Why is Parathyroid Hormone (PTH) elevated in patients with Chronic Kidney Disease (CKD) or Acute Kidney Injury (AKI) and how is it treated?

Why PTH is Elevated in CKD/AKI and Treatment Approach

Pathophysiology of PTH Elevation

PTH rises in CKD due to a cascade initiated by phosphate retention, which triggers vitamin D deficiency, hypocalcemia, and increasing FGF-23 levels, ultimately driving compensatory parathyroid gland hyperplasia and hormone secretion. 1

The pathophysiological sequence unfolds as follows:

• Phosphate retention occurs early as the primary initiating factor, even before hyperphosphatemia becomes evident on laboratory testing, particularly in early CKD stages 1, 2
• Reduced calcitriol production develops as failing kidneys lose their ability to convert 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D3, leading to decreased intestinal calcium absorption 1, 3
• Hypocalcemia develops as a consequence of impaired vitamin D activation and reduced calcium absorption 1, 3
• FGF-23 levels increase progressively as kidney function declines, contributing to further suppression of calcitriol production 1, 4
• Parathyroid gland resistance to both PTH and vitamin D develops, requiring higher PTH levels to maintain mineral homeostasis 1

Note: In AKI, PTH elevation is typically less pronounced and may represent acute mineral disturbances rather than the chronic adaptive response seen in CKD 1

Treatment Algorithm: Stage-Based Approach

Step 1: Assess CKD Stage and PTH Severity

Do NOT treat based on a single elevated PTH value - modest PTH elevations may represent appropriate adaptive responses to declining kidney function 1

• CKD Stage 3-4 (non-dialysis): Reserve active vitamin D therapy only for severe and progressive hyperparathyroidism, not moderate elevations 1
• CKD Stage 5 (dialysis): Target PTH range of 2-9 times upper limit of normal (approximately 150-600 pg/mL), NOT normal range 2, 5

Step 2: Address Modifiable Risk Factors FIRST

Before initiating any PTH-lowering therapy, correct the following 1, 6:

• Control phosphate: Target 3.5-5.5 mg/dL in dialysis patients through dietary restriction (800-1,000 mg/day) and phosphate binders 1, 2, 5
• Avoid processed foods with phosphate additives, which promote secondary hyperparathyroidism even without hyperphosphatemia 1, 2
• Replete nutritional vitamin D: Use ergocalciferol or cholecalciferol (NOT calcitriol) if 25-OH vitamin D <30 ng/mL - give ergocalciferol 50,000 IU weekly for 12 weeks, then monthly maintenance 5, 6
• Optimize calcium: Provide calcium carbonate 1-2 g three times daily with meals as phosphate binder and calcium supplement 5

Step 3: Pharmacologic Therapy for Severe/Progressive Hyperparathyroidism

Critical Threshold: Only initiate active vitamin D therapy when PTH remains severely elevated (>300 pg/mL in dialysis patients, or progressive elevation in non-dialysis CKD) despite addressing modifiable factors 1

For CKD Stage 5 (Dialysis):

• First-line: Calcitriol or vitamin D analogs (paricalcitol, doxercalciferol, alfacalcidol) 1
• Start low, titrate slowly to avoid hypercalcemia, which increases mortality risk 1
• Alternative/Adjunct: Cinacalcet (calcimimetic) - particularly useful when hypercalcemia or hyperphosphatemia limit vitamin D therapy 7
  • Start at 30 mg daily, titrate every 3-4 weeks to maximum 180 mg daily 7
  • Target iPTH ≤250 pg/mL but NOT below 100 pg/mL to avoid adynamic bone disease 7

For CKD Stage 3-4 (Non-Dialysis):

The 2017 KDIGO guidelines represent a major paradigm shift: Routine use of calcitriol or vitamin D analogs is NO LONGER RECOMMENDED for moderate PTH elevations 1

• Rationale: PRIMO and OPERA trials demonstrated increased hypercalcemia risk without cardiovascular benefit 1
• Reserve vitamin D analogs only for severe and progressive secondary hyperparathyroidism 1
• When used: Start with low doses and titrate based on PTH response while avoiding hypercalcemia 1

Step 4: Monitoring Protocol

Intensive monitoring is essential to prevent complications 5:

• During titration: Check calcium and phosphorus every 2 weeks for first month, then monthly for 3 months 5
• PTH monitoring: Every 1-3 months in Stage 5, every 3-6 months in Stage 3-4 5
• Alkaline phosphatase: Every 3-6 months if PTH elevated 5

Step 5: Surgical Intervention

Parathyroidectomy is indicated when medical therapy fails 1, 8:

• Persistent iPTH >800 pg/mL despite maximal medical therapy 1
• Associated with refractory hypercalcemia and/or hyperphosphatemia 1
• Symptomatic disease (bone pain, fractures, pruritus) 8
• Options: Subtotal parathyroidectomy or total parathyroidectomy with autotransplantation 1

Critical Pitfalls to Avoid

Never attempt to normalize PTH to the reference range for patients without CKD - this causes adynamic bone disease with increased fracture risk and inability to buffer calcium-phosphate loads 2, 5, 7

Never start active vitamin D therapy with phosphorus >4.6 mg/dL - this worsens vascular calcification and increases calcium-phosphate product 5

Never use calcitriol or active vitamin D sterols to treat nutritional vitamin D deficiency - use ergocalciferol or cholecalciferol instead 5

Monitor for hypocalcemia with calcimimetic therapy - mild asymptomatic hypocalcemia may be acceptable, but significant or symptomatic hypocalcemia requires calcium supplementation, vitamin D adjustment, or dose reduction 1, 7

Watch for upper GI bleeding with cinacalcet, especially in patients with gastritis, esophagitis, or ulcers - monitor for worsening nausea/vomiting 7

Avoid oversuppression - if iPTH falls below 150 pg/mL, reduce or hold therapy to prevent adynamic bone disease 7