| Abstract|| |
The incidence of urolithiasis in children has shown an increase in recent years which may be attributed to changing dietary patterns, sedentary lifestyles, and obesity. Among the various etiologies for renal stones in children, two rare entities worth mentioning are cystinuria and 2, 8-dihydroxyadenine (DHA) urolithiasis. Cystinuria is an inherited cause of nephrolithiasis which occurs due to impaired cystine reabsorption in the renal proximal tubule. 2, 8-DHA urolithiasis is an inherited autosomal recessive disease resulting in urinary stone disease secondary to deficiency of adenine phosphoribosyltransferase (APRT) activity. We describe two children who presented to our clinic with these two rare causes of stones.
|How to cite this article:|
Kumar G, AlAni RR. Renal stones in two children with two rare etiologies. Saudi J Kidney Dis Transpl 2018;29:1203-6
| Introduction|| |
The incidence of urolithiasis in children has shown an increase in recent years attributable to changing dietary patterns, sedentary lifestyles, and obesity. Cystinuria is an inherited cause of nephrolithiasis which occurs due to impaired cystine reabsorption in the renal proximal tubule.
2, 8-dihydroxyadenine (DHA) urolithiasis is an inherited autosomal recessive disease resulting in urinary stone disease secondary to deficiency of adenine phosphoribosyltransferase (APRT) activity.
We describe our experience of two children who presented to our clinic with these two rare causes of stones.
| Case Reports|| |
A 3-year-old male child who presented at the age of two years with urinary tract infection and was found to be passing gravel in the urine. Clinical examination was unremarkable. Renal ultrasound showed a small right kidney and mild compensatory enlargement of the left kidney with multiple calculi in the left kidney, with mild hydronephrosis. A single calculus in the right kidney was seen without significant hydronephrosis. Renal function was normal with cystatin C estimated glomerular filtration rate: 114.5 mL/min/1.73 m2. He underwent extracorporeal shock wave lithotripsy and left double J stent insertion. Stone analysis showed that the stone was composed of DHA. He was started on allopurinol and citrate. The passage of gravel was reduced. The most recent ultrasound done around a year later showed multiple echogenic foci, some of them with posterior acoustic shadowing in keeping with stones identified in the right kidney which appeared of small size measuring 5.1 cm in length. The left kidney was large measuring 8 cm in length and appeared sonographically normal with no evidence of pelvicalyceal dilatation or renal stones identified (expected renal sizes at 3 years of age 71 ± 4.5 mean ± standard deviation).
A 2.5-year-old female child born to consanguineous parents presented at the age of 17 months with urinary tract infection and subsequently developed recurrent episodes of urinary infections. Clinical examination was normal. Renal ultrasound showed multiple bilateral renal stones, the largest was in the right kidney measuring 1.42 cm. The largest stone in the left kidney measured 0.88 cm.
Hydronephrosis of the right kidney was noted with right kidney measuring 10.35 cm in length and 1.32 cm parenchymal thickness. The left kidney appeared small in size measuring 6.07 cm in length and 0.88 cm parenchymal thickness with no hydronephrosis. MAG3 scan showed the poor function of left kidney (uptake in the left kidney 16.9% and in the right kidney 83.1%).
Quantitative urine amino acid analysis using automated high-pressure liquid chromatography analyzers showed high levels of cystine (127 μmol/mmol creatinine, normal <50), ornithine (41 μmol/mmol creatinine, normal <30), and arginine (52 μmol/mmol creatinine, normal <30). Stepwise analysis of SLC3A1, SLC7A9 sequencing and then deletion and duplication testing revealed homozygous variant in SLC7A9 gene, c.1166C>T (p.Thr389Met). This variant has previously been described as pathogenic for cystinuria.,
Hence, a genetic diagnosis of cystinuria was established. It was planned to started him on tiopronin. However, as this drug was not available, she was continued on citrate supplements only.
