We all are drowning in e-mail. Today I got one from Akhtar Ashfaq, Senior Vice President, Clinical R&D, and Medical Affairs Renal Division at OPKO Pharmaceuticals.

The e-mail promises that new research shows that using calcifediol to correct PTH slows the progression of chronic kidney disease. Big if true. It is not true, and this publication actually lays bare how cynical some pharma-sponsored publishing can be.

The Tweet (actually in this case a Tweetorial)

Hours after writing this I was thinking about the tweet and it hit me. If the data OPKO used to see that the drop in PTH was associated with decreased progression of CKD was from the pivotal trial they used for approval then it was a randomized, placebo-controlled, trial and that OPKO had the data that would actually answer the question. So I pulled up the methods of the manuscript to see where the data came from.

Yep, they were randomized, placebo controlled trials. The two trials were combined and published in this manuscript (Sprague, S Am J Nephrol 2016).

And the authors looked at the most important question regarding the treatment of secondary hyperparathyroidism in CKD, “Does it slow the loss of GFR?”

No. Despite a powerful effect on PTH, there was no signal that use of calcifediol made a bit difference in the loss of eGFR.

Now this study only had patients on placebo controlled medications for 26 weeks, so perhaps there was not enough time to see a difference. But this is not the only attempt to use vitamin D to preserve kidney function. The large (1300 people randomized) and long (5 years) VITAL Study included an analysis of CKD progression and found no effect on eGFR or albuminuria. (H/T Gunnar Henrik Heine)

And last year Yeung, et al did a meta analysis of vitamin D therapy in CKD and likewise found no effect on all-cause mortality (relative risk [RR], 1.04; 95% CI: 0.84, 1.24), cardiovascular death (RR, 0.73; 95% CI: 0.31, 1.71), or fractures (RR, 0.68; 95% CI: 0.37, 1.23).

Every hyponatremia consult recommends increasing protein intake to increase the solute load and increase urine output. But how much protein do you need to move the needle?

Here is another way to do the calculation

Protein is about 16% nitrogen

And urea is just under 50% nitrogen by weight

So if you are using 2 packets of urea (30 grams) a day for SIADH, you should get an equivalent amount of urinary solute (and increased urine output) with three scoops of protein powder.

For this calculation I used this protein powder which has 18 scoops for $22.

Published literature

The TREASURE Study (H/T Pablo Garcia) tested 17 patients with SIADH. They were given 90 grams of protein (three scoops!) for seven days then after a washout they were given 30 grams of urea. for seven days

The results were modest, but there was little material difference between the two therapies.

Patients quality of life improved during the protein phase and fell during the urea phase

The rating for overall well-being slightly improved from 7 VAS points (6-8) to 8 VAS points (7-8) (P = .24) upon protein intake, whereas it slightly worsened from 7 VAS points (6-7) to 6 VAS points (6-7) (P = .40) upon urea intake.

Update

David Goldfarb asked about changes in bicarb with the protein supplement

So I went digging into the supplement to see if they reported it. (They did not) and I came across this humdinger

It shows patient level data on the change in Na. Strange that they didn’t mention that almost a third of patients in the in protein supplement group had their sodium fail. No failures among the urea patients (except one person with inadequate protein intake. That is the asterisk).

Animated gif to make this more clear

I’m glad this is reported. But it should not be in the supplement, it should be in the main paper.

Hot Dog Therapy

In a related note, Roger Rodby suggests hot dog therapy.

I took Roger’s hotdog therapy and made it into an animated gif

Here are the two key slides in the build

and

Cardiology developed one the most fantastic medical technologies of the late twentieth century, the percutaneous coronary intervention. The problem that PCI tackled was obvious, patients with coronary artery disease had demonstrable arterial narrowing and we had a technique that could treat this narrowing. How could we not treat it? How could patients not benefit from this? And following these interventions patients had remarkable improvements in angina, the primary symptom of coronary disease. In addition to improving chest pain, this intervention had to prevent heart attacks and save lives. This assumption was accepted fact at the beginning of my career, however some cardiologists were unsatisfied with using intuition to guide therapy and PCI came under the sharp blade of the randomized controlled trial. COURAGE shot down the idea that providing cardiac (bare metal) stents in patients with stable coronary disease provided any survival benefit. This was repeated with ISCHEMIA (now with drug eluting stents). And then ORBITA used sham procedures to question whether PCI even reduced angina, a finding that was at least partly reversed by ORIBITA-2 which removed the use of anti-anginal medications.

This post is not intended to provide a comprehensive review of the use of PCI in coronary disease but to use it as a demonstration how an intuitive therapy that seems to have obvious and unquestioned use, can be questioned and through those qquestions we can reposition the procedure to use it where it is helpful and not waste resources and treat patients with science and not vibes.

