secondary hyperparathyroidism in ckd
TRANSCRIPT
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Lee Zhi YongHosp. Pekan
In Chronic Kidney Disease
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Types of Hyperparathyroidism(SHPT)
Primary HyperparathyroidismSecondary HyperparathyroidismTertiary Hyperparathyroidism
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ObjectiveTo learn:How secondary hyperparathyroidism (SHPT)
occurs in chronic kidney disease (CKD)?How SHPT lead to bone mineral disorder?Managing increased serum phosphorus (P)
levelManaging increased parathyroid hormone
(PTH)Roles of pharmacist in managing SHPT
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Feedback Loops in SHPT
Renal failure
Parathyroid gland
Increase Ca++
Bone
Renal
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How does PTH increase serum Ca++ level?
bone resorption
urinary excretion of calcium (kidney)
urinary excretion of phosphorus (kidney)
Stimulate production of active vitamin D in kidney
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Bone metabolism and disturbances occur in early stage of renal impairment and continue throughout progression loss of kidney function.
Early management is crucial to improve QOL and longevity of CKD patient
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Clinical Presentations
Bone painMuscle weaknessBone fractureGrowth retardationSkeletal deformityPruritis (Itch)
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Goal of Therapy
Maintain serum calcium and phosphorus level within normal range
Prevent or reduce development of hyperparathyroid hyperplasia
Restore skeleton to near normal as possiblePrevent extraskeletal calcificationAvoid exposure to toxic agents (eg: aluminium)Reduce cardiovascular morbidity and improve
long-term outcome
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Target Range of corrected Ca++ , P and Ca-P product
Stage CKD
Serum P(mg/dL [mmol/L])
Corrected Ca++
(mg/dL[mmol/L])Ca-P product(mg2/dL2 [mmol2/L2])
3 2.7-4.6 (0.87-1.49 mmol/L)
8.4-10.2 (2.1-2.54 mmol/L)
<55 (<4.5mmol2/L2)4
5 3.5-5.5 (1.13-1.78 mmol/L)
8.4-9.5 (2.1-2.37 mmol/L)
Ref: KDOQI 2003
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Corrected Ca++
-depend on albumin levelAlbumin < 40g/LCorrected Ca++ = 0.02(40- albuminpatient) +
measured Ca++
Albumin >45g/LCorrected Ca++ = 0.02 (Albuminpatient -45) –
measured Ca++
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Ca-P product
Ca-P product = [corrected Ca] x [ serum P]
•Ca-P product > target, increase calcification risk
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Frequency of Monitoring
Stage CKD Glomerular Filtration (GFR) ml/min/1.73m2
Serum Ca & P
3 30-59 Every 12 months
4 16-29 Every 3 months
5 <15 or dialysis Every month
Ref: KDOQI 2003
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Calcemic response to PTH
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How does serum P affect calcemic response to PTH?
1st mechanism:
High serum P
2nd mechanism:
High serum P
Paolo Raggi and Michael Kleerekoper (March 5, 2008).Contribution of Bone and Mineralabnormalities to Cardiovascular Disease in Patients with Chronic Kidney Disease, Clin J Am Soc
Nephrol 3:836-843.
Interact with free serum Ca++
Less free serum Ca++
Lowers parathyroid gland’s ability to detect
Ca++
Promote PTH release
Downregulating calcium sensing receptors in
parathyroid gland cells
Parathyroid gland fail to response to high serum Ca
level
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•avoid high protein diet, milk, carbonated beverage, cheese, sardine, soybean
•to keep dietary phosphorus at 800-1000mg/day ( or 800-1200mg/day if patient undergoes dialysis)
•Use Phosphate Binders (Calcium Carbonate / Aluminium Hydroxide / Sevelamer / Lanthanum)
Phosphate Restriction / Phosphate Binder
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Dietary P restriction
Reduced PTH level(independent of Ca & calcitriol level)
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bind to dietary P &reduce dietary P absorption from
GIT
forming insoluble complexes
excreted via stool
Mechanism of action of Phosphate binder
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1) Calcium containing product
MOH: Calcium carbonate 500mg tabletContain 40% elemental calcium
Dose:total daily dose:elemental calcium should not exceed 1500mg/day (phosphate binder alone) or 2000mg/day(from binder and diet).
