| Abstract|| |
Adenine phosphoribosyltransferase deficiency is a rare, inherited autosomal recessive disease presenting with 2,8-dihydroxyadenine (DHA) urolithiasis, DHA nephropathy, and chronic kidney disease. The presence of DHA crystals in urine and renal biopsy is pathognomonic of the disease. We report a 23-year-old female with acute renal failure and nephrotic proteinuria. Urinalysis showed reddish brown, round crystals with dark outline, and central spicules consistent with 2,8-DHA crystals. Renal biopsy showed membranous nephropathy and 2,8-DHA nephropathy. Our patient improved with liberal fluid intake, restriction of high adenine content foods, and oral xanthine dehydrogenase inhibitor febuxostat. Early diagnosis and initiation of treatment prevent renal complications.
|How to cite this article:|
Gopalakrishnan N, Rajasekar D, Dhanapriya J, Dineshkumar T, Sakthirajan R, Balasubramaniyan T, Murugesan V. Unusual cause of crystalline nephropathy. Saudi J Kidney Dis Transpl 2018;29:462-5
|How to cite this URL:|
Gopalakrishnan N, Rajasekar D, Dhanapriya J, Dineshkumar T, Sakthirajan R, Balasubramaniyan T, Murugesan V. Unusual cause of crystalline nephropathy. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2020 Jun 6];29:462-5. Available from: http://www.sjkdt.org/text.asp?2018/29/2/462/229280
| Introduction|| |
The 2,8-dihydroxyadenine (DHA) urolithiasis is a rare cause of urinary stone disease secondary to deficiency of adenine phosphoribosyl transferase (APRT) enzyme activity and under- recognized cause of chronic kidney disease (CKD). The prevalence is more in Japanese than other races. On computed tomography imaging, the stone was low density and had an unusual linear central lucency. Although this is an inherited disease, 60%–75% of the cases occur in adults. We describe here a female patient with 2,8-DHA nephropathy and deficient APRT activity in erythrocyte lysates.
| Case Report|| |
A 23-year-old female was admitted with anasarca and oliguria of one-week duration. She was treated for primary infertility with native medications. Her blood pressure was 120/80 mm Hg. Laboratory tests showed urinalysis: 4+ proteinuria; blood hemoglobin: 7.8 g/dL; total count: 7900 cells/L; platelet count: 240,000/mm3; blood urea: 66 mg/dL; serum creatinine: 3.3 mg/dL; and serum complements: normal. Peripheral smear showed microcytic and hypochromic anemia. Serum ANA, dsDNA, and viral markers were negative. Renal biopsy revealed early spike formation over the glomerular basement membrane without endocapillary proliferation. Reddish brown round crystals seen within tubules (which were radially arranged) and interstitium [Figure 1a]. These crystals were birefringent under polarized light [Figure 1b]. Immunofluorescence showed IgG (+3) and C3 (+1) positivity over the capillary walls. The diagnosis of membranous nephropathy with 2,8-DHA crystals (crystalline nephropathy) was made.
|Figure 1a: Renal biopsy showing reddish brown round crystal in the tubules (H and E).|
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Repeat urine microscopy revealed reddish brown round crystals with dark outline and central spicules which is characteristic of 2,8- DHA crystals in urine [Figure 2]. Diagnosis of APRT deficiency was made as 2,8-DHA crystals are pathognomonic of APRT deficiency. Spectrophotometer was used to measure APRT enzyme activity in red blood cell (RBC) lysates, and it was 5.4 μmol/min/mg of Hb (normal: 16–32 μmol/min/mg of Hb).
|Figure 2: Urine microscopy showing reddish brown round crystals with the radial arrangement, dark outline with central spicule.|
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The probable cause of membranous nephropathy could be native medication intake. Antibodies against MPLA2R and other tests for secondary causes of membranous nephro- pathy were negative. Patient was treated with tablet febuxostat 80 mg/day with increased water intake around 4–5 L/day. After one week of therapy, crystals decreased in urine and renal failure recovered. Membranous nephropathy was managed with angiotensin-converting enzyme inhibitors and supportive measures. On recent follow-up after eight months, her creatinine was 0.9 mg/dL and urine protein creatinine ratio was 1.1 g/day. 2,8-DHA crystals disappeared in urine after initiation of febuxostat therapy. Patient advised to continue febuxostat 80 mg/day for lifelong.
