In Chronic Kidney Disease

Lee Zhi Yong Hosp. Pekan

Types of Hyperparathyroidism(SHPT)
Primary Hyperparathyroidism Secondary Hyperparathyroidism Tertiary Hyperparathyroidism

Objective
To learn: How secondary hyperparathyroidism (SHPT) occurs in chronic kidney disease (CKD)? How SHPT lead to bone mineral disorder? Managing increased serum phosphorus (P) level Managing increased parathyroid hormone (PTH) Roles of pharmacist in managing SHPT

Feedback Loops in SHPT

Parathyroid gland

Bone Renal

Increase Ca++ Renal failure

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 pain

Muscle weakness
Bone fracture

Growth retardation
Skeletal deformity

Pruritis (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 possible Prevent extraskeletal calcification Avoid 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 3 4 Serum P (mg/dL [mmol/L]) 2.7-4.6 (0.87-1.49 mmol/L) 3.5-5.5 (1.13-1.78 mmol/L) Corrected Ca++ Ca-P product (mg/dL[mmol/L]) (mg2/dL2 [mmol2/L2]) 8.4-10.2 <55 (2.1-2.54 mmol/L) (<4.5mmol2/L2)

8.4-9.5 (2.1-2.37 mmol/L)

Ref: KDOQI 2003

Corrected Ca++
-depend on albumin level

Albumin < 40g/L

Corrected Ca++ = 0.02(40- albuminpatient) + measured Ca++ Albumin >45g/L Corrected 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 30-59 16-29 <15 or dialysis Serum Ca & P

3
4 5
Ref: KDOQI 2003

Every 12 months Every 3 months Every month

Calcemic response to PTH

How does serum P affect calcemic response to PTH?

1st mechanism: High serum P 2nd mechanism: High serum P

Interact with free serum Ca++ Less free serum Ca++

Downregulating calcium sensing receptors in parathyroid gland cells

Lowers parathyroid glands ability to detect Ca++

Parathyroid gland fail to response to high serum Ca level

Promote PTH release

Paolo Raggi and Michael Kleerekoper (March 5, 2008).Contribution of Bone and Mineral abnormalities to Cardiovascular Disease in Patients with Chronic Kidney Disease, Clin J Am Soc Nephrol 3:836-843.

Phosphate Restriction / Phosphate Binder

avoid high protein diet, milk, carbonated beverage, cheese, sardine, soybean to keep dietary phosphorus at 8001000mg/day ( or 800-1200mg/day if patient undergoes dialysis)

Use Phosphate Binders (Calcium Carbonate / Aluminium Hydroxide / Sevelamer / Lanthanum)

Dietary P restriction

Reduced PTH level

(independent of Ca & calcitriol level)

Mechanism of action of Phosphate binder

bind to dietary P & reduce dietary P absorption from GIT

forming insoluble complexes excreted via stool

1) Calcium containing product

MOH: Calcium carbonate 500mg tablet Contain 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

Dose : 300-600mg TDS with meal

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.

Endogenous active vitamin D (calcitriol)

Vitamin D Receptor Activator (VDRA)

-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)

Where does vitamin D act?

2 types of receptor on parathyroid gland:
Vitamin D receptor (VDR) Ca sensing receptor Cinacalcet (Sensipar)

Target Range of Intact Plasma PTH, Serum Calcium and Phosphorus by Stage of CKD
CKD Target iPTH Stage (pg/ml [pmol/L]) Target Serum Calcium (mg/dL[mmol/L]) Target Serum Phosphorus (mg/dL [mmol/L])

3
4 5

35-70 (3.85-7.7 pmol/L)

70-110 (7.7-12.1 pmol/L) 150-300 (16.5-33.0 pmol/L)

8.4-10.2 (2.1-2.55 mmol/L)

2.7-4.6 (0.87-1.49 mmol/L)

8.4-9.5 (2.1-2.37 mmol/L)

3.5-5.5 (1.13-1.78 mmol/L)

Drug choice in reducing PTH level

Phosphorus PTH

Ca++ low Ca++ within target

Ca++ > 2.54 mmol/L, < 2.87 mmol/L

Calcitriol
-non-selective
VDRA

Paricalcitol
-selective VDRA

Available formulation of calcitriol

Oral calcitriol
Daily /conventional dose:

IV calcitriol
Intermittent dose:

0.25-0.5mcg/day
Intermittent dose:

1 (0.02mcg/kg) -2mcg EOD

-Adjust dose by 0.5-1 mcg at 2-4 weeks interval

0.5-1.0mcg EOD
-preferred in patient with hypocalcemia
-preferred in patient without HD or undergoes PD as no IV access

-preferred in patient with HD as its administration is coordinate with dialysis

Monitoring for vitamin D therapy

Stage 3&4: Phosphorus

Calcium

iPTH
Every 3 months

Every month x 1st 3 months Then every 3 months thereafter

Stage 5: Phosphorus

Calcium

iPTH

Every 2 weeks x 1month then monthly Every month x thereafter 3months then every 3 months

Dose Titration for Calcitriol

iPTH Levels
the same or increasing Decreasing < 30% Decreasing > 30% but < 60% Decreasing > 60%

Calcitriol Dose Adjustment

increase

increase
maintain

decrease

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:
Injectable CKD Stage 5 Oral capsule 1, 2 , 4 mcg CKD Stage 3& 4

MOA: -selective VDRA -Bind to and activate VDR at target tissue -Inhibit PTH gene transcription and parathyroid cell mitotic activity

Initial Dose of Paricalcitol

IV route
Initial dose 0.04-0.1mcg/kg IV EOD with each dialysis

Oral route
Baseline iPTH < 500pg/mL > 500pg/mL Daily dose EOD

1 mcg 2 mcg

2 mcg 4 mcg

* Dose adjustment : 2-4 weeks interval

Monitoring for Paricalcitol

IV route

Oral route

Ca & P level PTH level Twice weekly Every 3 months Once dose established, then monthly Every 2 weeks x 3 months Monthly x 3 months Every 3 months

Dose titration for paricalcitol

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 Decrease by less than 30% Decrease by >30% , <60% Decrease by >60%

Increase (by 2-4 mcg)

Increase by 1 mcg

Increase by 2 mcg

maintain

maintain

Maintain

Decrease (by 2-4 mcg)

Decrease by 1 mcg

Decrease by 2 mcg

Micromedex, Product Info Zemplar

Monitoring..
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)

Paricalcitol vs Calcitriol
Incidence of hypercalcemia?? Paricalcitol is 10 times weaker than calcitriol in mobilizing bone calcium

Effectiveness??

Paricalcitol suppresses serum intact parathyroid hormone as effectively 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

Cinacalcet
Selectively target calcium sensing receptor at parathyroid cell Used when serum calcium > 8.4mg/dL (2.1mmol/L) Take with meal, not to break/crush Can be used alone or combine with phosphate binder and vitamin D sterol Starting dose :30mg OD (titrate every 2-4wk)

Roles of Pharmacist

Counsel/ providing information

 Indication

Administration
Enhance Benefit Use

compliance

of OTC product

Management Secondary Hyperparathyroidism

Dietary Phosphorus Restriction Vitamin D therapy

Phosphate binder

Reduce P level

Reduce PTH secretion

Is a MUST!!!

Increase Ca++ level and maintain Ca++ balance

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 SWALLOW To take with MEAL To take with MEAL SPACE 2 hours with iron supplement SPACE 2 hours with iron supplement Aluminium hydroxide tablet for SHORT term therapy

Conclusion
High iPTH, serum calcium, phosphate and CaP 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 Patients compliance should be enhanced and assessed

Thank You!