Topic Discussion During Internal Medicine Rotation

1. 1
Stage eGFR
G1 >/= 90
G2 60-89
G3a 45-59
G3b 30-44
G4 15-29
G5 < 15
G5D < 15 + dialysis
Substance Ca Phos.
PTH
1, 25 dihydroxyvitamin
D (calcitriol)
Background
Anna Sandler
Mineral and Bone Disorder in CKD
PharmD Candidate, 2023
Physiology and Pathophysiology: When tight control is disrupted
 Mineral and bone disorders (MBDs) commonly accompany
chronic kidney disease (CKD)
 Associated with:
o Imbalance of calcium (Ca), phosphorous, parathyroid
hormone (PTH) and vitamin D
 CKD-MBD has been linked to cardiovascular mortality1
o Disruptions in mineral homeostasis
o Vascular calcification
 2017: > 60% of CV deaths in dialysis patients
 The kidney responds to signals from the parathyroid
gland
 The parathyroid gland has a calcium-sensing receptor
(CaSR) that allows it to control serum Ca levels
 In response to low Ca levels, the PTH gland stimulates the
kidney to reabsorb Ca from the blood
 The kidney produces more activated vitamin D to increase
intestinal Ca absorption
Renal failure
Phosphorous Calcitriol
Secondary Hyperparathyroidism
Drug Target
CaSR
1: Hyperphosphatemia, vascular calcification, and elevated fibroblast growth factor 23 (FGF23) seen in CKD are
associated with increased CV morbidity and mortality. Mortality in CKD patients on dialysis is approximately 20
times higher than that of the general population.
 In renal failure, the tight control is lost
o Impaired excretion of phosphorous
o Decreased production of calcitriol
o Decreased sensitivity of CaSR

2. 2
High Phos +Low Vit.
D + Decreased CaSR
Hyperparathyroidism Renal osteodystrophy
Abnormality Levels Presentation
Hypercalcemia >10.5mg/dL (total
normal 8.5-10.5
mg/dL)
Vascular
calcifications, chronic
hypertension
Hyperphosphatemia >4.5 mg/dL (normal
2.8-4.5 mg/dL)
Vascular
calcifications, chronic
hypertension
Renal
osteodystrophy
PTH > ~55-65 pg/mL
(high-turnover)
Bone pain, fractures,
deformities
Presentation and Diagnosis
General Approach to Treatment
 Based on metabolic abnormality
and severity of kidney dysfunction
o Secondary
hyperparathyroidism
o Hyperphosphatemia
o Decreased calcitriol
 Tailor treatment to stage of CKD and
whether patients are on dialysis
o Many recommendations for
stages G3a-G5 and G5D
Ca/Vit D balance Hyperparathyoridism
Hyperphosphatemia
General
considerations
 Presentation based on metabolic abnormality
and severity of disease
 Big victim: Bones!
 Detectable biomarkers:
o Increased Fibroblast growth factor 23
(FGF23)
 Gold standard for diagnosis and classification for
bone disease:
o Bone biopsy (not always feasible)
 More common:
o Ca, Phosphorous, PTH, bone-specific
alkaline phosphatase levels + radiograph
Renal osteodystrophy
Increased bone turnover Low bone turnover
2017 KDIGO Guideline
Updates

