Naturally occurring vitamin D (cholecalciferol) requires hydroxylation in the liver at position 25 and again by a 1α-hydroxylase enzyme (mitochondrial cytochrome P450) mainly in the distal convoluted tubule, the cortical and inner medullary part of the collecting ducts and the papillary epithelia of the kidney to produce the powerfully metabolically active 1,25-dihydroxycholecalciferol (1,25-(OH)2D3). The 1α-hydroxylase activity is increased by high plasma levels of parathyroid hormone (PTH), low phosphate and low 1,25-(OH)2D3. 1,25-Dihydroxycholecalciferol and 25-hydroxycholecalciferol are degraded in part by being hydroxylated at position 24 by 24-hydroxylase. The activity of this enzyme is reduced by PTH and increased by 1,25-(OH)2D3 (which therefore promotes its own inactivation).

Reduced 1α-hydroxylase activity in diseased kidneys results in relative deficiency of 1,25-(OH)2D3. As a result, gastrointestinal calcium and to a lesser extent phosphate absorption is reduced and bone mineralization impaired. Receptors for 1,25-(OH)2D3 exist in the parathyroid glands, and reduced occupancy of the receptors by the vitamin alters the set-point for release of PTH in response to a given decrement in plasma calcium concentration. Gut calcium malabsorption, which induces a tendency to hypocalcaemia, and relative lack of 1,25-(OH)2D3, contribute therefore to the hyperparathyroidism seen regularly in patients with renal impairment, even of modest degree.