our trial. So with that, I think Patient-Reported Outcomes beats proteinuria, but only just.

For the overall win, 40% reduction in eGFR has it all. It’s reasonably effective and will allow us to improve CKD progression trials. It represents a compromise, but in the end, in life, and in clinical trials, we usually learn that compromise is best.

– Post written by Paddy Mark. Follow him @drpaddymark

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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