Secondary Hyperparathyroidism Flashcards
Clinical Implications of Secondary hPTH
Renal osteodystrophy with increased risk of fractures: a. Osteomalacia b. Osteopenia c. Adynamic bone disease d. Mixed bone disease
Clinical Implications of Secondary hPTH
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).
Diagnosis of Secondary hPTH
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).
Pathogenesis of Secondary Hyperparathyroidism
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.
Pathogenesis of Secondary Hyperparathyroidism
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.
Pathogenesis of Secondary Hyperparathyroidism Phosphate retention leads to cont’d:
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)
Pathogenesis of Secondary Hyperparathyroidism
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
Pathogenesis of Secondary Hyperparathyroidism
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.
Pathogenesis of Secondary Hyperparathyroidism
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
Pathogenesis of Secondary Hyperparathyroidism
Other notes regarding FGF-23 in CKD
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.
Other notes regarding FGF-23 in CKD
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.
Other notes regarding FGF-23 in CKD
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.
Other notes regarding FGF-23 in CKD
FGF-23 in CKD:
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.
Other notes regarding FGF-23 in CKD
FGF-23 in CKD:
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.
Management of Secondary hPTH
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.
Management of Secondary hPTH
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)
Management of Secondary hPTH
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).
Management of Secondary hPTH
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.
Management of Secondary hPTH
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
Management of Secondary hPTH
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)
Management of Secondary hPTH
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)
Management of Secondary hPTH
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.
Management of Secondary hPTH
- 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 - Sevelamer, a non–calcium binder, may bind vitamin D. Higher vitamin D supplements may be necessary.
