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Do you give a Flux about Flux?

There is a spirited debate in our hospital system about the use and availability of high flux membranes. Part of the debate centered around middle molecule clearance and its relationship to uremia. I fell back to my old standard the HEMO trial.

A study as long and as expensive as HEMO will not be let to rot after its first paper, and the research parasites extracted a number of tantalizing findings. In 2003 JASN published an analysis that looked at flux when patients were divided by vintage. Dialysis patients who have been on dialysis for more than 3.7 years had improved outcomes with high flux dialyzers:

In the subgroup that had been on dialysis for >3.7 yr, randomization to high-flux dialysis was associated with lower risks of all cause mortolity (RR, 0.68; 95% CI, 0.53 to 0.86; P = 0.001), and cardiac deaths (RR, 0.63; 95% CI, 0.43 to 0.92; P = 0.016), compared with low-flux dialysis.

Though the data is not so compelling when the vintage is divided by quintiles:

Even more damning ,was the fact that the longer the patients were randomized, the smaller the effect of high flux membranes:

Longer years of follow-up should show more protection from high-flux membranes (lower RR in the table) but the opposite is actually seen.

Additional post-hoc analysis was done here, showing decreased cerebrovascular disease for longer vintage patients:

I then came across the membrane permeability outcome study, MPO, published in 2009 in JASN. This European study was designed to answer the following question:

This prospective, randomized Membrane Permeability Outcome (MPO) study was designed to compare the impact of membrane permeability on survival in incident HD patients who had either low ( 4 g/dl) or normal albumin ( 4 g/dl) and were treated with a minimum dialysis dose (single-pool Kt/V [spKt/V]) of 1.2. 

Use of incident patients will eliminate the vintage advantage seen in the two post-hoc HEMO studies discussed above. Separating patients based on albumin at baseline seems a bit wonky. Lots of patients have low albumin at the start of dialysis. And I doubt there is an inherent biological reason for this. Turns out, the two tiers were due to pokey enrollment after 11 months and they changed enrollment rules.  They also changed the rules by extending the time patients could take to get to a spKt/V from 1 month to 3 months. The things we do for enrollment!

The top-line results showed no difference in survival by flux:

But when the authors looked at the pre-specified sub-group analysis for patients with a baseline albumin less than 4, the data showed protection with high-flux membranes:
This isn’t just any pre-specified sub-group, this was supposed to be the entire cohort, and only became a sub-group after they amended the protocol.
They also found an interaction between flux and diabetes. This was post-hoc analysis:
So, in the end this seems like a tale told by an idiot (your truly), full of sound and fury signifying nothing because we have all moved on to high flux dialyzers, except in the hospital where F16 low flux dialyzers are available and cheaper than their high flux brethren.

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My concerns with the wearable artificial kidney

Last week the Wearable Artificial Kidney reached some sort of new benchmark and a bunch of press ensued. I stumbled across this one.

And I tweeted:
I know it’s technological marvel but I see a deadend. This isn’t the answerhttps://t.co/PzDAvRHRuG pic.twitter.com/1Aa6nvgJid

— Joel Topf, MD FACP (@kidney_boy) May 2, 2016

This was a popular tweet 
but not a popular opinion. Most people say that it is great to see out of the box thinking in nephrology. They advised me not to look at the technology as it is today but envision where this technology could go.
@kidney_boy remember the first cell phones!!! This is great!!

— linda Radler (@radlerlk) May 7, 2016

I appreciate the technology and can totally see how something like this:

Could undergo a transition analogous to this:
My concern is not the size of the equipment, though by the looks of it, they still have a formidable chasm to cross. My concern has to do with access. This is hemodialysis. It still needs a way to get blood out of the body, into the machine, and back into the body, reliably, continuously and safely. This is not a trivial task and tunneled catheters have a high rate of infection and mortality. 

Persons using catheters had increased risk of all-cause mortality (RR=1.38, 95% CI=1.25–1.52), fatal (RR=1.49, 95% CI=1.15–1.93) and nonfatal (RR=2.78, 95% CI=1.80–4.29) infection, cardiovascular event (RR=1.26, 95% CI=1.11– 1.43), and hospitalization (RR=1.51, 95% CI=1.30–1.75) compared with those individuals using grafts. From Ravani, JASN 24:465-73, 2013.

They are public enemy number one in dialysis units and this technology depends on them. Vascular access is the weak link of hemodialysis, whether it is in-center, home or a WAK. And adding mobility, continuous use, and patient error to the equation probably will not help.
I look forward to sheepishly reading this post one day in our WAK future, but I suspect that future is populated by hover boards and self tieing shoes.
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Nephrology Education Legends

There are a few legendary nephrology education experiences:

  • The Brigham’s Board Review Class
  • Renal Pathology at Columbia
  • ASN Board Review (classically in San Francisco, but now ensconced in Chicago)
  • University of Colorado Electrolyte Review in Aspen
I have not gone to enough of these but each of them belong on your nephrology bucket list. The Aspen Electrolyte Review has morphed from a deep dive into electrolytes to a broader scope. This summer it looks like a great curricula focused on AKI, CKD and transplant. Two NephMadness alumni, Sarah Faubel and Lakhmir Chawla, are among the speakers, as is PBFluids Hero Robert Schrier.
I’m not sure I’m going to be able to make it but I’m going to try (It is really close to the dates of my second year renal pathophys teaching responsibilities). The conference looks awesome. They have mornings off to hike and enjoy the mountains.
Aspen in the summer and nephrology CME. What could be better? (And don’t say Aspen in the summer without nephrology CME). Check it out.
Disclosure: I met course director, Isaac Teitelbaum at the International Society for Peritoneal Dialysis meeting and he offered me free registration if I’m able to go. No payment was sought or offered for this post.
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Bayesian statistics and the absurdity of 70% sensitivity for colon cancer