3. 3
Drug Type Initial dosing and titration Pearls, AEs, monitoring
Calcium
carbonate
(Tums)
Calcium-
containing
500-100 mg elemental Ca TID
with meals, increase by 500 mg
increments per meal
40% elemental Ca
Binds to phosphate in GI tract to create
soluble complexes
Monitor: Ca*P product
AEs: constipation, calcifications
Calcium
acetate
(Phos-Lo)
Calcium-
containing
1334 mg TID with meals
Increase by 667 mg per meal
25% elemental Ca
May be more efficient > carbonate
Sevelamer
(Renvela,
Renagel)
Non-calcium
containing
800-1600 mg3
PO TID
depending on initial
phosphorous levels. Increase or
decrease by 400-800 mg/meal
if phos. Levels are < 3.5 mg/dL
or > 5.5 mg/dL respectively
Nonabsorbable cationic polymer that binds
phosphate through ion exchange
HCl salt (Renagel): Potential metabolic
acidosis
AEs: bowel obstruction, colitis, dysphagia4
Watch out for DDIs
Sucroferric
oxyhydroxide
(Velphoro)
Non-calcium
containing
2.5 g TID or 500 mg (elemental)
TID. Titrate in increments of
500 mg of iron/day beginning
week 1.
For eGFR < 15
AEs: diarrhea, nausea, constipation,
vomiting, dark stools
Monitoring: Iron hemostasis, Ca, phos,
PTH, drug-drug interactions
Lanthanum Non-calcium
containing
1500 mg daily with meals
increased by 750 mg daily
every 2-3 weeks
Chewable tablet, lower pill burden
Hyperphosphatemia
 Treatment:
o Dietary restriction
 Preventing > treating may be of value in stages G3a to G5D
 Normal phosphate levels may not be an indication to start phosphate-lowering
therapies
o Phosphate-reducing agents: persistent elevations > 5.5 mg/dL despite dietary restriction
 Calcium-containing or non-calcium-containing
 Avoid if Ca*P product >/= 55
 Non-dialysis:
o Moderate dietary restriction (~ 900 mg/day)
o Phosphate-reducing agents per criteria noted above
 Dialysis:
o Some clinicians may couple dietary restriction with medications
o Refractory: Consider decreasing PTH with calcimimetics, calcitriol, or vitamin D
analogs
Non-calcium
containing >
calcium containing
due to potential
mortality benefits2
2: A meta-analysis by Jamal 2013 revealed a decreasing tend in all-cause mortality in CKD patients
receiving non-Ca based agents compared with those receiving Ca-based agents.
3: Dose adjustment when switching between phosphate-binders: 667 mg calcium acetate ~ 800 mg
sevelamer
4: Use caution in patients with swallowing or GI motility disorders, or after major GI surgery
5: Binders may decrease absorption of many oral medications, so separation of administration is
recommended
Major points: Take with meals, evaluate for drug-drug
interactions5 What about
aluminum
hydroxide or
calcium citrate?

4. 4
High PTH
G3a-G5
Address
modifiable risk
factors
Vit D, phos, Ca
Vitamin D
supplements
Severe and
progressive + G4-
G5
Calcimimetics,
calcitriol, Vitamin
D analogs
G5D
Maintain iPTH 2-9
X UNL
Calcimimetics,
calcitriol, Vitamin
D analogs
Secondary
hyperparathyroidism
Treat High
Phosphorous
first
Dietary Binders
Maintain Ca
and Vit D
levels
Treat high
PTH
Phos < 5.5 +
Ca < 9.5
Calcitriol
Vitamin D
analogs
Inadequate
reduction of
PTH
Add
calcimimetic
Secondary hyperparathyroidism
KDIGO guidelines do not recommend
routine use of calcitriol or vit. D
analogs in CKD stage G3 to G5!
By increasing sensitivity to the
CaSR, what do we predict will
happen to calcium levels?
By providing vitamin D what
do we predict will happen to
the calcium and phosphorous
levels?

5. 5
Drug Class Initial dosing and titration Pearls, AEs, monitoring
Cinacalcet Calcimimetic 30 mg PO once daily,
increase every 2-4 weeks
in 30 mg increments up to
180 mg once daily as
needed to maintain PTH
levels
Increases sensitivity of CaSR to calcium
to reduce PTH levels
AEs: hypotension,
hypoparathyroidism, nausea, vomiting,
hyperkalemia,
Avoid if Ca < 8.4 mg/dL
Monitoring: s/sx hypocalcemia, PTH,
Ca, especially with CYP3A4 inhibitors
or CYP2D6 substrates, or those with
seizure disorders6
Monotherapy may be inadequate to
control hyper PTH in advanced disease
May be beneficial in older individuals
at higher CV risk (EVOLVE trial7
)
Calcitriol Active vitamin
D derivative
Dialysis, oral: 0.25 mcg
once daily, increase by
0.25 mcg increments daily
at 4-8 week intervals up to
0.5-1 mcg/day
Non-dialysis, oral: 0.25
mcg once daily or less
frequently/week
Avoid if Ca > 10.2, or phos > 5.5
Monitoring: Ca, Phos,
Doxercalciferol Synthetic
vitamin D
analog
Dialysis: 10 mcg 3
times/week at dialysis, no
more frequently than
every other day, titrate by
2.5 mcg/dose at 8-week
intervals
Non-dialysis G3-G5,
Oral: 1 mcg once daily,
titrate dose by 0.5
mcg/dose at 2-week
intervals
Monitoring: Ca, Phos,
AEs: edema, headache, malaise,
dizziness, anemia, constipation, n/v
Use caution in patients with hepatic
impairment
Drug Table
6: Ca reductions lead to lowering of the seizure threshold; therefore, Ca levels need to be closely monitored
7: Despite a nonsignificant reduction seen in the unadjusted primary endpoint of all-cause mortality, nonfatal MI, unstable
angina hospitalization, CHF, or peripheral vascular events, a significant treatment-age interaction (P = 0.03), led to
speculation that cinacalcet may be effective in older dialysis patients. Significant risk reduction in the primary endpoint was
also demonstrated in the > 65 years old subgroup.
What are some s/sx of
hypocalcemia?

