It started with a tweet. It always does.

Daniel Coyne is one of my heroes in nephrology. Starting in fellowship and for the first decade of being a nephrologist, I was suckered into the normalization of hemoglobin delusion. The idea that we could heal our patients’ hearts by treating the ubiquitous anemia of CKD was seductive. The theory made sense. The retrospective data looked amazing. Many really smart nephrologists promoted the idea. Living through the medical reversal of CHOIR, CREATE, and finally TREAT was both academically traumatic and a profoundly formative moment in my career. One of the major components of the CKD-anemia delusion was the role that KDOQI played in promoting the high hemoglobin targets before the clinical data showed the folly of this strategy. Dr. Coyne is one of the first nephrologists to ring the warning bells. We highlighted his story in NephMadness 2016. So when Dr. Coyne criticized the nutrition guideline my ears were perked.

The thread highlighted above is convincing and I amplified it.

Subsequently,` I received a polite email from one of the guideline authors suggesting I may have gone too far in criticizing the guideline. Time to put up or shut up. Here are my thoughts, at longer than tweet-length, regarding the protein restriction guideline. Much of this comes from Dr Coyne’s thread, so read that first, so you know where the smart stuff comes from.

Guidelines should only express certainty when there is certainty. When guidelines flip-flop with each new edition doctors lose credibility while taking care of patients. Consistency is important. Because of this I want guidelines to be late adopters rather than on the cutting edge, and for guidelines to be humble about the frailties of human knowledge. 

This puts me in opposition to many guidelines but this 1A guideline on low protein diet seems particularly egregious. The guideline I’m focused on is:

The Detailed Justification of this guideline provides this guidance

Research reports a beneficial effect of protein restriction (0.55-0.6 g/kg per day) on ESKD/death in adults with CKD. In adults with CKD, 5 RCTs reported findings on the effect of protein restriction on survival/deaths. Three studies clearly indicated a beneficial effect of moderate restriction in dietary protein on the development of ESKD/death.153,164,168

So there are 5 RCT that looked at protein restriction for the development of ESRD/Death. Of these 5 studies (of which I could only find 4), 3 were positive, but one of them, Locatelli, is only positive if you consider a P value of 0.06 as significant.

It is so strange to see this reported as a positive trial, because when I would answer questions about low protein diets for my patients with relatively early kidney disease, I would say, this has been looked at in a number of studies but there were two big studies, one in Italy (this one) and one in the US (MDRD) and neither were able to show improvement in outcomes. But here, I guess, this is good enough to qualify for “clearly indicated a beneficial effect.”

The second reference is a small 82 person study by Henrik Hansen. I find this troubling because even though the KDOQI guideline specifically excludes people with diabetes, Hansen restricted enrollment to patients with diabetic nephropathy.

The last of the triplets is Rosman. I could not find Reference 168. This sounds like a study that was presented at a conference, Proceedings of the European Dialysis and Transplant Associations, European Renal Association 1985. Here is the pubmed listing. The abstract is pretty thin. I am particularly concerned because a later publication that seems to be long-term follow-up this cohort (no I don’t know how they picked up an additional 50 patients) and it spins a different tale. The title says it all:

I also highlighted a concerning line from the abstract, “The diet appeared to have a selective effect on the progression rate of renal failure: only patients with primary glomerular disease responded to the diet.” If this is the case this is something that should have given pause to the authors trying to generalize this recommendation for all people without diabetes and CKD 3-5 not on dialysis.

The three “positive” trials were published in 1991, 2002, and 1989. This means the cohorts were pre-ACEi/ARB. In fact, Locatelli’s study actively discouraged the use of ACEi.

Lastly, of the two negative trials (of the five that looked at ESRD/death) the authors brush off Cianciaruso for being, “a relatively small sample size.” Let’s take a look at the trials.

Cianciaruso had an N of 423, twice the size of Rosman’s study and five times the size of Hansen’s. The only study in the group of 5 larger was Locatelli with 456. Relatively small sample size? Come on.
We are currently in the midst of a revolution in evidence based nephrology with the data emerging about the effects of SGLT2i. One of the compelling findings with each subsequent blockbuster study is how consistent the data is regardless of how the outcome is assessed:

• Change in GFR? Yup, the SGLT2i is better
• Change in GFR slope? Check, SGLT2i again
• Fraction of patients that reach death or dialysis? SGLT2i still got you covered.

This is not the case for this guideline. The authors trumpet guideline 3.0.1 claiming a reduction in need for dialysis, but this benefit appears to be fragile because if instead we look at low protein diets (LPD) through the lens of the change in GFR, the data no longer points to a benefit. From the guideline:

This mismatch between the 1A conclusions about development of ESRD or death and the lack of biologic plausibility that one can prevent ESRD without preventing loss of GFR should be addressed in the guideline mentioned and probably should have forced the guideline committee to rethink the 1A grade they awarded to protein restriction. 

Coyne’s first tweet was in response to this

Dr Fouque expresses outrage that someone would question the safety of low protein diets. Well safety is a concern. As I wrote on this blog (see this and the follow up here). These posts are regarding long term follow-up of the MDRD cohort. MDRD is famous for not showing any difference in ESRD or death with either a low or very low protein diet, the long term follow up revealed that among people that did progress to dialysis, the patients randomized to the very low protein had nearly a two times higher risk of death (HR 1.92). So Dr. Fouque, with all due respect, I do think it is quite reasonable to question the risks of a low protein diet.

Dr. Fouque comment also highlights what is so dangerous about the 1A grade for protein restriction, it says this is settled science, we no longer need to investigate this. A 1A guideline insulates protein restriction from questions that need to be asked. This is not settled science. Not even close.

When the KDIGO Diabetic Kidney Disease Guidelines were published a lot of people went nuts over the fact that ACEi did not warrant a 1A recommendation.

If you find this curious, I advise you to listen to Freely Filtered #27 where Ian de Boer describes the logic for that 1B grade. Whether or not you find that admirable or absurd it is clear that the authors of the diabetic kidney disease guideline respect a score of 1A. They hold it in reverence and reserve it for only the most rigorous evidence. This argument came from the mind of Nayan Arora:

I can’t find the same respect for grading the evidence in the KDOQI nutrition guidelines.