I saw a patient with this lab in their chart:

Who the hell thought a test with a sensitivity of 70% would make a good screening test? pic.twitter.com/PvO21omMFJ

— Joel Topf, MD FACP (@kidney_boy) March 30, 2016

I got some push back:
@kidney_boy sens+spec impt in diagnostics, also I think you’re missing that test is for those who can’t/won’t be screened by other methods

— Shannon P (@kentuckyshan) March 30, 2016

I don’t know anything about Methylated Septin and not much more about colon cancer but a 70% sensitivity for a screening test seems a bit absurd. So I ran the numbers.

Using a colon cancer prevalence of 1,169,000 in the U.S. compared to an adult population of 245,270,000 gives a pre-test probability of 0.47%.

Getting a negative Methylated Septin result lowers the post-test probability to 0.2%.

Getting a positive Methylated Septin result increases the post-test probability to 2.9%.

Think about that, 97% of the people with a positive Methylated Septin* are actually cancer free.

*assuming you are testing an unselected population.

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The essential lesson from the Missteps in Nephrology #NephMadness Bracket

The idea of a bracket full of nephrology mistakes was a bit controversial. Matt and I are pretty optimistic about the field of nephrology and really want NephMadness to showcase the best of the specialty. So how can a bracket of missteps fit into that idea?

The vision was to explore the moments nephrology went off the rails in order to inoculate us from making the same mistake in the future. Its okay to make mistakes, as long as we don’t keep making the same mistakes. The four missteps we chose each demonstrate a unique failure.

In chronologic order lets review the nature of the missteps.

Aluminum

Science is hard

A generation of patients suffered CNS, bone, and blood pathology from aluminum hydroxide prescribed to patients in order to prevent hyperphosphatemia. This was the young science of dialysis coming up against the limits of technology. Sure, there was the assumption that oral aluminum could not be absorbed, that was later shown to be false, but in the end, science is hard and mistakes are made when we are operating at the event horizon of knowledge. The lesson here should be that we should remain humble and maintain an open mind when operating at the edge of science. Long held assumptions can turn out to be wrong and harm can come from the most banal of sources. A phos binder. Really?

Steroids for Membranous

Statistics are a bitch

The positive finding in the Collaborative Study of Adult Nephrotic Syndrome is a cruel twist of fate. When examining the Missteps, I wanted to find a villain in each story I wanted each one to be a modern medical morality tale. I looked for a way to blame the greedy, or the arrogant, or the sloppy, but the story of membranous is just a story about bad luck affecting good people trying their hardest to do honest science. Dumb luck resulted in 9 of the most aggressive cases of membranous nephropathy all landing in the placebo group. The steroids didn’t preserve function, the placebo group  just crashed and burned for no good reason. Bad things happen to good science. It happens because statistics demands it. Our only defense is to be vigilant against over interpreting fragile results and single trials.

Duel ACEi and ARB for Proteinuric Chronic Kidney Disease

It is easiest to fool people who want to believe

The story of of combining of ACEi and ARB is the classic medical reversal. The physiology and pathology tells explain that proteinuria is toxic. Two drug classes ACEi and ARBs have each separately been shown to be safe, effective and kidney protective. Early data shows that combining them unlocks synergistic reductions in the consensus surrogate outcome, proteinuria. The story was only missing improved hard outcomes with ACEi ARB therapy. This was satisfied by the 2002 COOPERATE trial in the Lancet. The trial answered all the hopes and dreams of nephrologists. It showed successful retardation of proteinuria and delayed dialysis. But when the trial is everything you ever hoped for, it probably would be wise to take a second look and go through the results patient by patient. The COOPERATE trial turned out to be a fraud. What is the lesson from ACEi and ARB? Stories that fit together like a perfect little present probably don’t and deserve special scrutiny.

Normalization of Hemoglobin

Don’t be distracted by the perfect little story, keep your eyes on the prospective data

The story of the normalization of hemoglobin and the damage it did has been told over and over. Much of the blame is directed at the companies that profited from the drugs, but nephrologists have agency. We are not automatons that are incapable of individual thought. Beserab published the truth in 1998 and we let conflicted parties set the guidelines and agenda in opposition to that truth. There is fault enough for all, but before nephrologists can wag their collective finger at the editors at NEJM, or the authors of KDOQI, or the share holders of AMGEN, we need to come to terms with how we ignored what was right in front of our eyes. We wanted to believe that improving hemoglobin could magically erase the cardiovascular disease killing our patients. It was a nice fairy tale, but it wasn’t true.

Medical marketing used to mean mugs, pens and ads in journals. Now it means thought leaders, surrogate outcomes, studies and guidelines.

— Joel Topf, MD FACP (@kidney_boy) March 31, 2016