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. 

Klotho information

I went to an afternoon of lectures at ASN on Klotho and its relationship to calcium. I thought they talked about klotho being involved with proximal tubule transcellular calcium reabsorption via TRPV5/6 but after posting a comment about that here, I find that my memory failed me.

It looks like Klotho binds FGF-23 receptor and makes it more specific for binding FGF-23 which then increases the production of calcitriol. Additionally free Klotho in the urine increases expression of TRPV5/6 which enhances DCT and connecting tubule transcellular calcium absorption.

the Recent advances that have given rise to marked progress in clarifying actions of alpha-Klothootho (alpha-Klotho) and FGf23 can be summarized as follows:

  1. alpha-Klotho binds to Na, K-ATPase, and Na, K-ATPase is recruited to the plasma membrane by a novel alpha-Klotho dependent pathway in correlation with cleavage and secretion of alpha-Klotho in response to extracellular Ca.
  2. The increased Na gradient created by Na, K-ATPase activity drives the transepithelial transport of Ca in the choroid plexus and the kidney, this is defective in alpha-Klotho(-/-) mice.
  3. The regulated PTH secretion in the parathyroid glands is triggered via recruitment of Na, K-ATPase to the cell surface in response to extracellular Ca concentrations.
  4. alpha-Klotho, in combination with FGF23, regulates the production of 1,25 (OH) Vitamin D in the kidney. In this pathway, alpha-Klotho binds to FGF23, and alpha-Klotho converts the canonical FGF receptor 1c to a specific receptor for FGF23, enabling the high affinity binding of FGF23 to the cell surface of the distal convoluted tubule where alpha-Klotho is expressed.
  5. FGF23 signal down-regulates serum phosphate levels, due to decreased NaPi-IIa abundance in the apical membrane of the kidney proximal tubule cells.
  6. alpha-Klotho in urine increases TRPV5 channel abundance at the luminal cell surface by hydrolyzing the N-linked extracellular sugar residues of TRPV5, resulting in increased Ca influx from the lumen. 

These findings revealed a comprehensive regulatory scheme of mineral homeostasis that is illustrated by the mutually regulated positive/negative feedback actions of alpha-Klotho, FGF23, PTH and 1,25 (OH) Vitamin D. In this regard, alpha-Klotho and FGF23 might play pivotal roles in mineral metabolism as regulators that integrate calcium and phosphate homeostasis, although this concept requires further verification in the light of related findings. Here, the unveiling of the molecular functions of alpha-Klothootho and FGF23 has recently given new insight into the field of calcium and phosphate homeostasis. Unveiled molecular functions of alpha-Klotho and FGF23 provided answers for several important questions regarding the mechanisms of calcium and phosphate homeostasis that remained to be solved, such as :

  1. What is the non-hormonal regulatory system that directly responds to the fluctuation of extracellular Ca? 
  2. How is Na, K-ATPase activity enhanced in response to low calcium stimuli in the parathyroid glands?
  3. What is the exact role of FGF23 in calcium and phosphorus metabolism?
  4. How is Ca influx through TRPV5 controlled in the DCT nephron?
  5. How is calcium homeostasis regulated in cerebrospinal fluid?

However, several critical questions still remain to be solved. So far reported,alpha-Klotho binds to Na, K-ATPase, FGF receptors and FGF23, and alpha-Klotho hydrolyzes the sugar moieties of TRPV5. Does alpha-Klotho recognize these proteins directly or indirectly?Is there any common mechanism?How can we reconcile such diverse functions of alpha-Klotho?What is the Ca sensor machinery and how can we isolate it?How do hypervitaminosis D and the subsequently altered mineral-ion balance lead to the multiple phenotypes?What is the phosphate sensor machinery and how can we isolate it? How does the Fgf23/alpha-Klotho system regulate phosphorus homeostasis? How are serum concentrations of Ca and phosphate mutually regulated?

Calcium and the great case report

I gave my first lecture to the residents at Providence Hospital on Friday before Labor Day. I did a new lecture on calcium. I tried to base this lecture around this incredibly interesting patient I had a few years ago at St. John.

He was a young man who came in with a fracture due in part from his rip-roaring uncontrolled secondary hyperparathyroidism, which had actually progressed to tertiary hyperparathyroidism. We treated his hypercalcemia, got him a parathyroidectomy and then watched in horror as his hypercalcemia switched to hypocalcemia as part of a wicked case of Hungry Bone Syndrome. To cap it off he developed acute symptomatic hypocalcemia after meeting Alonzo Mourning.

On that one admission, in one patient my team got to see and study:

  1. Renal osteodystrophy with skeletal complications
  2. Diagnosis and management of Hypercalcemia
  3. Diagnosis and management of tertiary hyperparathyroidism
  4. Diagnosis of Hungry Bone Syndrome
  5. Management of severe hypocalcemia
  6. Relationship of ionized calcium to pH

I call it the greatest case report ever told and regarding calcium it probably is the best.

Again I provided the resident with a booklet and did the lecture Seder Style. This was the best use of that style yet.

Calcium Case Report

iPhone version