Tag: metabolic bone disease

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The agony and ecstasy of of secondary hyperparathyroidism

Managing secondary hyperparathyroidism in dialysis patients should be a rewarding aspect of nephrology. I thrive on complex management that involves balancing various numbers with clever treatment strategies. It is exactly what I find so exhilarating about a juicy electrolyte case in the ICU.

The principle variables in secondary hyperparathyroidism are:

  • PTH
  • Phosphorous
  • Calcium
And I use one additional lab that is generally ignored in the guidelines, alkaline phosphatase.
To bend these numbers we have a variety of tools with interesting effects, mechanisms of action and side-effects. The principle therapeutics:
  • low phosphorous diet
  • calcium containing binders
  • non-calcium binders
  • calcitriol
  • paricalcitol and doxercalciferol
  • cinacalcet
And additional therapeutics that can be brought to bear in difficult cases or in unusual circumstances
  • dialysate calcium concentration
  • parathyroidectomy

And K/DOQI provided cleanly laid out treatment goals:

  • PTH 150-300
  • Caclium 8.4-9.5
  • Phosphorous 3.5-5.5
  • Calcium x phosphorous product < 55
Patients that achieve those targets have a lower mortality risk than patients that miss these targets:

The numbers (0 of 3, 1 of 3, etc) refer to the number of months a patient is at the K/DOQI target in the quarter, PTH was measured only once a quarter

The problem is that no one has performed a prospective randomized controlled trial showing these targets improve outcomes. We want to believe that the retrospective data showing a survival advantage with cinacalcet and paricalcitol are real and that the observational data showing better calcium and phosphorous (and to a smaller degree, PTH) results in better patient outcomes.

Teng et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med (2003) vol. 349 (5) pp. 446-56

Block et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol (2004) vol. 15 (8) pp. 2208-18
But given nephrology’s previous relationships with retrospective data (see anemia, Kt/V, and statins, and homocysteine) I can’t accept that data. I can’t take these treatment goals seriously. I appreciate that the fresh KDIGO guidelines readily admit that the emperor has no clothes and that the best they can recommend is to generally keep the calcium and phosphorous close to normal (evidence level 2D) and the PTH anywhere from 150 to 600 (evidence level 2c) or roughly wherever the hell you want it.

I love this figure from KDIGO, essentially once the PTH rises over 150 it provides no information. PTH > 300 has a positive predictive value of only 65% for high turnover disease. And don’t miss the laughably small numbers. We are basing global guidelines off of a study of less than 100 patients. From Barreto and Barreto.

It is shameful that Abbott has not done an RCT with survival as an endpoint on Zemplar or Calcijex. They have had 20+ years to do this. Both of the other players in CKD-MBD have taken a chance at building RCT data to support there products:

  • Genzyme took a poke with DCOR (RCT of sevelamer versus calcium based binders) 
  • Amgen is in the final countdown of EVOLVE (RCT of sensipar + usual care vs usual care)
Abbott the oldest player is sitting on the sidelines.
The lack of data, the lack of clarity, and the reliance on observational data muddles the issue enough that I don’t enjoy taking care of secondary hyperparathyroidism. But recently I had a great case, a situation where treating secondary hyperparathyroidism did more than loaded the dice in my patients favor but actually really made a difference.
I have a young dialysis patient who suffers from a horrific trauma a number of years ago. As a result he has profound chronic pain. Much of the pain is back pain but he also complained of diffuse body aches. Earlier this year his PTHs were consistently over a thousand with some over two thousand.
We added 90 mg of cinacalcet daily and the the PTH plummeted to goal. This was in a patient who had not responded to doxercalciferol 10 mcg three times a week. It was nice to see the PTH come down but what made this case standout was that his body aches melted away. We had been sending him to pain clinics and switching narcotics trying to get his pain tolerable and all of a sudden, done. Pain dramatically improved with a log reduction in PTH. 
Sometimes I get so carried away worrying about total mortality that I forget about the direct toxicity of high PTH. 
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Myles Wolf is coming to speak at Renal Grand Rounds today

Wolf has been everywhere and is one of the premiere scientists elucidating mineral metabolism. He was the senior author on the article in the NEJM on FGF-23 and dialysis survival and the recent article on the survival advantage with phosphorous binders.

Just a quick review of FGF-23 so I’m not an idiot when this rock star nephrologist starts talking. (FYI don’t let the clean cut pic above fool you, he came to the lecture in full rock-star fashion with the long hair, groupies (supplied by Genzyme) and everything)

FGF-23 is produced by osteocytes.

Klotho seems to be a required co-factor for FGF-23, such that mice that are Klotho deficient mimic the phenotype of FGF-23 deficiency.

FGF-23 increases renal phosphorous clearance by blocking Na-Phos reabsorbtion in the proximal tubule. FGF-23 also inhibits 1-alpha-hydroxylase, decreasing 1,25 OH-vitamin D.

Some of the biology is still a mystery. The highest density of fgf-23/klotho receptors are located in the distal tubule but the biologic effects stem from the proximal tubule.

FGF-receptor and Klotho are also found in the parathyroid gland but the exact role it plays is unclear. Some data points to direct stimulation of PTH and both molecules tend to rise together but this may be due to FGF-23 surpressing 1,25 OH D and secondary increases in PTH.

Increased phosphate and 1,25 vitamin D both stimulate the production of FGF-23. [Note Wolf provided data that phosphate levels do not increases FGF-23. He proposed that it is phosphate balance that is important, his supporting data included lupron treated patients bump their phosphorous by half a point but FGF-23 doesn’t budge, I couldn’t find this article on Google]. The Phex endopeptidase cleaves and inactivates FGF-23 so that is another control factor. [Wolf also discussed iron infusions causing phosphorous wasting due to excess FGF-23 ref pubmed related search]

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Monday was the highest traffic day on this site. Ever.

My post on Everything I learned in fellowship is wrong was featured on the home page of renalWEB.

It feels weird that my post was listed at the top under “News Headlines.” The ATN article came out in July and I just got around to writing about it six months later. I wrote it so that when I discuss the findings on rounds, I have a way to quickly find an abstract of the study with my personal observations. And I will discuss it with the fellows because even though the study was a negative study it is a benchmark study in nephrology. The article is a negative study but it is negative in the way that HEMO was negative, not the way that DCOR was.

  • HEMO is usually listed as a disappointing study because we were not able to help patients by ratcheting up their dose of dialysis from 1.16 to 1.53 (eKt/V).
    But as Glen Chertow argued persuasively, the HEMO trial was a triumph of evidence based medicine. We were able to definitively argue against the desire to incrementally enhance three-times a week day-time dialysis. The increasing evidence for daily and in-center nocturnal dialysis are by-products of the failure of HEMO. If HEMO had been a positive trial we would probably be focusing on a HEMO II with a targetted eKt/V of 1.8. The negative result has sparked innovation and a search for novel ideas.
  • DCOR on the other hand has almost nothing definitive to show despite being “the largest outcomes study ever done in the hemodialysis population.” The failure of DCOR can be attributed to a low event rate, a high but undefined cross-over rate and a 50% drop-out rate. All of these conspired to produce an under-powered study and clinicians are left in a sea of phosphorous binder marketing without near term hope for better guidance.

So the negative finding of the ATN group advances the science of nephrology, removes an important question and will allow us to move on to new strategies to help patients with acute kidney injury.

A final note to the editor of RenalWEB, my bullet on the dose of dialysis referred to the HEMO trial, which did not look at frequency of dialysis or radical increases in dose. The jury is still out on those techniques but I’m with you. Those two strategies seem right and beneficial.