Lecture on CKD-MBD

The St John Nephrology Fellowship is excellent. One of the reasons it is good is ¬†we continually use feedback to fix holes. In last year’s in-service exam we found some weakness in calcium so I was asked to buff the fellows calcium knowledge.

Today I started that with a lesson on CKD-MBD where we focused on the KDIGO 2017 update. I pulled what I feel are the the most important articles in this area published recently. Here is what I pulled:

PRIMO. Paricalcitol in pre-dialysis CKD does not magically heal the heart.
Phosphate binder network meta analysis. Concluded that calcium-free based binders are better. All binders have lots of side effects.
The guideline
Executive summary of the guideline with a useful side-by-side comparison of the 2009 and 2017 guidelines.
Phosphorus binders in pre-CKD patients don’t do a lot of good and increase coronary calcification.
Evolve. Prospective data in CKD MBD that produced a nice separation in PTH and not much else.
FGF-23 still has not made it into the guidelines but it is the phantom menace soon to be unveiled.

What did articles did I miss? What are your favorite CKD-MBD articles

P.S. My favorite part of the guidelines, the part that tell you everything you need to know about KDIGO is 4.2.2:

Here it is in 2009:

And here it is in 2017

And the best part is how the level of evidence has not changed. 2C for both. It’s like they just woke one morning on a different side of the bed.

Great update from Swapnil

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. 

KDIGO


bill goodman talking on KDIGO. Goodman wrote the article that interested me in the topic of vascular calcification and binder choice.

What is KDIGO
Kidney Disease Improving Global Outcomes
established in 2003

Independent non-profit, established by the NKF
The concept was to take K/DOQI and generalize the guidelines for a global audience.

The KDIGO mission is to provide:

  • Clinical Practice Guidelines
  • Guideline database
  • Work groups
  • Controversy conferences
  • Mineral and bone inititative (in draft)
  • Hepatitis C in kidney disease (coming)
  • Care of transplant patient (coming)
  • Acute kidney disease (coming)

CKD Mineral and Bone Disease
A rose from the perception that international perspective needed to define renal osteodystrophy

use the phrase ROD exclusively to define: alterations in bone morphology in patients with CKD
classification based on bone histology, bone turnover, mineralization and volume.

CKD-MBD is a systemic disorder of mineral and bone metabolism due to ckd manifested by either one or a combination of the following:

  • abnormalities of Ca, Phos, PTH, Vitamin D
  • abnormal bone turnover, mineralization, volume, linear growth or strength
  • vascular or soft tissue calcification

KDIGO revisited the concept of guidelines
They graded evidence and created their guidelines by limitting the data to:

  • RCT of at least six months in duration
  • N>50 excepts for pediatrics and bone biopsy
  • Intermediate endpoints including: BMD, bone biopsy, vascular calcification and biochemical endpoints are not considered unless they have been validated prospectively [unclear if any surrogates have been validated]
  • Observational studies acceptable if a clinical outcome examined conducted with a high methodological quality and had a relative risk of >2.0 or <0.5

treatment of CKD-MBD

  • lowering high phos
  • abnormal PTH levels in CKD-MBD
  • treatment of bone and bisphosphonates, other osteoporosis medication and growth hormone
  • evaluation and treatment of kidney transplant bone disease

there is little evidence to provide guidance for a specific therapeutic target range for any biochemical parameter

  • extreme values are associated with greater mortality risk
  • little evidence to support preferred treatments

KDIGO concluded that PTH guidelines are mainly opinion based and not informed by randomized clinical trials

150-300 is based on evidence just not rct and outdated

phos and calcium guidelines are loose

repeated emphasis through out document on the lack of evidence from RCT with hard outcomes

Data Gaps

Evolve is really important, largest prospective clinical trial on dialysis population