Monday, October 3, 2011

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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