Secondary Hyperparathyroidism

Question 1

Clinical Implications of Secondary hPTH

Answer 1

Renal osteodystrophy with increased risk of fractures: a. Osteomalacia b. Osteopenia c. Adynamic bone disease d. Mixed bone disease

Question 2

Clinical Implications of Secondary hPTH

Answer 2

Calcific uremic arteriolopathy, a.k.a. calciphylaxis: See End-stage renal disease Accelerated atherosclerosis Refractory anemia Tertiary hPTH Increased morbidity and mortality: 1% increase in relative risk of all-cause mortality per 100 pg/mL increase in PTH and a 2% increase in cardiovascular mortality (0.007).

Question 3

Diagnosis of Secondary hPTH

Answer 3

Secondary hPTH may be diagnosed in patients with CKD and is characterized by elevated serum PTH levels with associated normal to high serum phosphate and normal to low SCa (prior to the administration of calcium-containing agents and/or vitamin D supplementation).

Question 4

Pathogenesis of Secondary Hyperparathyroidism

Answer 4

Reduced kidney mass results in: a. Reduced 1α-hydroxylase level thus reduced 1,25-vitamin D levels. b. Reduced glomerular filtration leading to phosphate retention.

Question 5

Pathogenesis of Secondary Hyperparathyroidism

Answer 5

Phosphate retention leads to: a. Increased FGF-23 synthesis. FGF-23 in turn reduces 1,25 vitamin D production by inhibiting 1α-hydroxylase and increasing 24-hydroxylase. b. Hyperphosphatemia has direct effects on the parathyroid gland to increase PTH secretion and parathyroid cell growth.

Question 6

Pathogenesis of Secondary Hyperparathyroidism Phosphate retention leads to cont’d:

Answer 6

c. Hyperphosphatemia is also associated with the following: 1. Skeletal resistance to PTH which contributes to hypocalcemia 2. Parathyroid cell resistance to calcitriol 3. Reduced calcitriol synthesis (feedback phenomenon: calcitriol increases phosphate level while hyperphosphatemia reduces calcitriol synthesis)

Question 7

Pathogenesis of Secondary Hyperparathyroidism

Answer 7

Reduced 1,25-vitamin D leads to: a. Reduced GI absorption of calcium, thus hypocalcemia and subsequent hPTH b. Reduced repression of PTH gene transcription and parathyroid cell proliferation c. Reduced expression of parathyroid VDR and CaSR d. Increased set point for calcium-regulated PTH secretion

Question 8

Pathogenesis of Secondary Hyperparathyroidism

Answer 8

Patients with kidney disease may also have low 25-vitamin D due to reduced skin conversion of 7-dehydrocholesterol to cholecaliferol and liver hydroxylation of cholecalciferol 25-OH vitamin. Hypocalcemia due to reduced vitamin D, poor dietary intake, and CaPO4 precipitation leads to uninhibited parathyroid proliferation and PTH secretion.

Question 9

Pathogenesis of Secondary Hyperparathyroidism

Answer 9

Intrinsic parathyroid cell abnormalities in CKD below can also contribute to hPTH: a. Decreased expression of VDR and CaSR b. Increased set point for calcium-regulated PTH secretion

Question 10

Pathogenesis of Secondary Hyperparathyroidism

Answer 10

Question 11

Other notes regarding FGF-23 in CKD

Answer 11

Binding of FGF-23 and its cofactor klotho to the receptor complex klotho-FGFR1 in the kidney leads to phosphaturia via suppression of Na-Pi 2a and 2c expressions in the brush border of proximal tubules.

Question 12

Other notes regarding FGF-23 in CKD

Answer 12

NOTE: Recall FGF-23 has low affinity for its receptor (FGFR) and requires the cofactor klotho to effectively bind and activate the receptor. Of interest, klotho expression is reduced early in the course of CKD. This is thought to be the reason for reduced phosphaturia in patients with CKD. Reduction of klotho has also been implicated in inducing a more rapid progression of CKD.

