Severe hypercalcaemia poses a real threat of end organ damage mainly to the kidney and the skeleton. While an accurate diagnosis of the cause of the severe hypercalcaemia is important for effective management, initial treatment often has to be instituted before all tests are completed. The kidney is pivotal in this respect since it is the only way in which the body can excrete an unwanted calcium load. Hypercalcaemia impairs renal function by reducing GFR and also by causing nephrogenic diabetes insipidus with a consequent inability to conserve water. Dehydration augments proximal renal tubular sodium reabsorption and this leads to enhanced calcium reabsorption with substantial impairment in the ability of the kidney to excrete an unwanted calcium load.
Hyperparathyroidism is an unusual cause of very severe hypercalcaemia and most cases will have an underlying malignancy. In patients where the tumour is actively causing bone destruction through local invasion, the introduction of potent intravenous bisphosphonates has had a major impact on the effectiveness of treatment. However, where bone resorption is increased due to the production of PTHrP by the tumour bisphosphonates are much less effective because the level of serum calcium is largely determined by distal renal tubular reabsorption which is enhanced by PTHrP rather than by an increased calcium load from bone destruction is reduced.This remains the major challenge to effective treatment.