**2.1. Genetics of Conditions predisposing to medullary nephrocalcinosis**

Stone initiation and growth is prompted by the urine becoming supersaturated with a sol‐ ute of calcium, oxalate, uric acid, and cystine, which leads the dissolved salts to condense into solids, thus forming the stone. But urinary CaOx supersaturation is a common finding in normal individuals too, who develop no stones. This is most likely due to the presence of crystallization inhibitors such as citrate or pyrophosphate in their urine. In addition to the concentration of solutes, urinary pH is a crucially important factor influencing crystal solubility. Supersaturation and crystallization in the urine also rely on the presence of mac‐ romolecules capable of binding and forming complexes with Ca and Ox. Mammalian urine contains numerous macromolecules that inhibit crystal formation, growth, and aggregation in the kidney. Levels of supersaturation and crystallization are kept under control by the proper functioning of a variety of cells lining the renal tubules [12, 13].

Conditions predisposing to medullary nephrocalcinosis may be either those that raise the urinary concentration of inductors of calcium crystal deposition or those that lower the con‐ centration of the inhibitors of this process. The former category includes hypercalciuria, hyp‐ eroxaluria, the latter hypocitraturia and hypomagnesuria. Renal tubular acidosis (RTA), on the other hand, is responsible for changes in urinary pH, which has a fundamental role in favoring crystallization. In some cases, there may also be specific anatomical abnormalities that predispose to the onset of nephrocalcinosis, as in medullary sponge kidney (MSK).

Several genetic disorders have been found associated with conditions that predispose individu‐ als to the development and progression of nephrocalcinosis. Most of them are tubular disorders associated with epithelial cellular and paracellular ion transport disruptions that result in the urinary excretion of higher levels of calcium, phosphate or oxalate and lower levels of citrate and magnesium. **Table 1** shows the genetic basis for the link between some inherited disorders and medullary nephrocalcinosis [7]. **Figure 1** shows the list of intrarenal transport defects that prompt a dysfunctional renal handling of the two most important divalent cations Ca2+ and Mg2+ [14]. As can be noted, not all cation‐handling disorders are associated with nephrocalcinosis.

The kidney handles calcium, phosphate, and oxalate in the proximal tubules, in the thick ascending limb (TAL) of the loop of Henle, and in the distal convolute tubule (DCT), shown in **Figure 2** [6]. Knowing the site where the tubular exchanger and transporter proteins involved in regulating urinary calcium, phosphate, and oxalate work help us better understand the mechanisms underlying nephrocalcinosis.

Bearing in mind that 98% of interstitial crystal deposition occurs in the medulla around each pyramid, Sayer et al. proposed the model of nephrocalcinosis shown in **Figure 3**.

We focus our attention on the genetic defects that alter the kidney's homeostatic capacity.
