Renal Calculi in Hyperparathyroidism

Overview

• Robbins & Kumar Basic Pathology, p. 765
• Smith and Tanagho's General Urology, 19th Ed.

Types of Hyperparathyroidism and Renal Stone Risk

1. Primary Hyperparathyroidism (PHPT)

• Most commonly caused by a sporadic solitary parathyroid adenoma; less commonly by parathyroid hyperplasia (as in MEN-1 and MEN-2A).
• Results in autonomous, unregulated PTH secretion - hypercalcemia does NOT suppress PTH release.
• <10% of patients with clinically obvious PHPT present with nephrolithiasis.
• This group represents <5% of all patients with urinary stones, and is more common in women.
• Patients with calcium phosphate stones, women with recurrent calcium stones, and those with both nephrocalcinosis and nephrolithiasis should be suspected of having underlying PHPT.

2. Secondary Hyperparathyroidism

• Caused by chronic hypocalcemia, most often from chronic kidney disease (CKD).
• PTH is elevated reactively - this causes renal hypercalciuric nephrolithiasis through a vicious cycle (see below).
• The distinction between primary and secondary HPT is clinically important: a thiazide challenge (hydrochlorothiazide 50 mg twice daily for 7-10 days) can help - serum PTH normalizes in secondary HPT, but remains elevated in primary HPT.
• Smith and Tanagho's General Urology, 19th Ed.

Pathophysiology: How Hyperparathyroidism Causes Renal Stones

PTH Actions on Calcium Homeostasis

• Robbins & Kumar Basic Pathology, p. 765

Stone Formation Mechanism in Primary HPT

1. Elevated serum calcium leads to increased glomerular filtration of calcium.
2. Even though PTH increases tubular calcium reabsorption, the filtered load is so high that urinary calcium excretion remains elevated.
3. Hypercalciuria (>400 mg/day in 24-hr urine) supersaturates urine with calcium salts.
4. PTH-induced phosphaturia raises urinary phosphate concentration.
5. PTH also impairs urinary acidification - alkaline urine favors calcium phosphate precipitation.
6. Renal concentrating ability is impaired - lower urine volume further concentrates calcium.
7. Result: Calcium phosphate stones (and sometimes calcium oxalate) precipitate.

Key: Urinary calcium/creatinine ratio >0.2 mg/mg in 24-hour collection is characteristic of PHPT (vs. FHH where ratio is typically <0.01 mg/mg).

• NKF Primer on Kidney Diseases, 8th Ed.

Renal Hypercalciuric Nephrolithiasis (Secondary HPT Loop)

• Urinary calcium loss → relative hypocalcemia → reactive PTH rise (secondary HPT)
• PTH mobilizes bone calcium, increases gut absorption
• More calcium delivered to kidneys → more calcium in urine → stone formation
• These patients have: elevated fasting urine Ca²⁺, normal serum Ca²⁺, secondarily elevated PTH

• Smith and Tanagho's General Urology, 19th Ed., p. 277

Stone Composition in Hyperparathyroidism

• Calcium phosphate (apatite) - the alkaline urine from phosphaturia promotes phosphate crystallization
• Calcium oxalate - from hypercalciuria more generally

• Tietz Textbook of Laboratory Medicine, 7th Ed., p. 1898

Renal Morphological Consequences

• Nephrocalcinosis - calcium deposition within the renal parenchyma
• Impaired renal concentrating ability (nephrogenic DI)
• Impaired urinary acidification (predisposes to distal RTA-like picture)
• Over time: progressive CKD from calcium deposition
• Robbins & Kumar Basic Pathology, p. 765

Diagnosis

Biochemical workup

• Serum Ca²⁺: elevated in PHPT (correct for albumin; ionized Ca²⁺ if albumin is low)
• Serum PTH (intact PTH): elevated (or inappropriately normal in context of hypercalcemia)
• Serum phosphate: low (phosphaturia)
• 24-hour urine calcium: >400 mg/day (>10 mmol/day) - key criterion
• Urinary Ca²⁺/creatinine ratio: >0.2 mg/mg in primary HPT
• Serum alkaline phosphatase: may be elevated (increased bone turnover)

Imaging

• Renal ultrasound or non-contrast CT: detects nephrolithiasis and nephrocalcinosis
• DXA scan: bone mineral density (osteoporosis assessment)
• Sestamibi scan (⁹⁹ᵐTc-sestamibi): preoperative localization of parathyroid adenoma

Indications for Parathyroidectomy in PHPT With Renal Calculi

1. Serum calcium >1.0 mg/dL above the upper limit of normal
2. History of symptomatic kidney stones OR imaging-confirmed nephrolithiasis/nephrocalcinosis (automatic indication)
3. T-score ≤-2.5 on DXA at any site, or vertebral fracture on imaging
4. Creatinine clearance <60 mL/min
5. 24-hour urine calcium >400 mg/day with increased stone risk on kidney stone profile
6. Age <50 years
7. Patient preference to avoid longitudinal monitoring

• NKF Primer on Kidney Diseases, 8th Ed., pp. 632-644

Post-surgical note

• Surgical removal of the parathyroid adenoma is the definitive treatment.
• However, up to 10% of patients develop new urinary stones even after successful parathyroidectomy - more commonly in men. This is likely due to pre-existing metabolic abnormalities that persist.

Management of Hypercalcemia (Acute)

Note: Thiazide diuretics are contraindicated in hypercalcemia (they reduce urinary calcium excretion and worsen hypercalcemia).

• NKF Primer on Kidney Diseases, 8th Ed., Table 11.1

Summary Table