*3.2.3.1. Allopurinol*

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

58 Updates and Advances in Nephrolithiasis - Pathophysiology, Genetics, and Treatment Modalities

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‐

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

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‐

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

/24‐hour. If the oxalate level in 24‐hour urine is higher than 0.7 mmol/1.73 m2

/24‐hour, and it is usually higher than 1 mmol/1.73

/24‐hour in

mended for pediatric patients, because L‐methionine cannot be used for them [6, 7].

hydrochlorothiazide treatment appears to be favorable for bone growth.

nase; and type 3, a deficiency of 4‐hydroxy 2‐oxoglutarate aldolase [66].

level in 24‐hour urine is 0.45 mmol/1.73 m2

*3.2.2. Hyperoxaluria*

*3.2.2.1. Pyridoxine*

m<sup>2</sup>

disease, close follow‐up for complications is required [60].

Hyperuricosuria occurs when uric acid is higher than 10 mg/kg in 24‐hour urine [6]. Urinary excretion of uric acid is high in infants [26]. In acidic urine, solubility of uric acid is decreased. This is more apparent when pH is lower than 5.8 [6]. Hyperuricosuria not only causes uric‐ acid stones but also plays a role in forming calcium‐oxalate stones through epistaxis [31]. If hydration and alkalization fail, allopurinol could be begun, particularly in children who have hyperuricosuria with hyperuricemia. Allopurinol inhibits the xanthine dehydrogenase enzyme, thereby decreasing the concentration of uric acid and increasing the concentration of xanthine in the urine [26]. The pediatric dose is 10 mg/kg [6]. Skin rashes may be seen, and very rarely, allopurinol hypersensitivity syndrome (AHS) may develop [73]. AHS is a fatal side effect that also includes a rash (Stevens‐Johnson syndrome, toxic epidermal necrosis), eosinophilia, leukocytosis, hepatitis, fever, and renal failure [73]. This fatal complication has no specific treatment other than termination of treatment and support therapy [73]. Therefore, it is very important to educate patients and families about symptoms and to make an early diagnosis. To prevent such complications, it may be useful to begin with a low dose and increase it [73].

Hypoxanthine guanine phosphoribosyl transferase (HPRT) is a purine metabolism enzyme. HPRT deficiency, the severest form of which is Lesch‐Nyhan syndrome, may occur with neu‐ rologic symptoms, mental retardation, and nephropathy, and in the early stages of life, kid‐ ney stones [74]. Deficiency of glucose‐6‐phosphate dehydrogenase leads to hyperuricemia, increasing the intracellular phosphoribosyl pyrophosphate in type 1 [75]. In both of these metabolic diseases, allopurinol therapy is indicated for hyperuricemia and hyperuricosuria. In addition to metabolic diseases, myeloproliferative diseases may also cause hyperuricos‐ uria, and in children with hyperuricosuria who develop new stones and for whom hydration and alkalization are insufficient, allopurinol may be begun at 10 mg/kg [6].

Furthermore, deficiency of adenosine phosphoribosyl transferase (APRT), a purine metabo‐ lism enzyme, converts adenine into 8‐hydroxyadenine and xanthine dehydrogenase enzyme into 2,8‐dihydroxyadenine (DHA) [76]. Transfer of DHA into the urine is high, and its solubil‐ ity is low, even in alkaline urine, so DHA stones form. Alkalization therapy is not useful in such cases, and therapy must consist of 5–10 mg/kg of allopurinol and sufficient hydration [77].

Xanthinuria has two types: type 1 develops with a deficiency of xanthine dehydrogenase enzyme and type 2 develops with a deficiency of aldehyde oxidase enzyme [78]. These two types are differentiated using an allopurinol test [78]. In addition, xanthinuria may develop after Lesh‐Nyhan syndrome is treated using allopurinol [79]. Xanthinuria has no specific treat‐ ment but responds well to hydration, urine alkalization, and reduction of dietary purine [80].
