Renal stone and chronic kidney failure associated with hypouricemia: Answers

  • Gulsah Kaya AksoyEmail author
  • Mustafa Koyun
  • Kimiyoshi Ichida
  • Elif Comak
  • Sema Akman
Clinical Quiz


Renal transplantation Hereditary xanthinuria Intronic mutation 


  1. 1.

    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.

  2. 2.

    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].

  3. 3.

    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.



Xanthine urolithiasis is an infrequent type of renal stone formation caused by xanthinuria, a rare hereditary disorder. An affected patient presented with hypouricemia, hypouricosuria, and recurrent urolithiasis [9]. The most common symptoms are urinary tract infections, hematuria, and renal colic; but rarely, patients can also refer to acute renal failure, arthropathy, myopathy, or duodenal ulcer [10]. These patients usually presented as case reports in the literature [4, 11, 12]. Acute renal failure is usually caused by bilateral stone-induced obstruction [10].

HX type 1 and type 2 have similar clinical features and can be differentiated by laboratory tests or by genetic analysis. When allopurinol is given to the patient, it is metabolized to oxipurinol by aldehyde oxidase enzyme (allopurinol loading test). In type I, the level of oxipurinol is detectable in blood, but not in type II [9]. In our clinic, we could not evaluate the level of oxipurinol, so allopurinol loading test could not be performed. Secondly, xanthinuria is typed using urinary metabolomics: N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-5-carboxamide (4PY) are the final products excreted in urine in the nicotinamide catabolism produced by aldehyde oxidase. 2PY and 4PY are normal in the urine of patients with HX type 1 [6]. The 2PY level of our patient was determined to be detectable and HX type 1 was diagnosed with this finding. Lastly, HX diagnosis is confirmed by genetic analysis.

Type I xanthinuria is caused by a mutation in xanthine dehydrogenase/oxidase gene mapped to chromosome 2p23.1, whereas type II is caused by deficits of xanthine dehydrogenase/oxidase and aldehyde oxidase caused by mutations in molybdenum cofactor sulfurase gene localized on chromosome 18q12.2 [8, 13]. Seventeen different mutations have been identified in the literature so far, including the xanthinuria type 1 gene [14]. Our patient’s mutation has not been reported previously, and 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.

In this disease without a curative treatment option, patients usually progress to end-stage renal failure secondary to recurrent stone and urinary tract infections. As far as we know, this is the first case with hereditary xanthinuria, who underwent successful renal transplantation. In the post-transplant period, the patient is followed with intensive hydration and purine-restricted diet. In the 4.6-year follow-up period of the patient whose serum uric acid level was low, there was no deterioration in graft function and urolithiasis.


Although it is rarely seen, low serum uric acid level should not be overlooked. Hereditary xanthinuria is a rare disease requiring early diagnosis and regular follow-up. Despite all supportive treatments, xanthinuria can be followed by end-stage renal failure. Renal transplantation seems to be a good treatment option in patients with hereditary xanthinuria who progressed to end-stage renal disease.


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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© IPNA 2018

Authors and Affiliations

  • Gulsah Kaya Aksoy
    • 1
    Email author
  • Mustafa Koyun
    • 1
  • Kimiyoshi Ichida
    • 2
  • Elif Comak
    • 1
  • Sema Akman
    • 1
  1. 1.Department of Pediatric Nephrology, School of MedicineAkdeniz UniversityAntalyaTurkey
  2. 2.Department of PathophysiologyTokyo University of Pharmacy and Life SciencesHachiojiJapan

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