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CKD-MBD

Western Conference Peritoneal Dialysis Days Conference 2016
by

Clifford Lo

on 10 January 2017

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Transcript of CKD-MBD

Calcimimetic
Background
Pathophysiology
When the eGFR falls below
60 ml/min
....
Hyperphosphatemia
Definition of chronic kidney disease - mineral & bone disorder (CKD-MBD)
Consequences of CKD-MBD
Vitamin D
Summary
CKD-MBD is a systemic disorder
Questions?
CKD-MBD: pharmacological treatment and its controversies
Clifford Lo, BSc(Pharm), PharmD, MHA, BCPS
No conflicts of interest
Clifford.lo@fraserhealth.ca
Clinical Pharmacy Specialist - FH Renal Program
Pharmacy Lead, Special Projects & Initiatives - BCPRA
Clinical Instructor - UBC Pharmaceutical Sciences

Learning objectives:
Review the pharmacological treatment of CKD-MBD
Discuss the scientific evidence and controversies
CKD-MBD is a
systemic disorder
manifested by either
one or a combination
of the following:
Abnormalities of calcium (Ca), phosphorous (P04), parathyroid hormone (PTH) or vitamin D metabolism
Abnormalities in bone turnover, mineralization, volume, linear growth, or strength
Vascular or other soft-tissue calcification
These are ALL surrogate markers for
fractures
or
mortality
KDIGO. 2009. “Clinical Practice Guidelines for the Diagnosis, Evaluation, Prevention and Treatment of CKD-MBD.” Kidney Int. 76 (suppl 113): S3-S8
Definition
Renal osteodystrophy

Osteomalacia:
low bone turnover with abnormal mineralization
Softening of bone
Historically due to aluminum usage (now uncommon)
Adynamic bone disease:

low bone turnover
Osteitis fibrosa cystica:
high bone turnover
Softening of bone, bone deformation, bone pain, fractures

KDIGO. 2009. “Clinical Practice Guidelines for the Diagnosis, Evaluation, Prevention and Treatment of CKD-MBD.” Kidney Int. 76 (suppl 113): S3-S8
1. Vasculature (occurs in
50 to 90%
of dialysis patients):
2. Soft tissue:
Visceral organs, eyes, skin, joints
Moorthi RN, Moe SM. CKD-mineral and bone disorder: core curriculum 2011. Am J Kidney Dis. 2011 Dec;58(6):1022-36
KDIGO. 2009. “Clinical Practice Guidelines for the Diagnosis, Evaluation, Prevention and Treatment of CKD-MBD.” Kidney Int. 76 (suppl 113): S3-S8

Extraskeletal calcification
Systemic medial calcification of
arterioles
may lead to ischemia and subcutaneous necrosis (calciphylaxis)
Coronary artery calcification (CAC)
is theorized to contribute to the high rate of mortality from CVD
Aortic
stiffness may increase pulse pressure and induce left ventricular hypertrophy
Exclusively describes
bone pathology
related to CKD-MBD:
Bone biopsy is the gold standard for diagnosis
Adynamic bone disease
49% in
peritoneal dialysis
patients
Based on 2015 study by de Oliveria et al. (n=41)
59% in
hemodialysis
patients
Based on a 2008 study by Ferreira et al. (n=110)
Patients were treated according to K/DOQI guidelines
Ferreira et al. Effects of sevelamer and calcium carbonate on enal osteodystrophy in HD patients. J Am Soc Nephrol. 2008;19(2):405
de Oliveria et al. PD per se is a risk factor for sclerostin-associated adynamic bone disease.Kidney Int. 2015 May;87(5):1039-45
KDIGO. 2009. “Clinical Practice Guidelines for the Diagnosis, Evaluation, Prevention and Treatment of CKD-MBD.” Kidney Int. 76 (suppl 113): S3-S8
Represents the major bone pathology in dialysis patients
In 2009, KDIGO guidelines recommended PTH levels be increased to
2 to 9x
the ULN (~13 to 70 umol/L depending on assay)
The 2003 K/DOQI target was 16.5 to 33 umol/L (
do not use
)
Phosphate
Calcium
Parathyroid
hormone
Inactive vitamin D
25(OH)D
Active vitamin D
(calcitriol)
Releases Ca and PO4 from bone
Ca x PO4 deposition and calcification
Reduced absorptoin of Ca
and
PO4
Less suppression of PTH
Failing signal to excrete PO4, conserve Ca and activate more vitamin D
1 a hydroxylase
FGF-23
Phosphate elimination with PD
MW = 96 Da (urea = 60 Da, SCr = 113 Da)
Negatively charged (so are capillary walls and the intersitial matrix)
Mainly intracellular and has a slow transfer rate
15 to 20% is bound to protein
Kuhlmann MK. Phosphate elimination in modalities of hemodialysis and peritoneal dialysis. Blood Purif. 2010;29(2):137-44
Weekly burden from diet ~ 5,000 mg
(1000 mg/day with 70% absorption)
Goals of therapy
Prevent complications
Prevent need for a parathyroidectomy
Achieve Ca, PO4 and iPTH KDIGO (2009) targets:
1. Bone disease (renal osteodystrophy)
2. Extraskeletal calcifications
Dietary phosphate restriction
Limit intake to
800 to 1,000
mg/day
Clin J Am Soc Nephrol 2011 Mar;6(3):620
Population:
Post hoc
analysis of the HEMO study (n=1,751 from 15 centers in US)
Intervention:
PO4 intake of...
< 871 mg per day (confirmed by an intake diary)
Comparator:
PO4 restriction of...
871 to 999 mg/day
1000 mg/day
Outcome:
all-cause mortality

