Can patients with nephrotic syndrome experience hypocalcemia?

Hypocalcemia in Nephrotic Syndrome

Yes, patients with nephrotic syndrome commonly develop hypocalcemia, primarily due to urinary losses of vitamin D-binding protein and 25-hydroxyvitamin D, leading to decreased ionized calcium levels despite sometimes normal total calcium concentrations. 1

Mechanism of Hypocalcemia

The pathophysiology involves multiple interconnected factors:

• Urinary protein losses: Massive proteinuria causes urinary loss of vitamin D-binding protein (DBP) and 25-hydroxyvitamin D (25-OH-D3), resulting in vitamin D deficiency 1
• Decreased vitamin D metabolites: Blood levels of 25-OH-D, 1,25-(OH)2D, and 24,25-(OH)2D are all significantly reduced in nephrotic syndrome 2
• Impaired calcium absorption: Vitamin D deficiency leads to markedly impaired intestinal calcium absorption, with some patients having fecal calcium equal to or exceeding dietary calcium intake 3
• Reduced PTH responsiveness: Resistance to the calcemic action of parathyroid hormone develops, further contributing to hypocalcemia 2

Important Measurement Considerations

Total serum calcium underestimates true calcium status in nephrotic syndrome due to hypoalbuminemia 1. The most accurate assessment requires:

• Ionized (free) calcium measurement is essential, as total calcium levels are misleadingly low due to decreased protein-bound calcium 1
• Corrected total calcium formulas may still be inaccurate in severe hypoalbuminemia 1
• Both free and total calcium can be truly reduced in nephrotic syndrome, not just an artifact of low albumin 4, 2

Clinical Monitoring and Management

The 2021 ERKNET-ESPN consensus guidelines recommend close monitoring of ionized calcium, 25-OH-D3, and PTH levels with supplementation when deficiencies are identified 1:

• Monitor ionized calcium, 25-OH-D3, and PTH levels regularly 1
• Supplement with oral vitamin D3 (cholecalciferol) or 25-OH-D3 (calcifediol) plus calcium (250-500 mg/day) when 25-OH-D3 is low and/or ionized calcium is low and/or PTH is elevated 1
• Reduced ionized calcium and elevated PTH levels are clear indicators for vitamin D and calcium supplementation 1

Disease Course and Reversibility

The severity and persistence of hypocalcemia correlates with disease activity:

• During active nephrotic syndrome (relapse): Hypocalcemia, hyperparathyroidism, and strikingly low 25-OH-D levels are present 5
• During remission: Most calcium and vitamin D abnormalities normalize as proteinuria resolves 4, 5
• Prolonged or relapsing disease: Patients who do not achieve complete remission continue to have low 25-OH-D levels and remain at risk for metabolic bone disease even with normal kidney function 4, 5

Clinical Pitfalls to Avoid

• Do not rely solely on total calcium levels - always measure ionized calcium in nephrotic patients to avoid missing true hypocalcemia 1
• Do not assume normal calcitriol levels are adequate - in the presence of hypocalcemia and hyperparathyroidism, "normal" 1,25-(OH)2D levels may represent relative deficiency 5
• Do not overlook bone disease risk - children and adults with relapsing or protracted nephrotic syndrome are at risk for metabolic bone disease even without impaired kidney function 5
• Standard vitamin D supplementation (1.25 mg/day calciferol) may not significantly improve calcium absorption in active nephrotic syndrome 3

Special Considerations in Congenital Nephrotic Syndrome

For children with congenital nephrotic syndrome, the 2021 consensus guidelines are particularly emphatic 1:

• High-energy (130 kcal/kg/day) and high-protein (4 g/kg/day) diet is recommended 1
• Hypothyroidism should be monitored and treated, as it occurs due to urinary loss of thyroxine-binding proteins 1
• Growth hormone therapy may be needed for persistent growth failure 1