1/ The classic presentation at morning report for hypercalcemia starts with polyuria, constipation and confusion. #UncleBob wanted to understand why - stimulated by @CuriousClinPod ? @HannahRAbrams @tony_breu @AvrahamCooperMD

2/ Let's start with confusion. Finding information on this is very non-specific but I think this quote helps: High calcium levels can be a catalyst for neuronal demise, possibly due to glutaminergic excitotoxicity and dopaminergic and serotonergic dysfunction.

3/ But colleagues and learners know that I am most interested in the polyuria. I have taught that hypercalcemia can cause nephrogenic diabetes insipidus, but the mechanism was unclear. Let's review how ADH works and then look at an interesting study that suggests an answer.

4/ Antidiuretic hormone stimulates water reabsorption: stimulating insertion of "water channels" or aquaporins into kidney tubule membranes which transport solute-free H20 through tubular cells & back into blood, -> decrease in plasma osms and an increase urine osms.

5/ Thus we need to stimulate ADH production and have aquaporins (specifically aquaporin-2) available for transport. In general nephrogenic DI occurs because of the lack of aquaporin-2(AQP2).