K/DOQI 2003
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Cont…
Side effect:
hypercalcemia, constipation, vascular calcification
Monitoring:
a) serum calcium level to avoid hypercalcemia
b) avoid Ca-P product >55mg2/dL2 (> 4.5 mmol2/L2) that may increase risk of calcifications, cardiovascular disease
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2) Aluminium containing product MOH: Aluminium hydroxide 600mg tablet
Disadvantages- May increase [ serum Al ] & deposit in bone and other
tissues --> osteomalacia, microcytic anemia, neurotoxicity
-accumulation in brain -> encephalopathy, dementia-GI intolerance eg: constipation, stomach cramp, nausea,
vomiting-limited as short term therapy of up to 4 weeks to avoid
aluminium accumulation.
Dose : 300-600mg TDS with meal
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Endogenous active vitamin D (calcitriol)
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-to suppress PTH secretion-Examples:a) Vitamin D:Alfacalcidol (1-alpha-hydroxyvitamin D3)Calcitriol (1,25-dihdroxyvitamin D3)
b) Vitamin D analog: Paricalcitol (19-nor-1,25-dihydroxyvitamin D2)Doxercalciferol (1-alpha-hydroxyvitamin D2)
Vitamin D Receptor Activator (VDRA)
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Where does vitamin D act?
2 types of receptor on parathyroid gland:
•Vitamin D receptor (VDR)
•Ca sensing receptorCinacalcet (Sensipar®)
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Target Range of Intact Plasma PTH, Serum Calcium and Phosphorus by Stage of CKD
CKD Stage
Target iPTH (pg/ml [pmol/L])
Target Serum Calcium (mg/dL[mmol/L])
Target Serum Phosphorus (mg/dL [mmol/L])
3 35-70 (3.85-7.7 pmol/L)
8.4-10.2 (2.1-2.55 mmol/L)
2.7-4.6 (0.87-1.49 mmol/L)
4 70-110 (7.7-12.1 pmol/L)
5 150-300 (16.5-33.0 pmol/L)
8.4-9.5 (2.1-2.37 mmol/L)
3.5-5.5 (1.13-1.78 mmol/L)
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Phosphorus PTH
Ca++ low Ca++ > 2.54 mmol/L, < 2.87 mmol/L
Calcitriol-non-selective
VDRA
Drug choice in reducing PTH level
Ca++ within target
Paricalcitol-selective VDRA
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Oral calcitriol IV calcitriol•Daily /conventional dose:0.25-0.5mcg/day•Intermittent dose:0.5-1.0mcg EOD
Intermittent dose:1 (0.02mcg/kg) -2mcg EOD-Adjust dose by 0.5-1 mcg at 2-4 weeks interval
-preferred in patient with hypocalcemia
-preferred in patient with HD as its administration is coordinate with dialysis
-preferred in patient without HD or undergoes PD as no IV access
Available formulation of calcitriol
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Monitoring for vitamin D therapy
Stage 3&4:
Stage 5:
Phosphorus Calcium iPTHEvery month x 1st 3 months
Then every 3 months thereafterEvery 3 months
Phosphorus Calcium iPTH
Every 2 weeks x 1month then monthly thereafter
Every month x 3months then every 3 months
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iPTH Levels Calcitriol Dose Adjustment
the same or increasing increase
Decreasing < 30% increaseDecreasing > 30% but < 60% maintain
Decreasing > 60% decrease
Dose Titration for Calcitriol
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Limitations of calcitriol (1,25-dihydroxyvitamin D3)
•Hypercalcemia
•Hyperphosphatemia
•Favours calcification -to discontinue calcitriol when Ca-P product > 70mg2/dL2 (5.6mmol2/L2)
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Paricalcitol (Zemplar®)Available formulation:
MOA:-selective VDRA-Bind to and activate VDR at target tissue-Inhibit PTH gene transcription and parathyroid cell
mitotic activity
Injectable Oral capsule 1, 2 , 4 mcg
CKD Stage 5 CKD Stage 3& 4