She required double J stent insertion on the right side and her most recent ultrasound showed normal right kidney and small scarred left kidney with no evidence of stone in the distal right ureter.
Laboratories results done for the children are shown in [Table 1].
| Discussion|| |
The incidence of nephrolithiasis among children is on rise with a mean annual incidence ranging from 36 to 57/100,000 children in US population-based observational studies.
Infants may present with nonspecific symptoms such as irritability, while older age group may present with flank pain, gross hematuria, nausea, and vomiting. Imaging modalities such as ultrasound and computed tomography scan and stone analysis aid in the diagnosis.
Some stones have an underlying genetic abnormality, and hence genetic studies play an important role in the diagnosis of these rare causes of nephrolithiasis.
Cystinuria is an autosomal recessive disorder caused by mutations in either the SLC3A1 or the SLC7A9 genes. This results in abnormal amino acid transport in the proximal tubule. Urinary findings include excessive excretion of cystine and dibasic amino acids, i.e., lysine, ornithine, and arginine. Normal individuals excrete <50–60 mg of cystine/day/1.73 m2 of body surface area while the losses may exceed 400 mg/day/1.73 m2 of body surface area in patients with cystinuria.
Cystinuria has wide genetic heterogeneity with a poor genotype/phenotype correlation as reported by Obaid et al. Markazi et al, described seven unrelated patients with cystinuria and identified a novel nucleotide substitution c.-29A>G in exon 1 of the SLC3A1 gene. Mutation similar to our index child (case 2) were reported by Wong et al, among 74 patients in a specialist cystinuria clinic in the UK.
Treatment strategies included dietary modifications, alkalinization of the urine, use of dpenicillamine, and use of α-mercaptopropionylglycine (tiopronin):
- Cystine is formed as a dimer of cysteine. Thiol agents reduce the disulfide bond that bridges the two molecules of cysteine and thiol group combines with cysteine to form a more soluble cysteine-drug product combination, which can be excreted.
APRT deficiency is a rare metabolic disorder leading to renal stones. APRT is an enzyme which catalyzes the formation of adenine monophosphate from adenine. In the absence of APRT, adenine is metabolized by xanthine oxidase to 2, 8-dihydroxyadenine which is insoluble in the urine is excreted by the kidneys resulting in 2, 8-dihydroxyadenine crystalluria and urolithiasis. APRT deficiency remains under-diagnosed given the estimated prevalence of 1/50,000–1/100,000.
Sreejith et al reported a three-year-old child with 2, 8-dihydroxyadenine urolithiasis and acute renal failure similar to our case. Mutation analysis was not done in our child. Marra et al, reported an infant affected by APRT deficiency diagnosed at 18 months of age with a de novo mutation. Nozue et al, described a two-year-old Japanese boy presenting with recurrent urinary infections and radiolucent urolithiasis who had 2,8-dihydroxyadenine stones and genetic analysis revealed compound heterozygous state for M136T and a novel missense mutation L33P.
Treatment strategies include high fluid intake and allopurinol (10 mg/kg/day to be given).
The clinical importance of diagnosing the rare entity is important as exemplified by a recent case of a 41-year-old female patient who had a late diagnosis of 2,8-dihydroxy-adenine nephropathy-induced end-stage renal disease, made on the native nephrectomy that accompanied the renal transplant, and who received timely intervention which prevented recurrence in the graft. It is extremely important for a clinician to be aware of these rare underdiagnosed causes of renal stones which are potentially treatable.
Adenine phosphoribosyltransferase deficiency should be suspected in patients with radiolucent kidney stones. The differential diagnosis of uric acid stones (radiolucent) may be excluded by stone analysis and further by genetic testing. A comprehensive metabolic evaluation can aid in reaching the etiological diagnosis and appropriate management of these treatable rare stone conditions.
Conflict of interest: None declared.
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Dr. Gurinder Kumar
Department of Pediatric Nephrology, Sheikh Khalifa Medical City, Abu Dhabi