This takes us to dialysis. Dialysis unquestionably helps some patients but I don’t think it helps all patients. Nephrology has rarely subjected dialysis to the rigors of a randomized controlled trial and this is to our patients detriment. We have little evidence to guide us as to when to offer dialysis and when not to. One area that has been extensively explored with RCTs is when to initiate dialysis in AKI, and honestly, it wasn’t pretty for dialysis.

Last week Dr. Manjula Tamura published a Target Trial Emulation of an RCT to see how survival differs between elderly patients (age over 65) with a GFR of 12 and immediately starting dialysis (average was 8 days after trial inclusion) versus delaying dialysis at least 30 days (average was 3 years after trial inclusion). The author tracked two outcomes:

1. Survival
2. Cumulative time at home

The results showed that starting dialysis at 12 ml/min resulted in survival for 770 days. For the cohort who delayed dialysis survival was 761 days. The difference was non-significant.

This image is powerful

The trial was covered in the New York Times!

I am confused by Target Trial Emulation. I am suspicious that people started on dialysis at a GFR of 12 and people that go for 3 years before starting dialysis (in the delayed group) are really interchangeable. I am confused how the late start group can start dialysis an average of 3 years after inclusion in the study while only surviving an average of 761 days (2.1 years) But it is clear to me that nephrology has failed at doing studies to determine who benefits from dialysis. And I believe that old frail people do not get the benefit from dialysis that we dream of. This was shown in an earlier study by Dr. Manjula Tamura which showed dialysis to be a blood bath for nursing home patients. (Tamura, NEJM 2009). I have used this study to guide me in the advice I give patients. It is just an observational study but it showed the folly in believing that the frail patient in the nursing home will turn around as soon you clear the uremia. That’s just a fairy tale we tell ourselves. It almost never happens and the reality is that almost all of these patients are either dead or further debilitated a year later.

As Dr Tamura says in her Tweetorial about the study, it is time for randomized trials to see where dialysis helps and where it falls down. We need to have the COURAGE to test whether what is intuitively helpful actually delivers benefits. The cardiologists have used clinical trials to define the role of PCI in coronary disease, we should do the same for our patients.

Good question about a confusing topic:

In Lecture 19, it is mentioned that hypokalemia leads to decreased NaCl reabsorption in the distal convoluted tubule. I do not understand why this occurs. Dr. Topf said that when you have hypokalemia, you will have decreased Na/Cl/K activity in the TAL, which will lead to increased Na and Cl delivery distally, so shouldn’t that increase NaCl reabsorption in the DCT?

It is also mentioned in this lecture that hypokalemia stimulates H+ secretion in the PCT. I am confused why this occurs as well.

Okay, let’s take this one question at a time, and let’s do it in anatomic order starting in the proximal tubule.

Hypokalemia and the the proximal tubule

In hypokalemia potassium leaks out of the cell to restore extracellular potassium. In order to maintain electroneutrality, Hydrogen ions (protons) move into the cell.

This causes intracellular acidosis. In the proximal tubule this intracellular acidosis “fools” the proximal tubule cells into thinking there is systemic acidosis and their natural response to this “acidosis” is to accelerate the movement of intracellular hydrogen into the tubule, there by increasing proximal tubule bicarbonate resorption.

Here are the relevant slides from the presentation:

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Anatomically the next relevant tissue is the thick ascending limb of the loop of Henle (TAL)

Here the question is how hypokalemia affects the TAL, the TAL is powered by the Na-K-2Cl pump, decreased potassium means decreased NaK2Cl activity, so less sodium is reabsorbed and more sodium moves distally. Here is the relevant slide from the deck.

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And finally to the crux of your question, “Shouldn’t that increase NaCl reabsorption in the DCT?”

YES it does!

The increased sodium reabsorption in the distal cortical collecting tubule is what drives further H and K secretion which perpetuates the metabolic alkalosis and hypokalemia!

Here is a text slide describing it followed by an animated gif of the relevant slides

I hope that helps clarify the question.

New question:

Good morning,

I hope you are well. I was looking at the explanation for this practice question that I believe is from your lectures, and I was a little confused at the explanation which describes this as a “SIADH syndrome from the patient not being able to excrete water taken in during the marathon”. Could you elaborate how you would know this is SIADH? My original thinking was that they were electrolyte depleted from the extended exercise as well as hyperglycemia, so having had an energy drink would have helped them.   

My answer:

This is classic exercise induced hyponatremia. 

The stress of extreme exercise (especially in people not in great physical condition) causes them to retain water via a non-osmotic release of ADH. 

These patients actually gain weight during the marathon and are not electrolyte depleted.

A great study on this was published in the NEJM in 2005

Here is the abstract

As part of this study they looked at sport drinks versus drinking pure water and it did not affect the risk of developing hyponatremia (which was 13% of Boston Marathon runners!):

Additional adjustment for female sex (P=0.20) or drinking 100 percent water (P=0.89) was not statistically significant and did not appreciably alter the coefficients of the remaining variables in the model.

Is this clear or do you need more?