Question 13

Other notes regarding FGF-23 in CKD

Answer 13

FGF-23 also acts on parathyroid cells via the FGF-23-klotho complex to reduce PTH synthesis and secretion and PTH proliferation.

Increase expression of CaSR and VDR.

Question 14

Other notes regarding FGF-23 in CKD

FGF-23 in CKD:

Answer 14

FGF-23 in CKD:

FGF-23 level is increased early in CKD, even before the rise in PTH levels.

FGF-23 level is increased in association with an increased phosphate “burden” alone and not necessarily high serum phosphate levels.

Question 15

Other notes regarding FGF-23 in CKD

FGF-23 in CKD:

Answer 15

FGF-23 is an independent predictor of mortality, progression of kidney disease, left ventricular hypertrophy, vascular dysfunction, and kidney transplant outcomes.

FGF-23 levels may remain increased post-kidney transplant with resultant hypophosphatemia and relative 1,25-vitamin D deficiency.

Question 16

Management of Secondary hPTH

Answer 16

Consistent control of mineral biochemical profile (PTH, calcium, phosphorus) is associated with improved survival.

Recommended goals:

a. KDIGO guidelines:
1. Maintain PTH levels, SCa, and phosphate levels within normal range for all CKD stages up to stage 5. However,
2. For dialysis dependent patients, PTH levels should be kept at two to five times upper-normal limit.

Question 17

Management of Secondary hPTH

Answer 17

b. KDOQI guidelines:
1. Maintain PTH level at 35 to 70 pg/mL for stage 3, 70 to 110 pg/mL for stage 4 CKD, and 300 to 500 pg/mL for stage 5 CKD.
2. Maintain SCa and phosphate levels within normal range for CKD stages 3 to 4.
3. Maintain calcium between 8.5 and 9.5 mg/dL and serum phosphate between 3.5 and 5.5 mg/dL for stage 5 CKD.
c. 25-vitamin D levels > 30 ng/mL (not evidence based)

Question 18

Management of Secondary hPTH

Answer 18

Phosphate control:

a. Dietary phosphorus restriction (typically 1,000 mg/d):

Of the 1,000 mg phosphorus ingested daily, ~60% is absorbed (600 mg/d or 4,200 mg/wk). A typical thrice weekly hemodialysis regimen removes 2,400 mg/week. Removal of the remaining weekly net gain of 1,800 mg requires the use of phosphate binders.

b. The most efficient phosphate binder is lanthanum which has twice the binding capacity for phosphate compared to most other agents (90 mg of phosphate removed per 1 g of lanthanum versus 45 mg of phosphate per 1 g of other commonly used agents).

Question 19

Management of Secondary hPTH

Answer 19

c. Dietary phosphate:
1. Organic phosphorus:
1a. Found in protein-rich foods from both animal and vegetarian sources of protein.
1b. Organic phosphorus are highly protein bound, which limits absorption. Phosphorus derived from plants (phytate) has lower bioavailability compared to that from animal source.
2. Inorganic phosphorus commonly found in food preservatives or flavor enhancers have 90% to 100% bioavailability because they are not protein bound.
3. NOTE: Active vitamin D increases GI absorption of phosphorus.

Question 20

Management of Secondary hPTH

Answer 20

d. Examples of high-phosphate-containing foods:
1. Dairy products: cheese, cream, custard, ice cream, milk, pudding, yogurt
2. Vegetables: beans, dried peas, lentils, mixed vegetables, soybeans and soy products
3. Protein foods: liverwurst, eggs, liver, salmon, sardines, tuna
4. Breads, cereals
5. Beverages: beer, colas (typically dark colas), some fruit punch
6. Others: chocolate, nuts, processed foods

