Lee Zhi YongHosp. Pekan

In Chronic Kidney Disease

Types of Hyperparathyroidism(SHPT)

Primary HyperparathyroidismSecondary HyperparathyroidismTertiary Hyperparathyroidism

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

Feedback Loops in SHPT

Renal failure

Parathyroid gland

Increase Ca++

Bone

Renal

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

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

Clinical Presentations

Bone painMuscle weaknessBone fractureGrowth retardationSkeletal deformityPruritis (Itch)

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

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

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++

Ca-P product

Ca-P product = [corrected Ca] x [ serum P]

•Ca-P product > target, increase calcification risk

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

Calcemic response to PTH

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

•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

Dietary P restriction

Reduced PTH level(independent of Ca & calcitriol level)

bind to dietary P &reduce dietary P absorption from

GIT

forming insoluble complexes

excreted via stool

Mechanism of action of Phosphate binder

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

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

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

Endogenous active vitamin D (calcitriol)

-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)

Where does vitamin D act?

2 types of receptor on parathyroid gland:

•Vitamin D receptor (VDR)

•Ca sensing receptorCinacalcet (Sensipar®)

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)

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

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

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

iPTH Levels Calcitriol Dose Adjustment

the same or increasing increase

Decreasing < 30% increaseDecreasing > 30% but < 60% maintain

Decreasing > 60% decrease

Dose Titration for Calcitriol

Limitations of calcitriol (1,25-dihydroxyvitamin D3)

•Hypercalcemia

•Hyperphosphatemia

•Favours calcification -to discontinue calcitriol when Ca-P product > 70mg2/dL2 (5.6mmol2/L2)

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

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

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

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®

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..

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)

Calcimimetic

Cinacalcet (Sensipar®)

Where does calcimimetic act?

2 types of receptor on parathyroid gland:

•Vitamin D receptor (VDR)

•Ca sensing receptor

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)

Roles of Pharmacist

Counsel/ providing information

IndicationAdministrationEnhance complianceBenefitUse of OTC product

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

Panduan Kandungan Fosforus dalam Makanan untuk Pesakit Ginjal, by University Kebangsaan Malaysia & Malaysian Society of Nephrology

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

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

Thank You!