Proximal Renal Tubular Dysfunction Induces Severe Hypocalcemia in the Elderly

Hypocalcemia is a common metabolic disorder. As aging progresses, the dietary intake and intestinal absorption of calcium decrease (1). Furthermore, in older people, the reduced efficiency of skin production and exposure to sunlight can decrease vitamin D production in the skin (2). Therefore, elderly people are at an increased risk of developing hypocalcemia even though serum calcium levels are closely regulated by homeostatic control mechanisms.

Furthermore, because older adults often consume many drugs, they experience drug-related problems, including a decrease in serum calcium levels. Bisphosphonates and denosumab, which are used to treat osteoporosis, prevent the release of calcium from bones and can cause hypocalcemia. Proton pump inhibitors can lead to lower calcium absorption, and loop diuretics can enhance the renal excretion of calcium. Chemotherapy, glucocorticoids, and anticonvulsants have also been reported to induce hypocalcemia, as has the loss of the renal function.

The renal proximal tubules absorb most of the glomerular filtrate, including small low-molecular-weight proteins, amino acids, glucose, and electrolytes. The circulating vitamin 25(OH)D3-vitamin D binding protein complex is filtered through the glomerulus into the proximal tubules and reabsorbed (3). The reabsorbed vitamin 25(OH)D3 is then hydroxylated and forms calcitriol (1,25-dihydroxycholecalciferol), the biologically active form of vitamin D, in proximal renal cells. Therefore, proximal renal tubular dysfunction might induce hypocalcemia.

Acute or chronic renal tubular injury can occur with various medications, including antimicrobial agents, analgesics, chemotherapeutic drugs, calcineurin inhibitors, contrast agents, and bisphosphonates. Bisphosphonates decrease serum calcium levels by reducing the release of calcium from bones and the formation of activated vitamin D. Because there are no specific therapies for tubular injury and immediately stopping the offending agent is important to avoid further kidney injury, clinicians should be alert for signs of drug-induced renal injury.

Moderate low blood calcium levels have been reported to cause several symptoms, including grade ≥2 hypocalcemia (corrected serum calcium ＜8.0 mg/dL; ionized calcium ＜1.0) (4). Symptoms of hypocalcemia include dry skin, brittle nails, coarse hair, and muscle cramps. In severe cases, memory loss, depression, and confusion may occur, and patients may experience life-threatening complications, such as cardiac arrest or seizures. However, the symptoms of hypocalcemia are not specific and tend to result from malnutrition and/or geriatric diseases, and many elderly patients with hypocalcemia may not receive appropriate treatment.

In this issue of Internal Medicine, Fujita et al. (5) reported an 80-year-old man who developed severe hypocalcemia (corrected serum total calcium level, 3.9 mg/dL and ionized calcium level 0.52 mmol/L). The patient had been diagnosed with bone and lymph node metastases from prostate cancer seven years previously and receiving hormonal therapy and zoledronate. His symptoms included general fatigue, muscle weakness, and body weight loss, which were not specific for hypocalcemia. His body weight gradually decreased to 20 kg, indicating severe malnutrition. The patient was unable to walk independently and had hypokalemia, hypouricemia, hypophosphatemia, and metabolic acidosis, indicating renal proximal tubular dysfunction. He also had hypomagnesemia, which may have been induced by malnutrition and caused secondary hypocalcemia.

This case raises several important points that need to be recognized in clinical practice. First, multifactorial causes of hypocalcemia are common in the elderly, particularly in patients with malignant tumors and/or malnutrition. Hypocalcemia was severe in this case, although drug-related hypocalcemia has been reported to be generally mild. Second, as the symptoms are nonspecific, diagnostic errors may occur frequently in elderly patients with hypocalcemia. Therefore, it is worth mentioning serum calcium levels, especially in patients with signs of renal proximal tubular dysfunction, such as hypokalemia, hypouricemia, hypophosphatemia, metabolic acidosis, and/or malnutrition.

Author's disclosure of potential Conflicts of Interest (COI).

Takashi Uzu: Honoraria, Eli Lilly Japan, AstraZeneca and Kyowa Kirin.