Question 21

Management of Secondary hPTH

Answer 21

Phosphate binders:

a. Commonly available agents: calcium carbonate, calcium acetate, magnesium carbonate (low efficacy), sevelamer HCl or carbonate (reduces low-density lipoproteins, reduces FGF-23, may attenuate progression of vascular calcifications), lanthanum carbonate, nicotinic acid/niacin (binds to gut Na-Pi 2b and reduces phosphate absorption)

Question 22

Management of Secondary hPTH

Answer 22

b. Newer agents:
1. Iron-containing agents:
1a. Ferric citrate (Auryxia)
1b. Stabilized polynuclear iron(III)-oxyhydroxide (PA21)
2. Colestilan (non–calcium-based phosphate binder that also binds bile acids and reduces LDL cholesterol)

Question 23

Management of Secondary hPTH

Answer 23

c. Special NOTES regarding various phosphate binders:
1. The use of phosphate binders in hemodialysis patients has been shown to reduce both cardiovascular and all-cause mortality by 20% to 30% in several large studies. Nonetheless, the use of phosphate binders in stages 3B to 4 CKD may be associated with an increase in annualized coronary artery and abdominal aortic calcium scores. This is thought to be due to the use of calcium-containing agents. Further studies are needed.

Question 24

Management of Secondary hPTH

Answer 24

2. Lanthanum, a non–calcium, non–resin-based binder:
   2a. May increase bone turnover
   2b. High phosphate-binding capacity, thus lower pill burden compared to others
3. Sevelamer, a non–calcium binder, may bind vitamin D. Higher vitamin D supplements may be necessary.

Question 25

Management of Secondary hPTH

Answer 25

4. Sevelamer-treated hemodialysis patients have been shown to experience lower cardiovascular and all-cause mortality (but not if analyzed for noncardiovascular mortality alone) compared to calcium-containing phosphate binders (Dialysis Outcomes and Practice Patterns Study (DOPPS)).
5. The use of >1.5 g/d of calcium-based phosphate binders can lead to positive calcium balance and is not recommended.

Question 26

Management of Secondary hPTH

Answer 26

Dialysis removal

a. Hemodialysis removes approximately 800 mg of phosphorus per treatment
b. Peritoneal dialysis removes approximately 300 mg of phosphorus per treatment
c. Since phosphorus is predominantly intracellular, there is a rebound phenomenon after dialysis due to extracellular shift.

Question 27

Management of Secondary hPTH

Answer 27

d. Prolonged and frequent dialysis (i.e., nocturnal or daily hemodialysis) are superior in phosphorus removal than conventional hemodialysis.
e. NOTE: Increasing blood flow rate in hemodialysis is not effective in increasing phosphorus removal.

Question 28

Management of Secondary hPTH

Answer 28

Vitamin D supplementation:

a. Ergocalciferol (25-Vitamin D2 - plant source) or cholecalciferol (25-Vitamin D3 animal source)
1. Rationale:
1a. Potential benefits other than for CKD-MBD: inflammation, immunity, cardiac function (reduced ventricular mass), response to erythropoietin stimulating agents, malignancy.
1b. Serves as substrate for 1,25 vitamin D synthesis
1c. Does help with CKD-MBD, but insufficient to reduce PTH levels, particularly in later CKD stages 4 and 5. Therefore, concurrent use of active vitamin D analogs may also be required in later CKD stages.
2. NOTE: Prior to any vitamin D supplementation, serum phosphate levels should be reduced to below 5.5 mg/dL, because vitamin D does increase GI absorption of phosphate and may worsen existing hyperphosphatemia.

