Renal stone and chronic kidney failure associated with hypouricemia: Answers

The most striking finding in our patient was hypouricemia. Hypouricemia may be due to increased renal clearance or decreased formation of uric acid. The causes of increased uric acid excretion are renal hypouricemia or renal tubular diseases such as Fanconi syndrome, but isolated uricosuria is not expected. Primary hereditary renal hypouricemia is an autosomal recessive disorder of renal urate reabsorption, resulting in hypouricemia and uricosuria, with a fractional excretion of uric acid greater than 10% [1]. Renal hypouricemia is mainly caused by urate transporter mutations such as SLC22A12 and SLC2A9 [2]. Urinary excretion of uric acid in our patient was very low, which supports low uric acid production. Low uric acid production may be due to hereditary xanthinuria. In our patient, there was a detection of xanthine stone on stone analysis and a history of recurrent nephrolithiasis; we suspected hereditary xanthinuria.

Hereditary xanthinuria (HX) is a rare genetic disease caused by xanthine dehydrogenase/oxidase deficiency [3]. Hereditary xanthinuria has been classified into two subtypes. While xanthinuria type 1 is the isolated deficiency of xanthine dehydrogenase/oxidase, xanthinuria type 2 is defined as deficiencies of both the enzyme xanthine dehydrogenase/oxidase and aldehyde oxidase [4]. As a result of the deficiency of xanthine dehydrogenase/oxidase enzyme, which converts xanthine to uric acid in the last step of purine metabolism, the excretion of hypoxanthine and xanthine increases in urine. Xanthine has less solubility than uric acid and urinary system stones result from the renal accumulation of xanthine [4]. Our patient urine xanthine/creatinine ratio was 205.0 μmol/mmol (N < 30 μmol/mmol) [5]. Urinary concentrations of purine metabolite (N1-methyl-2-pyridone-5-carboxamide (2PY)) were used to distinguish between type 1 and type 2 HX. Water acuity system with PDA method was used to measure 2PY levels [6]. Our patients 2PY to urinary creatinine ratio was 25.6 μmol/mmol. Although the reference range of urine 2PY/ Cr ratio is not reported, it is known that 2PY is undetectable in the urine of patients with HX type II [6]. This finding suggests that our patient has HX type 1. The gene analysis of the patient and the mother showed homozygously c.306+1 G>A in xanthine dehydrogenase gene, while that of the father showed heterozygously. This mutation results in the loss of the consensus sequence, GT at the 5′end of the intron four, leading to abnormal splicing such as skipping of an exon. The mutation that has not been reported previously found in our patient suggests that this intronic change may be responsible for the disease, because the change in the intron caused loss of the intron, and it plays role in exon-intron junction [7, 8].

Although they are not curative, intensive hydration and purine-restricted diet may slow development of stones. Alkalinization of urine has not been proven to be effective [3]. Our case was diagnosed at 15 years of age when he had stage 4 chronic renal failure, but despite intensive hydration and purine-restricted diet, he progressed to end-stage renal failure at 17th month of his follow-up. Because he refused dialysis treatment, and his mother was a donor candidate, it was decided to perform renal transplantation. Despite hypouricemia, the mother did not have nephrolithiasis, and serum creatinine level was normal. At the time of transplantation, genetic analyses of the mother were not completed. With the discovery of this mutation which poses an additional risk for the mother, the frequency of outpatient visits for the mother was increased, and regularly, she has been examined with USG for the presence of nephrolithiasis. Until post-transplant 4.6th years, neither the patient nor his mother developed any unexpected complications or nephrolithiasis.