Calcium is the most represented bivalent cation in the organism, and it is essential for a
variety of actions. It supports the body, and works as a second messenger, modulating different
intracellular and extracellular processes. The balance of parathyroid hormone (PTH), calcitonin, and
vitamin D has long been considered the main regulator of calcium metabolism, but the function of
other “actors”, such as fibroblast growth factor-23 (FGF-23), Klotho gene, and transient receptor
potential cation channel, subfamily V, member 5 (TPRV5) should be considered. Hypercalcemia
may cause renal damage both temporary (alteration of renal tubular function for instance) and
persisting (relapsing nephrolithiasis, especially with high kidney stones) by different ways, leading
to a progressive loss of renal function, and ultimately the end stage renal disease with subsequent
need of renal replacement therapy. A worsened renal function stimulates further alterations of
calcium metabolism, and renal osteodistrophy may result. Hypercalcemia is a common problem also
in renal transplant recipients, although in most cases spontaneous resolution occurs, and a
modification of the PTH set up, unrelated with extracellular calcium levels, appears very often. In
any case, hypercalcemia can lead to alteration of almost the whole renal tubules, modifying the
glomerular filtration rate both in direct (vasoconstriction) and indirect (modification of filtration
coefficient) ways. Nephrological therapies can treat both acute and chronic hypercalcemia, and it
seems to be effective also in secondary hyperparathyroidism (HPT), but in other situations, such as
posttransplantation HPT, a surgical approach is often needed.