Question 29

Management of Secondary hPTH

Answer 29

b. Active vitamin D a.k.a. vitamin D receptor activator (VDRA) supplementation:
1. Calcitriol (Rocaltrol): 1,25(OH)2D3
2. Doxercalciferol (Hectoral): 1(OH)D2 (needs to be converted to 1,25(OH)2D3 in liver)
3. Pericalcitol (Zemplar): 19-nor1,25(OH)2D2

Question 30

Management of Secondary hPTH

Answer 30

c. Comparative effects of commercially available VDRA:
1. Doxercalciferol and paricalcitol may have less calcemic and phosphatemic effects compared to calcitriol. However, all three agents have similar PTH-lowering effect.
2. Intravenous paricalcitol:
2a. May reduce PTH faster with fewer sustained episodes of hypercalcemia and/or CaPO4precipitation compared with calcitriol.
2b. May confer less-vascular calcification and better-vascular wall remodeling compared with calcitriol and doxercalciferol
3. Despite the potential advantage of VDRA on left ventricular mass noted in animal studies, the Paricalcitol Capsules Benefits in Renal Failure Induced Cardiac Morbidity in Subjects with CKD Stage 3/4 (PRIMO) study did not show a significant reduction in LV mass index at 48 weeks in paricalcitol treated versus placebo group.

Question 31

Management of Secondary hPTH

Answer 31

d. NOTE: doxercalciferol 1(OH)-vitamin D needs to be hydroxylated at the 25 position to 1,25-vitamin D in the liver before it becomes an active vitamin D. Thus, doxercalciferol may not be optimally effective in advanced liver patients.

Question 32

Management of Secondary hPTH

Calcimimetics:

Answer 32

Calcimimetics:

a. Cinacalcet (30 to 180 mg/d):
1. May be indicated for secondary hPTH in patients with CKD and on dialysis
2. May lower SCa and should only be used in patients with SCa > 8.4 mg/dL
3. May increase serum phosphorus levels in CKD stages 3 and 4

Question 33

Management of Secondary hPTH

Calcimimetics cont’d:

Answer 33

b. Mechanism of action: acts directly on CaSR as a positive allosteric modulator to increase cellular sensitivity to extracellular calcium.
c. Effective in controlling difficult-to-treat secondary hPTH in both hemo- and peritoneal dialysis patients (i.e., cases resistant to optimal doses of VDRA and phosphate binders)
d. Cinacalcet has been shown to reduce FGF-23 levels whereas VDRA increase FGF-23 levels.

Question 34

Management of Secondary hPTH

Calcimimetics cont’d:

Answer 34

e. Cinacalcet effects on morbidity and mortality:
1. Reduction in risk of parathyroidectomy, fractures, and hospitalization based on post-hoc analysis of four randomized controlled trials, n = 1,184, follow-up 6 to 12 months.
2. There are data to suggest that cinacalcet-centered therapy (i.e., cinacalcet + low-dose vitamin D-based regimen) may be advantageous in controlling secondary hPTH.
3. Cinacalcet has been suggested to reduce the incidence of calcific uremic arteriolopathy.
4. Recent Cochrane analysis revealed no survival benefit.

Question 35

Management of Secondary hPTH

Answer 35

New agent being reviewed by FDA: velcalcetide, an intravenously administered agent that directly activates CaSR (unlike cinacalcet whose action requires calcium for CaSR activation). Velcalcetide has also been shown to reduce both PTH and FGF-23 levels.

Indications for parathyroidectomy in patients with CKD and secondary hPTH

Question 36

Management of Secondary hPTH

Answer 36

Question 37

Management of Secondary hPTH

Management of hypocalcemia:

Answer 37

Management of hypocalcemia:

a. As per KDIGO and KDOQI guidelines, maintain SCa levels in normal range. Calcium supplement should not exceed 1,000 mg/d.
b. Avoid excess calcium supplement due to concerns for increased vascular calcifications and increased cardiovascular and all-cause mortality.
c. For hemodialysis patients, dialysate calcium concentration of 1.25 mmol/L (2.5 mEq/L) provides neutral calcium balance, whereas calcium concentration of 1.5 mmol/L (3 mEq/L) may lead to significantly positive balance and potential increased associated complications.