6. 6
Topic 2017 2009 Rationale
G3a-G5D: Phosphate
levels
Lower TOWARDS the
normal range
Maintain in the normal
range
Lack of data to support
maintaining phosphate
in the normal range
provides benefit to
G3a-G4 patients and
some safety concerns8
G3a-G5D: Phosphate-
lowering treatment
Decision to start should be
based on progressively or
persistently elevated serum
phosphate
Suggest using in the
treatment of
hyperphosphatemia
Data does not currently
support “preventive”
phosphate-lowering
treatment
Additional considerations
o Need for further randomized controlled trials
o Comparing phosphate-lowering strategies
and safety/efficacy in stages G3a-G4
o More studies in children
o Individualizing dialysate Ca concentrations in CKD
G5D to optimize Ca and phosphate balance,
improving bone metabolism and reducing
accelerated arteriosclerosis and CV mortality
Comparing the 2017 and 2009 KDIGO guideline recommendations for adults with CKD
8: There was some concern about vascular calcifications in a 2012 study by Block et al who evaluated the effects of
phosphate binders in moderate CKD.

7. 7
1. Block GA, Kilpatrick RD, Lowe KA, Wang W, Danese MD. CKD–Mineral and Bone Disorder and
Risk of Death and Cardiovascular Hospitalization in Patients on Hemodialysis. CJASN.
2013;8(12):2132-2140. doi:10.2215/CJN.04260413
2. Block GA, Wheeler DC, Persky MS, et al. Effects of phosphate binders in moderate CKD. J Am Soc
Nephrol. 2012;23(8):1407-1415. doi:10.1681/ASN.2012030223
3. Jamal SA, Vandermeer B, Raggi P, et al. Effect of calcium-based versus non-calcium-based
phosphate binders on mortality in patients with chronic kidney disease: an updated systematic
review and meta-analysis. Lancet. 2013;382(9900):1268-1277. doi:10.1016/S0140-
6736(13)60897-1
4. Ketteler M, Block GA, Evenepoel P, et al. Executive summary of the 2017 KDIGO Chronic
Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what’s changed and
why it matters. Kidney Int. 2017;92(1):26-36. doi:10.1016/j.kint.2017.04.006
5. Shah A, Aeddula NR. Renal Osteodystrophy. In: StatPearls. StatPearls Publishing; 2022. Accessed
September 24, 2022. http://www.ncbi.nlm.nih.gov/books/NBK560742/
6. Sprague SM, Martin KJ, Coyne DW. Phosphate Balance and CKD–Mineral Bone Disease. Kidney
International Reports. 2021;6(8):2049-2058. doi:10.1016/j.ekir.2021.05.012
7. The EVOLVE Trial Investigators. Effect of Cinacalcet on Cardiovascular Disease in Patients
Undergoing Dialysis. N Engl J Med. 2012;367(26):2482-2494. doi:10.1056/NEJMoa1205624
8. Toussaint N, Cooney P, Kerr PG. Review of dialysate calcium concentration in hemodialysis.
Hemodial Int. 2006;10(4):326-337. doi:10.1111/j.1542-4758.2006.00125.x
Picture Links:
https://www.imdb.com/title/tt0460627/
https://www.parathyroid.com/blog/what-do-our-parathyroid-glands-do
https://www.netmeds.com/health-library/post/kidney-disease-signs-symptoms
https://www.pinterest.com/pin/783978247613644996/
https://www.freseniusmedicalcare.asia/en/healthcare-professionals/acute-therapies/crrt-fluids
UpToDate Link:
https://www.uptodate.com/contents/overview-of-chronic-kidney-disease-mineral-and-bone-
disorder-ckd-
mbd?search=mineral%20bone%20disease&source=search_result&selectedTitle=1~150&usage_t
ype=default&display_rank=1#
References

8. 8
Appendix
The interplay between phosphate,
calcium, FGF23, PTH and bone processes
in CKD.

9. 9