I started this calcium series in January. This was the second lecture. The fellows are clever so instead of a formal lecture the presentation is designed to stimulate discussion and pose a number questions using real cases.
The Calcium Haggadah
The Calcium Haggadah
- PDF (11 MB)
- Pages document (44 MB)
- 28 5.5×8.5 pages with a front and back cover, introduction, and table of contents
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:
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
How about the top line recommendation to do BMD?
Mostly based on research done by this researcher: https://t.co/6IAWiYPRDD+ (see the @AJKDonline retraction) pic.twitter.com/eADgja8PGm
— Swapnil Hiremath @hswapnil@bsky.social (@hswapnil) January 27, 2018
Hypercalcemia from 1,25 vitamin D toxicity
I received an outpatient consult for acute kidney injury. One of the things that makes Saint Clair Nephrology a remarkable nephrology group is our ability to get patients in quickly. While competing practices in the area have a 3-month wait list to see new patients we get patients in within a week. This patient was seen two days after his doctor called.
The patient was frightened. He had previously been healthy and his doctor told him his kidneys were failing and that he needed to see a nephrologist. He arrived with a creatinine in the high 2s from a base line of 1.2 mg/dL. Along with the AKI his blood pressure was touching 180 systolic, out of character for him. Of note on the initial labs his calcium was 13.6 mg/dL.
The initial work-up showed suppressed PTH. SPEP and UPEP were normal.
On the next visit I checked the 1,25 vitamin D and it was 117 IU. I suspected lymphoma or sarcoidosis but the chest x-ray was unremarkable and the patient did not have any palpable lymph nodes or abnormalities on the CBC. No weight loss, night sweats, or fevers. ACE levels were unremarkable.
On further questioning on his third visit, the patient mentioned he was taking a generic knock off of Mega Red Fish Oil. Fish oils can have significant amounts of vitamin D and the supplement is famously lax with quality control. He stopped the fish oil, we started him on oral prednisone and the 1,25 vitamin D level quickly responded within a couple of weeks. The patient had a full recovery from the hypercalcemia, hypertension, and acute kidney injury.
Update
Some great comments from Twitter
Why did you start steroids if sarcoidosis was low in your ddx?
— Adam Bregman (@abregman42) January 11, 2018
steroids lower 1,25 vitamin D levels
— Joel M. Topf, MD FACP (@kidney_boy) January 11, 2018
Steroids only work if there’s a granuloma right? But this was an external source…
— Anitha Vijayan (@VijayanMD) January 11, 2018
Good question. Found this: https://t.co/TxUB2LdPqh
Agree, not the most compelling.
— Joel M. Topf, MD FACP (@kidney_boy) January 11, 2018
This is much better from the @NEJM in 1969. Just a couple of months shy of my birthday.https://t.co/Res8GKCDSF pic.twitter.com/KjPz1Jzdo1
— Joel M. Topf, MD FACP (@kidney_boy) January 11, 2018
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
- low phosphorous diet
- calcium containing binders
- non-calcium binders
- calcitriol
- paricalcitol and doxercalciferol
- cinacalcet
- 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
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 |
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)
Mixed acid-base disorder and altered mental status
An 80 year old woman was readmitted to the hospital with mental status changes. She was recently discharged following successful treatment for heart failure and associated fluid overload. Her discharge medications were as follows: (You know the joke: senior asks the intern, “What medications is she on?” And the Intern looks up and says, “uhm, all of them.”)
She was brought to the ED with a week history of increasing confusion and weakness. The patient had some shortness of breath but this was typical for her baseline.
Initial labs:
The ABG showed:
- pH: 7.47
- pCO2: 71
- paO2: 74
- HCO3: 51
- First look at the pH
- It’s elevated so this is a alkalosis
- Look at the bicarbonate and the pH
- If they both are moving in the same direction it is metabolic
- If they are moving in opposite directions it is resiratory
- Here the pH and bicarb are up, so it is metabolic
- Put the two together and identify the primary disorder:
- Metabolic Alkalosis
- Calculate the predicted pCO2 from the bicarbonate
- Calculate how far the bicarbonate has increased, this is the delta bicarbonate
- Take two-thirds of the delta and add it to 40, the normal pCO2
- In our patient the bicarb has risen from 24 to 51, a delta of 27, two-thirds of that is 18, so the pCO2 should be 58 +/-2
- Is there a second primary disorder affecting the pCO2?