| Discussion|| |
APRT deficiency is a rare inborn error of salvage pathway of purine metabolism as shown in [Figure 3]. In the presence of APRT deficiency, adenine accumulated and oxidized to 2,8-DHA by xanthine dehydrogenase (XDH). 2, 8, -DHA is excreted mainly through kidneys by filtration and tubular secretion which is extremely insoluble in urine at any pH and forms crystals. The crystals can aggregate in collecting system and/or precipitate into tubular lumens, epithelial cells, and in the interstitium causing crystalline nephropathy.
APRT deficiency case was first reported from the UK in 1974. The estimated prevalence among Caucasians, Japanese, and Iceland is 0.5-1, 0.25, and 8.9/100,000, respectively. In a case series of 67 patients, 40% diagnosed at <16 years of age. Most common clinical presentation is urolithiasis with or without obstruction followed by crystal nephropathy. Around 15% of individuals are asymptomatic. In infants, reddish brown diaper may be the manifestation due to crystals. Allograft dysfunction can happen within few weeks if APRT deficiency was not treated before and after transplantation.
The APRT gene located on 16q24 is 2.6 kb long with five exons. Two types of APRT deficiency are described. Type I (complete deficiency in vivo and in vitro) is most common type and predominantly affects Caucasians. Type II (complete in vivo but 10%–25% activity in vitro) has been described exclusively in the Japanese. Around 40 different mutations reported include missense, nonsense, insertion, deletion, and splicing in over 300 affected individuals.
Diagnosis of APRT deficiency can be done by identifying 2,8-DHA crystal in urine and/or stone which is pathognomonic of this disease. Diagnosis can be confirmed by measurement of APRT activity in erythrocyte lysates or by molecular genetic testing. In CKD, patients’ crystals cannot be documented due to poor clearance of 2,8-DHA crystals. Stone analysis by stereomicroscope and infrared spectroscopy can confirm the 2,8-DHA crystals.
Renal biopsy demonstrates 2,8-DHA crystal within tubules, epithelial cells, and interstitium. Polarized microscopy or Fourier transform infrared microscopy can be used to examine the crystal in biopsy. APRT activity is measured in red cell lysates using radiolabeled 14C-adenine in a chromatographic assay and measures 16–32 μmol/min/mg in normal individuals. The enzyme activity is absent in all diseased and some APRT-II deficiency patients. Recent transfusion or heterozygotes may demonstrate normal level enzyme activity.
Genetic testing is useful as a confirmatory test but not mandatory. Screening should be done in children with radiolucent stones and recurrent stones with CKD or ESRD patients. Genetic counseling for family members is also important. Treatment with XDH inhibitors (allopurinol/febuxostat) blocks the formation of 2,8-DHA from adenine, thereby preventing the occurrence and progression of crystal nephropathy and stone formation. Patient should be advised to increase fluid intake and to avoid purine-rich foods. Early diagnosis of APRT deficiency and initiation of therapy is the key to prevention of renal failure.
| Acknowledgment|| |
We would like to thank Dr. Anila Abraham Kurien from Renopath, Chennai, for her help in evaluating renal biopsy and Dr. P. Kalaiselvi MSC, PhD, assistant professor, Dr. ALM PGIBMS, University of Madras, Chennai, for help in measuring RBC APRT enzyme activity.
Conflict of interest: None declared.
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Dr. Jeyachandran Dhanapriya
Institute of Nephrology, Rajiv Gandhi Government General Hospital, Madras Medical College Chennai - 600 003, Tamil Nadu
[Figure 1a], [Figure 1b], [Figure 2], [Figure 3]