Secondary Hyperparathyroidism in Chronic Kidney Disease

2009/11/13신장내과 R3 이완수

Definition

– Excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia, hyperphsophatemia

– Associated hypertrophy of the glands

– Especially seen in chronic kidey disease– Also result from malabsorption

• Chronic pancreatitis• Small bowel disease

• Secondary hyperparathyroidism ?

Calcium and Phosphorus Homeostasis

Pathophysiology

Functional Mass of Kidneys

Activation of Vitamin D3

Excretion of Phosphrus

Serum Phosphorus

Serum Calcium

PTH

Bone disease

FGF-23

3 mechanism CaHPO4

1-α hydroxlase inhibition

Parathyoid Hormone (PTH)

• most important regulator of calcium metabolism

• secreted by the chief cells of the parathyroid glands in response to hypocalcemia and hyperphosphatemia

• half-life (2 to 4 minutes) before being degraded to various inactive fragments

“intact” PTH assay is widely used

to estimate active PTH level

Parathyoid Hormone (PTH) ① Bone

stimulates the “osteoclasts” and causes “bone resorption”

P ↑ , Ca ↑

② Kidney

stimulates the “1-α hydroxylase” activity in the kidney

“1,25 dihydroxyvitamin D” production ↑

increases the reabsorption of calcium in the distal renal tubules

Ca ↑

decrease the reabsorption of phosphorus in the proximal renal tubules

P ↓

③ Intestine

indirectly increases intestinal calcium and phosphorus absorption

P ↑ , Ca ↑

Vitamin D

• Essential factor in the regulation of calcium and phosphorus balance

• Synthesized in the skin but is also present in the diet

• Along with PTH, vitamin D is a required factor in the bone resorption process

• Increases the reabsorption of urinary calcium and phosphorus in the renal tubules ( P ↑ , Ca ↑)

• Through the vitamin D receptors it has a direct effect on the parathyroid glands to “suppress PTH secretion”

Fibroblasts Growth Factor-23

• New protein with “phosphaturic activity”

• secreted by osteocytes

• now considered to be the most important factor for regulation of phosphorus homeostasis

• Through the “Klotho receptor” it acts mainly on the kidney to increase phosphorus clearance

• inhibits the 1- α hydoxylase activity, causing a low 1,25 dihydroxyvitamin D level

• Hyperphosphatemia is the principal stimulator for FGF-23

Effect of secondary hyperparathyroidism on mortality

• 3 independent risk factors for all-cause and cardiovascular mortality

34% increased risk of mortality and metastatic calcification

Risk factors HR

Hyperphosphatemia (PO4 〉 6.1 mg/dL) 1.18

Hypercalcemia (Ca 〉 10 mg/dL) 1.16

High PTH ( 〉 600 pg/mL) 1.21

The last phase of the Dialysis Outcomes and Practice Patterns Study

calcium-phosphorus product ＞ 72 mg2/dL2

Renal osteodystrophy (ROD)

• “Bone mineralization deficiency” electrolyte and endocrine derangements chronic kidney disease

• “The silent crippler” (no symptom)– if shows symptoms bone and joint pain

bone deformation and fractures

• High bone turnover (secondary to high levels of circulation PTH)– “Osteitis fibrosa cystica”

• Low bone turnover (excessive suppression of PTH)– Adynamic bone disease (most common osteodystrophy)– Osteomalacia (Increased volume of unmineralized bone)

plus vitamin D deficiency

Management

Stage Description GFR

Ⅰ Kidney damage with normal or increase GFR

>= 90

Ⅱ Kidney damage with mild decrease GFR

60-89

Ⅲ Moderate decrease GFR

30-59

Ⅳ Severe decrease GFR 15-29Ⅴ Kidney failure < 15 or

dialysis

PTH

P

should be started at the beginning of CKD III

Stage (GFR) PTH P , Ca Target PO4 PTH

Ⅲ (30~59) q 12m

q 12m 2.7~4.6 30~70

Ⅳ (15~29) q 3m q 3m 2.7~4.6 70~100

Ⅴ (<15 or dialysis)

q 3m q 1m 3.5~5.5 150~300

Adapted from the National Kidney Foundation 2003

Stepped Approach

STEP Drugs Used Goals

1Low phosphorus dietPhosphate bindersErgocalciferol (stage III, IV)