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Initial Dose of Paricalcitol
IV route
Oral route
* Dose adjustment : 2-4 weeks interval
Initial dose 0.04-0.1mcg/kg IV EOD with each dialysis
Baseline iPTH
Daily dose EOD
< 500pg/mL 1 mcg 2 mcg
> 500pg/mL 2 mcg 4 mcg
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Monitoring for Paricalcitol
Ca & P level PTH level
IV route Twice weekly Once dose established, then monthly
Every 3 months
Oral route Every 2 weeks x 3 monthsMonthly x 3 months
Every 3 months
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iPTH level relative to baseline iPTH
Dose adjustment for IV paricalcitol
Dose adjustment for oral OD regimen
Dose adjustment for oral EOD regimen
Same or increasing
Increase(by 2-4 mcg)
Increase by 1 mcg
Increase by 2 mcg
Decrease by less than 30%
Decrease by >30% , <60%
maintain maintain Maintain
Decrease by >60%
Decrease(by 2-4 mcg)
Decrease by 1 mcg
Decrease by 2 mcg
Dose titration for paricalcitol
Micromedex, Product Info Zemplar®
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The dose should be reduced/interrupted if:
serum iPTH < 100 pg/mL
serum Ca++ > 11.5 mg/dL (2.87 mmol/L)
Ca-P product > 75mg2/dL2 (6.05mmol2/L2)
Monitoring..
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Paricalcitol vs Calcitriol
Incidence of hypercalcemia??Paricalcitol is 10 times weaker than calcitriol in
mobilizing bone calcium
Effectiveness??Paricalcitol suppresses serum intact parathyroid
hormone aseffectively as equipotent doses of calcitriol (1mcg calcitriol = 4mcg paricalcitol)
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Calcimimetic
Cinacalcet (Sensipar®)
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Where does calcimimetic act?
2 types of receptor on parathyroid gland:
•Vitamin D receptor (VDR)
•Ca sensing receptor
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CinacalcetSelectively target calcium sensing receptor at
parathyroid cellUsed when serum calcium > 8.4mg/dL
(2.1mmol/L)Take with meal, not to break/crushCan be used alone or combine with phosphate
binder and vitamin D sterolStarting dose :30mg OD (titrate every 2-4wk)
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Roles of Pharmacist
Counsel/ providing information
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IndicationAdministrationEnhance complianceBenefitUse of OTC product
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Management Secondary Hyperparathyroidism
Dietary Phosphorus Restriction
Phosphate binderVitamin D therapy
Reduce P level Reduce PTH secretion
Increase Ca++ level and maintain Ca++
balanceIs a MUST!
!!
Take with/without meal
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Panduan Kandungan Fosforus dalam Makanan untuk Pesakit Ginjal, by University Kebangsaan Malaysia & Malaysian Society of Nephrology
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Phosphate binder
Calcium carbonate tablet
• to CHEW
•To take with MEAL
•SPACE 2 hours with iron supplement
Aluminium hydroxide tablet
•for SHORT term therapy
•To SWALLOW
•To take with MEAL
•SPACE 2 hours with iron supplement
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ConclusionHigh iPTH, serum calcium, phosphate and Ca-P
will increase mortality risk and lead to many complications.
Goal of therapy : to treat as early as possible and to achieve and maintain monitoring parameter at target (within K/DOQI recommendation)
Therapy should be optimized to improve outcome and reduce mortality
Patient’s compliance should be enhanced and assessed
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Thank You!