HR 0.73 (0.54 to 0.97) with 1,001 to 2000 mg/day
HR 0.71 (0.55 to 0.92) with no restriction
1,001 to 2,000 mg/day
No restriction
- KDOQI 2003

Limitations:
Confounders may exist due to the retrospective, observational design (e.g. PO4 binder usage unknown)
Lessons:
Advice on dietary PO4 management should be individualized
Not all PO4 containing foods are equal
Controversy # 2
Controversy # 1
:
there are no studies examining the benefits of targeting different Ca, PO4 or PTH levels.
Cardiovascular mortality (3 studies):
Risk increases by
10%
for every 0.3 mmol/L increase in PO4, RR 1.10 (1.06 - 1.13)
All-cause mortality (13 studies):
Risk increases by
18%
for every 0.3 mmol/L increase in PO4, RR 1.18 (1.12 - 1.25)
Calcium based phosphate binders
Non-calcium based phosphate binders
American College of Clinical Pharmacy, 2007 “Nephrology I,II and III.” PSAP VI

American College of Clinical Pharmacy, 2007 “Nephrology I,II and III.” PSAP VI

Cochrane Database Syst Rev. 2011 Feb 16;(2)
Population:
Adults with CKD stages 3 to 5D (n=7,631)
Intervention:
meta-analysis
RCTs or quasi-RCTs
published in MEDLINE, EMBASE, Cochrane Renal Group's Specialized Register and CENTRAL from 1966 to 2010
Comparator:
Calcium salts (acetate, carbonate, ketoglutarate) vs. lanthanum vs. sevelamer vs. placebo
Outcome:
Sevelamer and lanthanum decreased risk of hypercalcemia by 50 to 80%
Sevelamer had more GI side effects, RR 1.58, (1.1 to 2.3)
Lancet. 2013. 6736(13) 60897-1

Population:
Adults with CKD stages 3 to 5D (n=4,622)
Intervention:
meta-analysis
RCTs and non-randomized trials
published in MEDLINE, EMBASE, OVID, Cochrane central register and EBSCO from 1980 to 2012
Comparator:
Calcium acetate or carbonate vs. lanthanum or sevelamer
Outcome:
Patients assigned to non-calcium based binders had
reduced all-cause mortality
, RR 0.78 (0.61 to 0.98)
Commentary
7 of 9 studies

found no difference in mortality!

Borzecki et al:
1 retrospective,
observational
2-yr study found a reduction in all-cause mortality with
sevelamer
vs.
calcium carbonate,
0.67 (0.54 to 0.84).
Barreto et al. 2008. Nephron Clin Pract. 110(4):c273-c283
Author's warning,
"The protocol was not designed to look at mortality impact... the interpretation of this information may be misleading."
J Clin Pharm Ther; 2007; 32:617-24
Many clinicians are skeptical of the results from this meta-analysis.
Clin J Am Soc Nephrol 2016 (11): 232–244

Population:
Adults with CKD stages 3 to 5D (n=4,770)
Intervention:
meta-analysis
RCTs and quasi-randomized trials
published in MEDLINE and Cochrane central register from March 2009 to March 2015
Comparator:
Calcium salts vs. sevelamer
Outcome:
Sevelamer had
lower all-cause mortality
, RR 0.54, (0.32 to 0.93)
No difference in CV mortality or GI side effects
Commentary
Again, 7 of 9 studies

found no difference in mortality!

