*3.2.1.1. Thiazide‐type diuretics*

Thiazide‐type diuretics are especially indicated for normokalemic idiopathic hypercalciuria, which may be either absorptive or renal. Absorptive hypercalciuria may develop as three types: type 1, with direct absorption of calcium through the gastrointestinal system; type 2, with absorption of calcium associated with 1.25 dihydroxyvitamin D; or type 3, with renal calcium and phosphate absorption [54, 55]. Resorptive hypercalciuria is caused by primary hyperparathyroidism and develops with increased bone demineralization [54].

Thiazide‐type diuretics act on the distal tubules, in which 10% of the sodium chloride is reab‐ sorbed by a thiazide‐sensitive Na+/Cl carrier [56]. Salt restriction during the use of thiazide‐ type diuretics decreases its effectiveness. The side effects of using thiazides have been reported as hypokalemia, hyperglycemia, hypercalcemia, and renal injury [57, 58]. Hypokalemia occurs with high doses [56]. Hyperglycemia may develop when thiazides are used for hypertension, but it has not been observed when they are used for hypercalciuria indications [59]. There is little evidence of renal injury with prolonged use of low or medium doses [56]. Children who develop hypercalcemia during therapy must be examined for underlying, overlooked hyperparathyroidism [58]. The initial dose of hydrochlorothiazide is 1 mg/kg. High doses are associated with side effects [60]. Starting with a dose of 0.5 mg/kg and then titrating based on urine calcium levels enables both effective treatment and avoidance of side effects [61]. However, in cases where high doses of hydrochlorothiazide are necessary, including Dent disease, close follow‐up for complications is required [60].

In the presence of calcium‐phosphate stones, the possibility of hyperparathyroidism and RTA should be investigated [7]. In cases of high calcium and phosphate levels, it may have brushite‐type crystallization in a narrow pH range (6.5–6.8) [7]. Carbonate apatite is crystal‐ ized at pH 6.8 or higher and may present with infection stones or calcium‐oxalate stones [7]. Hydrochlorothiazide is also effective on brushite stones [7]. However, patients with these require urine acidification rather than urine alkalization. Cranberry juice may be recom‐ mended for pediatric patients, because L‐methionine cannot be used for them [6, 7].

In idiopathic hypercalciuria, decreased bone density may affect future bone health [62]. Thiazide‐derived diuretics support bone density, even in patients with restricted calcium [63]. Studies have suggested that hydrochlorothiazide is beneficial to bone density in children with hypercalciuria, but this effect has been reported as limited in older children who are devel‐ oping osteopenia [64, 65]. Controlled studies with larger populations are needed, but early hydrochlorothiazide treatment appears to be favorable for bone growth.

#### *3.2.2. Hyperoxaluria*

#### *3.2.2.1. Pyridoxine*

Pyridoxine is used for primary hyperoxaluria (PH) type 1. PH has three types: type 1, a defi‐ ciency of alanine glyoxylate aminotransferase; type 2, a deficiency of D‐glycerate dehydroge‐ nase; and type 3, a deficiency of 4‐hydroxy 2‐oxoglutarate aldolase [66].

In PH, due to the enzyme deficiency, glyoxylate cannot be converted into glycine in cofactors of pyridoxine (vitamin B6). Therefore, excessive oxalate is produced by the lactate dehydro‐ genase enzyme in the liver. Type 1 is the severest form, and accounts for 80% of PH cases [67]. Children with PH type 1 may develop nephrocalcinosis and end‐stage renal failure in addition to calcium‐oxalate stones. In contrast, in PH type 3, no end‐stage renal failure has been reported [68]. If PH is suspected in pediatric patients, it may be diagnosed using urinary oxalate values that have been corrected for body area. In children with PH, the normal oxalate level in 24‐hour urine is 0.45 mmol/1.73 m2 /24‐hour, and it is usually higher than 1 mmol/1.73 m<sup>2</sup> /24‐hour. If the oxalate level in 24‐hour urine is higher than 0.7 mmol/1.73 m2 /24‐hour in repeated tests, genetic examination should be performed after excluding causes for secondary hyperoxaluria. If it is not possible to diagnose with genetic examination despite high suspi‐ cion, enzyme activity should be analyzed in a liver biopsy [69]. In patients diagnosed with PH type 1, pyridoxine therapy should be prescribed in addition to hydration and citrate therapy. In type 1 PH, pyridoxine therapy is effective in 50% of patients and decreases the urinary‐ oxalate level by more than 30% [70]. New studies suggesting multiple effects of pyridoxine indicate promising ways to treat patients who have not benefited from existing treatments [71]. The initial pyridoxine dose is 5 mg/kg, and depending on the response, it can be titrated to 20 mg/kg. Although rare, sensorial neuropathy may develop with high doses [72].

Hyperoxaluria may also develop due to causes that include inflammatory bowel disease, short‐bowel syndrome, ethylene‐glycol intoxication, and excessive intake of vitamin C. In patients with secondary hyperoxaluria, dietary oxalate and salt restrictions and alkalization therapy should be begun, and in resistant patients, pyridoxine therapy should be used [6]. The initial dose of pyridoxine may be 2–5 mg/kg/day, and it can be titrated to 8–10 mg/kg/day.
