How to diagnose secondary hyperparathyroidism in a patient with Chronic Kidney Disease (CKD)?

Diagnosis of Secondary Hyperparathyroidism in CKD

Begin measuring serum calcium, phosphorus, and intact PTH when GFR falls below 60 mL/min/1.73 m² (CKD stage 3a), as PTH elevation and bone disease can develop at this early stage. 1

Core Diagnostic Laboratory Panel

The diagnosis of secondary hyperparathyroidism in CKD requires simultaneous measurement of multiple parameters to distinguish it from primary hyperparathyroidism and assess disease severity:

Essential Initial Tests

• Intact PTH is the primary diagnostic marker, with levels beginning to rise when GFR <60 mL/min/1.73 m² 1
• Serum calcium should be measured simultaneously with PTH—secondary hyperparathyroidism presents with hypocalcemia or normal calcium (never hypercalcemia, which indicates primary hyperparathyroidism) 2
• Serum phosphorus is expected to be elevated as renal function declines, which drives PTH secretion 1
• Serum creatinine and calculated eGFR must be tracked to determine CKD stage and monitor disease progression 1
• Alkaline phosphatase levels should be measured, as elevation suggests high bone turnover and increases the predictive power of PTH measurements 1

Critical Vitamin D Assessment

• 25-hydroxyvitamin D [25(OH)D] must be measured in all CKD patients, as 47-76% of CKD stage 3-4 patients have levels <30 ng/mL, which aggravates secondary hyperparathyroidism 1
• Vitamin D deficiency as low as <30 ng/mL is associated with increased PTH levels, reduced bone mineral density, and increased hip fracture rates even in early CKD 1

Diagnostic Algorithm by CKD Stage

The approach to diagnosis varies by CKD stage, with increasing frequency of monitoring as kidney function declines:

CKD Stage 3a-3b (eGFR 30-59 mL/min/1.73 m²)

• Measure calcium, phosphorus, and PTH at least once to establish baseline values 1
• Repeat measurements every 6-12 months if initial values are normal 3
• If PTH is elevated, verify the trend by repeating PTH measurement in 3 months, as therapeutic decisions should be based on trends rather than single values 1

CKD Stage 4 (eGFR 15-29 mL/min/1.73 m²)

• Monitor PTH, calcium, and phosphorus every 3-6 months 3
• Measure 25-hydroxyvitamin D if not previously done 1
• Monitor alkaline phosphatase every 3-6 months if PTH is elevated 3

CKD Stage 5 (eGFR <15 mL/min/1.73 m² or dialysis)

• Monitor PTH, calcium, and phosphorus every 1-3 months 3
• During active treatment titration, monitor calcium and phosphorus every 2 weeks for the first month, then monthly for 3 months 3
• Monitor PTH monthly for 3 months after initiation or dose adjustment of therapy 3

Key Diagnostic Distinctions

Differentiating Secondary from Primary Hyperparathyroidism

This distinction is critical and based on the calcium level:

• Secondary hyperparathyroidism: Elevated PTH with low or normal calcium 2
• Primary hyperparathyroidism: Elevated PTH with hypercalcemia (corrected calcium >10.2 mg/dL) 2
• If hypercalcemia is present with elevated PTH in a CKD patient, consider tertiary hyperparathyroidism (autonomous parathyroid function after prolonged secondary hyperparathyroidism) 2

PTH Assay Considerations

• Intact PTH assays overestimate biologically active PTH by detecting C-terminal fragments that may have inhibitory activity 1
• Different assay generations vary significantly—use assay-specific reference values rather than universal cutoffs 1
• PTH is most stable in EDTA plasma at 4°C rather than serum at room temperature 2
• Biological variation of PTH is substantial (20% in healthy individuals), so differences must exceed 54% to be clinically significant 2

Expected Laboratory Pattern in Secondary Hyperparathyroidism

The characteristic biochemical profile includes:

• Elevated intact PTH (typically >65 pg/mL, but target ranges differ by CKD stage) 3
• Low or normal serum calcium (8.6-10.2 mg/dL) 2
• Elevated serum phosphorus (>4.6 mg/dL in advanced CKD) 3
• Low 25-hydroxyvitamin D (<30 ng/mL in most cases) 1
• Elevated alkaline phosphatase (indicating high bone turnover) 1
• Low or normal 1,25-dihydroxyvitamin D (calcitriol), as reduced kidney mass cannot adequately convert 25(OH)D to active form 4

Common Diagnostic Pitfalls to Avoid

Do Not Rely on Single Measurements

• Base diagnostic and treatment decisions on trends in laboratory values rather than a single abnormal result 5
• Serial monitoring over 3-6 months provides more reliable assessment than isolated values 1

Do Not Ignore Vitamin D Status

• Measuring PTH without assessing 25-hydroxyvitamin D status is incomplete, as vitamin D deficiency causes secondary hyperparathyroidism that may be reversible with nutritional repletion alone 1
• PTH reference values are 20% lower in vitamin D-replete individuals compared to those with unknown vitamin D status 2

Do Not Overlook Calcium Correction

• If albumin is abnormal, calculate corrected calcium to avoid misleading total calcium measurements 2
• Consider measuring ionized calcium (normal: 4.65-5.28 mg/dL) for definitive assessment 2

Do Not Confuse Target PTH Ranges

• Never target normal PTH levels (<65 pg/mL) in dialysis patients—this causes adynamic bone disease with increased fracture risk 3
• The appropriate PTH target for CKD stage 5/dialysis is 150-300 pg/mL, not the normal range 3
• Target PTH ranges for CKD stage 3 are not well-defined; focus on trends and preventing progressive elevation 1

Additional Diagnostic Considerations

Assess for Complications

• 24-hour urine calcium or spot urine calcium/creatinine ratio should be obtained to assess for hypercalciuria 2
• Renal ultrasonography is recommended to assess for nephrocalcinosis or kidney stones 2
• Bone density scan (DEXA) should be considered if chronic hyperparathyroidism is suspected to assess for renal osteodystrophy 2

Rule Out Other Causes of Elevated PTH

• Ensure adequate dietary calcium intake (1000-1200 mg/day), as dietary calcium deficiency can cause secondary hyperparathyroidism 2
• Review medications that may affect calcium metabolism, including thiazide diuretics, lithium, and excessive calcium or vitamin D supplementation 2