Barreto et al. BRIC. 2008. Nephron Clin Pract. 110(4):c273-c283

Like the meta-analysis by Jamal et al., BRIC (2008) was 1 of 2 studies that favored sevelamer
The evidence to use
sevelamer
instead of calcium salts remains
underwhelming
.
No significant differences in mortality.
Calcium salts vs. placebo
Calcium acetate vs. calcium carbonate
Outcomes (continued)
No matter the combination...
Sevelamer vs. placebo
Sevelamer vs. calcium salts
Lanthanum vs. placebo
Lanthanum vs. calcium salts
Am J Kidney Dis. 2013 62(4):771-778.
Population:
New adult incident HD patients (n=466)
Intervention:
Open-label RCT for 24 months
Comparator:
Calcium carbonate vs. sevelamer
Outcome:
Sevelamer had lower CV mortality HR 0.06 (0.01 to 0.24)
Limitations:
Calcium group had higher baseline coronary artery calcification burden
Calcium group had poorer phosphate control (open-label design?)
Dramatic mortality benefit is inconsistent with current body of evidence
1. CMA code of ethics (2004): http://policybase.cma.ca/dbtw-wpd/PolicyPDF/PD04-06.pdf
2. St. Peter et al. Clin J Am Soc Nephrol 4: 1954–1961, 2009
3. Manns et al. Nephrol Dial Transplant (2007) 22: 2867–2878
Cost of
equivalent dose
phosphate binders (2016 CDN dollars)
Efficient resource allocation (economic analysis):
Manns et al. (2007) - sevelamer is
not cost-effective
at $157,500 per QALY gained
Economics
Some believe
high dose
vitamin D analog usage is a
risk factor
for calciphylaxis as it increases Ca x PO4 product
Controversy # 4
In calciphylaxis patient, "if PTH levels are elevated, the use of cinacalcet, rather than vitamin D analogs, to lower PTH is reasonable..."
Systematic review of calciphylaxis risk factors and treatment (unpublished)
Patient:
CKD stage 5D with calciphyalxis
Intervention:
systematic review
Published in PubMed, MEDLINE, EMBASE from 1946 to 2015
Comparison
Vitamin D analog vs. no vitamin D analog
No studies directly compare these vitamin D analogs
American College of Clinical Pharmacy, 2007 “Nephrology I,II and III.” PSAP VI
Outcome:
1 case-control study
did not
find vitamin D analog usage to be a risk factor for calciphylaxis, OR 1.03 (0.39 to 2.73)
4 case reports and 2 case series
stopped
vitamin D analogs upon start of treatment (STS etc.) => all lesions healed
5 case reports and 1 case series
continued
vitamin D analogs upon start of treatment (STS etc.) => 4 cases of full healing
Summary
There is
no
published evidence linking vitamin D analog usage with development of calciphyalxis
There is
insufficient evidence
to support automatic discontinuation of vitamin D with calciphylaxis
Unless new evidence emerges, use vitamin D analogs to keep Ca, PO4 and PTH within targets
Discontinue or hold vitamin D analogs if the patient is hypercalcemic or hyperphosphatemic
If cinacalcet is prescribed, use vitamin D analogs to help maintain Ca levels
Recommendations:
Therefore, CKD stage 5 patients should receive vitamin D3 supplementation
Controversy # 5:
inactive vitamin D
Vitamin D [25(OH)D] deficiency is common (70 to 80%) in CKD stage 5 patients
Evidence?
There is
no
published evidence evaluating inactive vitamin D on mortality, CVD or cancer in ESRD
There are 3 RCTs in CKD stage 5d patients which found vitamin D3 supplementation increased 25(OH)D levels but had
no impact
on Ca, PO4, PTH
More studies are required in ESRD patients before vitamin D3 can be widely recommended.
Recommendation:
In
observational studies
, vitamin D deficiency is associated with an increased risk of CVD, DM, CKD, and mortality
There are vitamin D receptors throughout the body and some of these tissues have the ability to convert vitamin D to its active form
A
secondary endpoint
in a 4 year RCT in 1,100 post-menopausal women (normal eGFR) found
vitamin D 1,100/Ca 1,500mg/day
reduced incidence of all-cancers RR 0.23 (0.09 to 0.6, p < 0.005)
1. KDIGO CKD-MBD 2009 guidelines
2. Levin et al.. Kid Int. 2005; 68:1973-1981
3. Nakashima et al. World J Diabetes 2016; 7(5): 89-100
4. Lappe et al. Am J Clin Nutr 2007;85:1586 –91.
EVOLVE (2012)
Population:
Adult HD patients (n=3,883) with a median iPTH of 76 umol/L
Intervention:
prospective randomized multi-centered study
Cinacalcet 30 mg/day with dose escalaton q4weeks (max 180mg/day) with CKD-MBD treatment at the discretion of MD
Comparator:
Placebo with CKD-MBD treatment at the discretion of MD
Outcome:
No difference
in mortality, MI, hospitalization for unstable angina, HF or peripheral vascular event, HR 0.93 (0.85 o 1.02, p=0.11)
Chertow et al. NEJM. 2012; (26):2482-94
Subgroup analysis from EVOLVE...
Moe et al. J Am Soc Nephrol 2014; 26
Cinacalcet
DID NOT
reduce the rate of fractures
Unadjusted HR with ITT, 0.89 (0.75 to 1.07)
Be skeptical of statistical adjustments for baseline characteristics with RCT
Parfrey et al. J Clin Endocrinol Metab, 2013; 98(12):4834–4844
Cinacalcet reduced the rate of severe unremitting hyperparathyroidism (PTH > 109 and Ca >2.6 or need for PTX)
Unadjusted HR 0.31 (0.26 to 0.37)
Floege J et al. Clin J Am Soc Nephrol. 2015; 10(5):800-7
Cinacalcet reduced the incidence of calciphylaxis*
Unadjusted HR 0.31 (0.13 to 0.79)
Chelation
iPTH target: 2 to 9x ULN
Mortality risk is highest outside of these extremes
Kalantar-Zadeh et al. KI. 2006 Aug;70(4):771-80.
However, the association between iPTH and mortality has not been consistently found in all studies
Palmer et al. JAMA, 2011 (305):1119-1127
Palmer et al. JAMA, 2011 (305):1119-1127
Severe PO4 restriction may result in unintended reductions in other beneficial nutrients
BRIC
1 prospective, open-label study in 101 patients on HD for an average of 3 years.
Given a 2-week washout, then randomized to Ca acetate or sevelamer and followed x 1 yr to evaluate CAC.
Observed
8 deaths with calcium acetate