- Compare the predicted pCO2 to the actual pCO2
- If the actual pCO2 is lower than predicted, the patient has an additional respiratory alkalosis
- If the actual pCO2 is higher than predicted, the patient has an additional respiratory acidosis
- Our patient’s actual pCO2 of 71, is way higher than the predicted 58+/-2.
- The complete interpretation of the ABG is: a primary metabolic alkalosis with an additional primary respiratory acidosis
The ED diagnosed her with acute hypercarbic respiratory failure, and blamed the mental status changes on CO2 retention. She was started on bipap and admitted. The following day her pCO2 improved to 50 but she had persistant confusion. At that point we were consulted for acute renal failure, and noted that she had severe hypercalcemia, calcium of 14.7 mg/dl.
Her phosphate was 1.9 and subsequent work-up showed a PTH of 20., with normal 25 OH and 1,25 OH vitamin D.
On the basis of a combined metabolic alkalosis, acute renal failure, normal PTH and elevated calcium we diagnosed her with Milk-Alkali Syndrome, and started her on IV normal saline and SQ calcitonin. We did not give steroids or bisphosphonates. Over the ensuing four days her calcium drifted down to 10.1. On the third day her sensorium cleared.
Our patient seems to perfectly match the modern form of Milk-Alkali Syndrome or Calcium-Alkali Syndrome using Patel and Goldfarb’s suggested nomenclature. The calcium and alkali were both supplied by calcium carbonate. Additionally she was on a thiazide-type diuretic which decreases calcium excretion. The classic 1930’s form of Milk-Alkali Syndrome was associated with high phosphorous levels while the contemporary form has hypophosphatemia. The principle difference comes from the source of calcium:
- In classic milk-alkali syndrome the patient is calcium loaded from milk, which is very high in phosphorous (370-450 mg per 8 oz)
- In contemporary milk-alkali syndrome the calcium carbonate provides the calcium and also acts as a phosphorous binder to prevent dietary phosphorous absorption.
Low phosphate levels stimulate the renal metabolism of calcitriol and, consequently, absorption of calcium by the gut. Levels of 1,25-hydroxyvitamin D in patients with the calcium-alkali syndrome, of course, are generally low in the setting of hypercalcemia, although some are in the low- normal range and perhaps inappropriately high. These latter levels may depend on previous exposure to vitamin D supplementation, because vitamin D is often added to some over-the-counter calcium preparations, but more epidemiology is needed to clarify this exposure.
Randomized clinical trial of calcium supplementation
Maybe not. This article from 2008 shows increased cardiovascular events in woman randomized to calcium supplementation. I had my mom stop her calcium supplement.
women were included in the study if they had been postmenopausal for more than five years, were aged 55 or more, and had a life expectancy of more than five years. We excluded women who were receiving treatment for osteoporosis or taking calcium supplements; those with an other major ongoing disease including hepatic, renal, or thyroid dysfunction, malignancy, or metabolic bone disease; and those with serum 25-hydroxyvitamin D levels less than 25 nmol/l.
Patients were then randomized to a gram of elemental calcium, as calcium citrate as Citracal or matched placebo.
Lecture for the St John Residents
I have been doing a monthly fluid and electrolyte conference for the residents at St. John. Today we did a case of hypernatremia initially due to hypercalcemia and then due to nephrogenic diabetes insipidus.
week-end call and a pair of crazy numbers: Glucose and Calcium
Calcium
The other crazy number was the most severe hypercalcemia I have ever seen. The calcium was 18 mg/dL with an albumin of 3.7 g/dL. The patient is a kidney transplant recipient who was recently seen in the outpatient clinic with hypocalcemia. His calcium was 6.5 and his calcitriol was increased from 0.5 mcg to 1 mcg twice daily. He was also continued on his calcium carbonate.
The other pertinent calcium labs:
- PTH: 3.2 pg/mL
- Vit D 1,25 dihydroxy: 36 pg/mL
- SPEP/UPEP: unremarkable
- PTHrp: pending
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]