Secondary Hyperparathyroidism in Chronic Kidney Disease 20091113 R

Secondary Hyperparathyroidism in Chronic Kidney Disease 2009/11/13 신장내과 R 3 이완수

Definition • Secondary hyperparathyroidism ? – 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

Calcium and Phosphorus Homeostasis

Pathophysiology Functional Mass of Kidneys Excretion of Phosphrus FGF-23 Serum Phosphorus 3 mechanism Activation of Vitamin D 3 1 -α hydroxlase inhibition Serum Calcium PTH Bone disease Ca. HPO 4

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 Risk factors HR Hyperphosphatemia (PO 4 〉6. 1 mg/d. L) 1. 18 Hypercalcemia (Ca 〉10 mg/d. L) 1. 16 High PTH (〉 600 pg/m. L) 1. 21 The last phase of the Dialysis Outcomes and Practice Patterns Study calcium-phosphorus product ＞ 72 mg 2/d. L 2 34% increased risk of mortality and metastatic calcification

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 -29 Ⅴ Kidney failure < 15 or dialysis should be. PTH started at the beginning of CKD III P

Stage (GFR) PTH P , Ca Target PO 4 PTH Ⅲ (30~59) q 12 m 2. 7~4. 6 30~70 Ⅳ (15~29) q 3 m 2. 7~4. 6 70~100 Ⅴ (<15 or dialysis) q 3 m q 1 m 3. 5~5. 5 150~300 Adapted from the National Kidney Foundation 2003

Stepped Approach For Management of Secondary Hyperparathyroidism STEP Drugs Used Goals 1 Low phosphorus diet Phosphate binders Ergocalciferol (stage III, IV) Ca, P (normal range) 2 Calcimimetics (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

Phosphate Binder • Mainstay of therapy for secondary hyperparathyroidism ① Aluminum hydroxide ◎ aluminum toxicity severe refractory microcytic anemia dementia, osteomalacia ② Calcium binder • Calcium acetate (Phoslo®) • Calcium carbonate (CACO 3®) 2 2 ③ Non Calcium binder calcium-phosphorus product ＞ 55 mg /d. L • Sevelamer hydrochloride (Renagel®) • Lanthanum carbonate (Fosrenol® )

Vitamin D and Its Derivatives • Oldest treatments for secondary hyperparathyroidism; PTH ↓ • ① Calcitriol (1, 25 -dihydroxyvitamin D 3) –Bonki natural form of. Calcio vitamin®D(oral) ® (IV) –Ca. IVisadministration is more effective ＜ 9. 5, PO 4 is ＜ 5. 5, PTH > 300 CKD stage V • ② Ergocalciferol (vitamin D 2) – 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/m. L • ③ Selective Vitamin D Analogues – more affinity to the kidney rather than intestinal receptors – cause less hypercalcemia and hyperphosphatemia

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/d. L

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/m. L • 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) i. PTH ≥ 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 cm 3 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