Renal Failure

Hypocalcemia in chronic renal failure is due to two primary causes - increased serum phosphorus and decreased renal production of 1,25 (OH)2 vitamin D. The former causes hypocalcemia by complexing with serum calcium and depositing it into bone and other tissues. The latter causes hypocalcemia by decreasing the GI absorption of calcium.

Hypoparathyroidism

There are several causes of hypoparathyroidism, as summarized in Table 3. Neck surgery that removes or destroys the parathyroid glands is the most common cause of hypoparathyroidism. These operations include: (1) thyroidectomy due to thyroid cancer or benign goiter, with inadvertent removal or destruction of parathyroid tissue; (2) parathyroidectomy, especially for multigland hyperplasia; and (3) laryngectomy. Post-surgical hypoparathyroidism can occur within hours after surgery or gradually over time when glands injured at surgery ultimately become non-functioning.

Idiopathic hypoparathyroidism can occur in isolation or in association with other endocrine or autoimmune disorders (Table 4), typically with adrenal insufficiency. The parathyroid glands can be absent, remnant, or compromised by an immune destruction. Anti-cytokine antibodies (e.g., against alpha interferons) or antibodies directed against parathyroid cell antigens (e.g., NALP5) may be present.

Pseudohypoparathyroidism (PHP) is a genetic disorder characterized by target-organ unresponsiveness to PTH. PHP mimics the hormone-deficient forms of hypoparathyroidism, with hypocalcemia and hyperphosphatemia, but PTH levels are elevated rather than low or absent.

Hypoparathyroidism can occur in an autoimmune setting (Table 4) associated with autoantibodies. The most commonly associated disorders are Addison disease and mucocutaneous candidiasis. Two of the 3 disorders in the triad are necessary for the diagnosis of APS1. These patients can be affected by other endocrinopathies or immune-mediated disorders (e.g., thyroid disease, diabetes mellitus,

pernicious anemia, and ovarian failure).

Other Causes of Hypocalcemia

Magnesium deficiency causes hypocalcemia by interfering with the end-organ actions of PTH and/or by inhibiting its secretion. Pancreatitis causes hypocalcemia through sequestration of calcium by saponification with fatty acids. Osteoblastic metastases similarly take up blood calcium. Excessive transfusion of citrated blood products may transiently lower ionized calcium and cause symptoms until citrate is cleared by the liver. In hyperphosphatemia, high levels of blood phosphorus complexes with calcium, and the product can precipitate into organs and soft tissues. Causes include renal failure, administration of phosphate, rhabdomyolysis, tumor lysis, and some cases of tumoral calcinosis. Vitamin D deficiency (or resistance syndromes) contributes to the hypocalcemia of osteomalacia and malabsorption. Iatrogenic causes include cancer chemotherapy, notably certain tyrosine kinase inhibitors. Other drugs reported to cause hypocalcemia include inhibitors of bone resorption; loop diuretics; and agents that accelerate vitamin D metabolism, like anticonvulsants. All inhibitors of bone resorption used to treat hypercalcemia (e.g., calcitonin, intravenous bisphosphonates, the receptor activator of nuclear factor kappa B ligand or RANK-L inhibitor denosumab) and the calcimimetics cinacalcet or etelcalcitide used to treat hyperparathyroidism can cause hypocalcemia.

Acute Hypocalcemia

Hypocalcemia can be an endocrine emergency requiring rapid intervention. Patients with either severe hypocalcemia, usually <7.5 mg/dl, or with neurological manifestations or stridor (laryngo/bronchospasm) should receive intravenous calcium. Calcium gluconate (90 mg calcium per 10 mL) should be given as intravenous slow pushes, generally one vial over 10 minutes, repeated once with electrocardiographic monitoring. A chronic intravenous drip is then started if the patient is still symptomatic and oral treatment cannot act rapidly enough. The infusion rate should be guided by signs, symptoms, and calcium measurements checked every 1-2 hours, preferably ionized calcium levels. Magnesium deficiency should also be treated when present, since it can attenuate the effect of the treatment by calcium and vitamin D (see below). Oral calcium (e.g., 1-2 grams of elemental calcium) and a rapidly acting preparation of vitamin D (e.g., 0.5-1.0 micrograms of calcitriol in divided doses) should be started as soon as practical. This is often limited by neck surgery. If necessary, intravenous calcium can be given for as long as necessary until oral therapy has taken effect. Patients taking cardiac drugs, especially digoxin, are predisposed to cardiotoxicity by infusion of calcium, so an EKG should be used for cardiac monitoring. Treatment must be assessed with frequent serum ionized calcium levels. Several preparations of calcium for oral use are available. The most commonly used are calcium carbonate and calcium citrate (Table 5). Recombinant human PTH (1-84) has been recently approved for the treatment of chronic hypoparathyroidism in adults and can reduce the amount of calcium and activated vitamin D supplements that a patient is required to take to control serum calcium levels in this disorder.

Hypomagnesemia should always be considered as a potential contributory cause of hypocalcemia, especially in post-operative and hospitalized patients. Low serum magnesium may reveal this, but the serum magnesium may be normal or low normal, since serum magnesium does not accurately reflect the stores of this primarily intracellular ion. Therefore, a therapeutic trial of magnesium, usually parenteral, may be needed to assess for magnesium deficiency. Oral magnesium is used for mild, chronic magnesium deficiency (e.g., daily dose of 200-300 mg). Many preparations are available including magnesium oxide, magnesium carbonate or magnesium sulfate. Parenteral magnesium (10% or 50% solutions of magnesium sulfate) is used for severe hypomagnesemia. A common regimen is 2-4 mls IV of a 50% solution given over 10-15 minutes followed by similar amounts given daily. Several days of treatment are usually required to replete magnesium stores.

The objective of chronic therapy for hypocalcemia is to keep the patient free of symptoms and to maintain serum calcium at approximately 8.0-9.0 mg/dL. With lower serum calcium levels, the patient may continue to experience symptoms over time. With serum calcium concentrations in the upper normal range, there may be significant hypercalciuria, especially when the hypocalciuric effect of PTH has been lost. This can predispose to nephrolithiasis, nephrocalcinosis, and renal damage. When the calcium x phosphorus product rises to near 55 mg²/dL² or greater, as it can in patients with hypoparathyroidism who also have a chronically elevated serum phosphorus level (due to the loss of PTH actions in the kidney), ectopic calcifications in other soft tissues like the brain (especially the basal ganglia), blood vessels, and eyes can occur.

Chronic Hypocalcemia

Calcium and vitamin D are used to treat most causes of chronic hypocalcemia, such as renal failure and hypoparathyroidism. Vitamin D is used to establish a baseline calcium level and calcium is added (or subtracted) for acute changes in calcium. Calcitriol is the preferred preparation of vitamin D because it is rapidly active and has a short half-life (i.e., rapidly reversible) in contrast to the other forms of vitamin D (Table 6). In patients with renal failure, treatment is directed at maintaining normal levels of calcium, phosphorus, and the calcium x phosphorus product and the intact PTH within an acceptable range for the chronic kidney disease. 1,25 dihydroxy-vitamin D or calcitriol or one of its analogs can be given orally or parenterally. Vitamin D2 or D3 may be used for nutritional deficiency. Recombinant human PTH(1-84) has been recently approved for the treatment of chronic hypoparathyroidism in adults and can reduce the amount of calcium and activated vitamin D supplements that a patient is required to take to control serum calcium levels in this disorder.