vs.

1 death with sevelamer
(16 vs 2%, p=0.014)
There are no RCTs examining mortality or CVD outcomes with lanthanum
Controversy # 3:

these are superior to calcium-based binders
St. Peter et al. (2009) - costs favor calcium over sevelamer, -$81 (-$321 to $157)
0.25 mcg alfacalcidol costs $0.53 per capsule
0.25 mcg calcitriol costs $1.01 per capsule
Moe et al. NDT 1998;13(5):1234-41
RCT of 18 CAPD patients
Calcitriol 0.75 mcg/day vs. 3 mcg 2x/week
No difference
in rate of decline of PTH, or time to target PTH, Ca, or PO4
Controversy # 4:
intermittent vs. daily dose
Herrmann et al. Nephron 1994;67(10):48-53
RCT of 45 HD patients
Calcitriol 0.75 mcg/day vs. 2.5 mcg 2x/week
No difference
in PTH, or incidence of hypercalcemia
Gu et al. Ren Fail. 2005;27(2):205-12
RCT of 158 HD patients
Alfacalcidol 0.5 mcg/day vs. 2 mcg 3x/week
No difference in PTH but
higher PO4
with daily dosing (1.7 +/- 0.36 vs. 1.9 +/- 0.36 mmol/L, p<0.05)
Theory
= similar (or better) PTH control with lower Ca and PO4 absorption
Summary
Intermittent dosing of vitamin D analogs
May result in less PO4 absorption
Has no additional costs or ADEs
Recommend:
Administer vitamin D analog 3x/week (at night)
Economics
Cinacalcet cost:
30 mg = $12.11 per tab
Economic analysis:
None published from the perspective of the Canadian health care system
Thank you!
The clinical advantages of therapies such as sevelamer, lanthanum and cinacalcet, do not justify their costs in most circumstances
Treatment focuses on correcting biochemical markers, which can be poor surrogates for hard endpoints
Consequences of CKD-MBD include fractures, calciphylaxis, cardiovascular events and mortality
Vitamin D3 supplementation is inexpensive ($0.05 per 1,000 IU)
1. Health Technol Assess. 2007 May;11(18):iii, xi-xiii, 1-167
2. Komaba et al. Am J Kidney Dis. 2012 Aug;60(2):262-71
3. Sharma et al. Clin Drug Investig. 2014 Feb;34(2):107-15. do
It is generally accepted that vitamin D analogs and/or parathyroidectomy are more cost-effective than cinacalcet for controlling iPTH (US, Japan and UK data)
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CKD-MBD PREZI

Moe et al. Circ 2015; 132:27-39
Cinacalcet reduced FGF23* by > 30% (65% vs. 28%, p<0.01)
After adjustments in baseline characteristics, in patients with an FGF23 reduction, there was a nominal statistically significant reduction in CV mortality
*End-point not prespecified
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