LAUSR

A 64-year-old female was referred to our hospital for evaluation of progressive kidney dysfunction with no other associated complaints. No one in her family had a history of kidney stones or kidney disease. Her medical history included treatment for hypertension, beginning while she was in her 40 s. Staghorn calculi were detected in the right renal pelvis when she was 46 years of age, and were removed by extracorporeal shock wave lithotripsy and retrograde intrarenal surgery. At that time, atrophy of the right kidney was noted. At age 60 years, her blood pressure increased to ~ 160/100 mmHg and new onset proteinuria was detected; treatment with amlodipine was initiated. At that time, urinary protein was 3.0 g/gCr and serum creatinine was 0.9 mg/dL; irbesartan, cilnidipine, and dipyridamole were added to her medication regimen and a low salt diet was recommended. While these therapies were effective for the treatment of hypertension and proteinuria, serum creatinine levels continued to increase. No abnormal physical findings were reported. Her urinalysis was notable for a large number of yellow to yellow–brown circular crystals (Fig. 1a–c). Urine protein was 0.45 g/gCr with no hematuria. Other laboratory values included serum creatinine at 1.55 mg/dL and estimated glomerular filtration rate (eGFR) at 26.9 mL/min/1.73 m2. Blood cell counts, electrolytes, and immunological tests were all within normal limits. An abdominal computed tomography (CT) image revealed significant atrophy of the right kidney; stones were detected in the renal pelvis. A 99mTc-DTPA scan confirmed that the right kidney was non-functional. After admission, her kidney function continued to deteriorate, to a serum creatinine of 1.93 mg/dL and eGFR of 21.2 mL/min/1.73 m2. The description of the yellow–brown axle-shaped, circular precipitates was consistent with a tentative identification of 2,8-DHA crystals. This identification was confirmed by chemical testing that included resistance to solubilization in response to heat (60 °C), acetic acid, or physiologic saline containing 0.4% tri-potassium ethylenediaminetetraacetate dihydrate (EDTA3K). Gene analysis revealed that she was a compound heterozygote with an unreported adenine phosphorolysyltransferase (APRT) gene mutation [c.407 T > C p.(Met136Thr), c.361C > T p.(Gln121 *)]. To confirm that these mutations were in located different alleles, long-range PCR of the entire APRT gene, spanning both mutations, were performed and cloned into plasmid vector. Sequencing revealed two types of clones, each having a different mutation, and compound heterozygosity was confirmed. In addition, GC/MS-based urine metabolomics was used to measure 2,8-dihydroxyadenine, 8-hydroxyadenine, and adenine. The z-scores were calculated by logarithmic transformation of the deviations between the measured values in this case and those in the healthy group. The z-scores of 2,8-dihydroxyadenine, 8-hydroxyadenine, and adenine were + 9.2SD, + 7.5SD, and + 9.6SD, respectively, indicating a decrease in the enzymatic activity of APRT. Upon treatment with febuxostat, almost no crystals were detected in the urine and renal function improved, with a * Keita Yamazaki [email protected]