Ca, P (normal range)

2Calcimimetics (Cinacalcet)Vitamin D sterols (calcitriol, paricalcitol, doxecalciferol)

PTH (normal range)

3 Adjust doses Ca, P, PTH (K/DOQI recommandation)

K/DOQI, Kidney Disease Outcome Quality Initiative

For Management of Secondary Hyperparathyroidism

Phosphate Binder

• Mainstay of therapy for secondary hyperparathyroidism

① Aluminum hydroxide

② Calcium binder• Calcium acetate (Phoslo®)• Calcium carbonate (CACO3®)

③ Non Calcium binder• Sevelamer hydrochloride (Renagel®)• Lanthanum carbonate (Fosrenol® )

◎ aluminum toxicity severe refractory microcytic anemia dementia, osteomalacia

calcium-phosphorus product ＞ 55 mg2/dL2

Vitamin D and Its Derivatives

• Oldest treatments for secondary hyperparathyroidism; PTH ↓

• ① Calcitriol (1,25-dihydroxyvitamin D3) – natural form of vitamin D– IV administration is more effective

• ② Ergocalciferol (vitamin D2)– needs to be metabolized in the liver and the kidneys– require at least some activity of the 1-α hydroxylase– Only CKD III, IV; 25-hydroxyvitamin D level ＜ 30 ng/mL

• ③ Selective Vitamin D Analogues– more affinity to the kidney rather than intestinal receptors– cause less hypercalcemia and hyperphosphatemia

Bonki ® (IV) Calcio ® (oral)Ca is ＜ 9.5, PO4 is ＜ 5.5, PTH > 300CKD stage V

Calcimimetics

• Sensitivity ↑ to calcium of calcium-sensing receptors in the parathyroid glands; PTH ↓

• Cinacalcet (Sensipar ®)

• Side effects

– gastrointestinal symptoms

– QT prolongation, mostly related to hypocalcemia

• Contraindicated in patients with Ca levels ＜ 8.4 mg/dL

Parathyroidectomy

Parathyroidectomy

• only used when all medical therapy is unsuccessful

• Strong indications for surgery

– Extraskeletal calcification,

– Calciphylaxis

– Debilitating bone disease

– Refractory pruritus

– severe hypercalcemia

– PTH levels ＞ 800 pg/mL

• Lack of osteoclastic activity “hungry-bone syndrome”– Hypocalcemia (Tetany)

Percutaneous ethanol injection (PEI)

• High-risk parathyroidectomy patients are good candidates for PEIT

• ① Indications – (i) iPTH ≥ 400 pg/ml– (ii) Osteitis fibrosa or high-turnover bone– (iii) Enlarged parathyroid glands detectable by sono– (iv) Resistant to medical therapy– (v) Parathyroid glands should be ≥ 1 cm in length, ≥ 0.5 cm3

in estimated volume

If three or more glands are enlarged by this amount

PEIT will be ineffective in the long term– (vi) Patients who have given informed consent to undergo PEIT

Guidline for PEI of parathyroid gland, Nephrology Dialysis Transplantation 2003

Percutaneous ethanol injection (PEI)

• ② Exclusion criteria– (i) Enlarged parathyroid gland located where sono-guided

puncture is impossible– (ii) Paralysis of the recurrent laryngeal nerve on the opposite

side– (iii) Operation on the neck region for thyroid carcinoma, etc. is

scheduled– (iv) Institutions without the equipment required or without skilled

operators