The estimated prevalence is 0.5 to 1 per 100,000 in the Caucasian population, 0.25 to 0.5 per 100,000 in the Japanese population and in Iceland the prevalence is 8.9 per 100,000. Possible explanations for the low prevalence in other countries include lack of awareness of the disorder, inadequate evaluation of patients with chronic kidney disease (CKD) and kidney stones, and misdiagnosis of 2,8-dihydroxyadenine (2,8-DHA) stones as uric acid or xanthine stones (they are all radiolucent).

Kidney stones are by far the most common clinical manifestation of APRT deficiency in all patients, while CKD is the second most common reported manifestation in adults. Acute kidney injury due to bilateral 2,8-DHA calculi and urinary tract obstruction is a well-recognised presentation in children. APRT deficiency is not known to affect organs other than the kidney; however, investigators have encountered occasional individuals with APRT deficiency complaining of eye discomfort.

APRT deficiency may present at any age; there is no typical age of onset. In a registry that includes individuals identified through family screening the disease presented or was established in almost half the patients by age 18 (Edvardsson et al, 2013). Many children are asymptomatic and in at least half of all instances the diagnosis of APRT deficiency is not made until adulthood.

The majority of symptomatic individuals with APRT deficiency experience recurrent 2,8-DHA kidney stones, abdominal pain and/or urinary tract infections. They may also develop CKD secondary to 2,8-DHA crystalline nephropathy. 2,8-DHA crystals are located throughout the kidney, in tubular lumina, inside renal epithelial cells and in the interstitium. Studies have shown that 15% of individuals had progressed to end-stage renal disease (ESRD) at the time of diagnosis of APRT deficiency. There is some evidence that APRT deficiency may be a seriously under-recognised cause of CKD that progresses to ESRD in a significant proportion of untreated patients. In some individuals the diagnosis has not been made until after kidney transplantation (Nasr et al, 2010).

APRT deficiency is most often suspected by the detection of 2,8-DHA crystals on routine urine microscopy or stone analysis, or through the screening of siblings of affected individuals. Exact diagnosis requires testing of APRT enzyme activity. When recognised early, the deleterious consequences of APRT deficiency and 2,8-dihydroxyadeninuria may be prevented with effective pharmacologic therapy.

It is recommended that siblings of an affected individual undergo APRT enzyme activity measurement or genetic testing (if available and if the disease-causing mutations in a family have been identified) to allow early diagnosis. Counselling should be provided to patients and their families. The disease is inherited in an autosomal recessive manner so each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being normal.

Diagnostic Clues

• Renal colic
• Radiolucent kidney stones (based on imaging techniques capable of detecting radiolucent stones, e.g. ultrasound or computed tomography (CT); they are not seen on plain abdominal x-ray)
• CKD of unknown cause, especially if with stones
• Crystal nephropathy on renal biopsy (2,8-DHA crystals are positively birefringent on polarized light microscopy)
• Infants with a history of reddish-brown nappy staining (this is a frequent manifestation of 2,8-DHA crystalluria in infants).

Establishing the Diagnosis

• Urine microscopy often (but not always) reveals characteristic round, brown 2,8-DHA crystals. Small and medium sized crystals display a central Maltese cross pattern when viewed by polarized light microscopy. See Figure One below.

Figure One: Crystals of 2,8-dihydroxyadenine (DHA) in a urine sample under a light microscope in normal light and in polarised light.

• Kidney stone analysis can easily differentiate 2,8-DHA from uric acid and xanthine, which also form radiolucent stones. Although stones in persons with APRT deficiency are predominantly composed of 2,8-DHA, they may contain trace amounts of uric acid.
• APRT enzyme activity measured in red cell lysates (or other cell extracts) is completely absent in almost all individuals with APRT deficiency.
• Renal histopathology examination can reveal diffuse 2,8-DHA crystalline deposits and tubulointerstitial abnormalities, even in the absence of a history of kidney stones.
• Genetic testing for mutations known to cause APRT deficiency. The diagnosis is confirmed in individuals with functionally significant biallelic mutations. However, genetic testing is not required for diagnosis except in ambiguous cases. Testing for enzyme activity is the preferred diagnostic test.

Enzyme activity analysis For enzyme activity analysis, send 4 mL blood in an EDTA (purple top) tube to: Dr Lynette Fairbanks / Dr Tony Marinaki Purine Research Laboratory, Biochemical Sciences, GSTS 4th Floor, North Wing St Thomas’ Hospital Lambeth Palace Road London SE1 7EH Tel. No. 0207 188 1266 / 0207 188 1265 Fax No. 0207 188 1280 Normal APRT enzyme reference range: 16 – 32 nmol/h/mgHb

Genetic analysis

The UK Genetic Testing Network does not currently have any member laboratories listed as providing testing for APRT deficiency, and therefore this test is not routinely available via the NHS. As stated above however, this is not usually essential in confirming a diagnosis, but would be pursued if there were any diagnostic doubt in an individual case.

Genetic testing is available on a non-NHS and research basis in Iceland. For this, blood (10 ml in an EDTA tube) and urine samples (50 ml plain universal container) should be sent to:

Landspitali – The National University Hospital of Iceland Department of Laboratory Hematology Attn: S. Oddsdottir & T. Runolfsdottir K-Building, Second Floor Hringbraut 101 Reykjavik Iceland

Treatment with the xanthine dehydrogenase (XDH) inhibitor allopurinol is effective and generally well-tolerated in individuals with APRT deficiency and has been used for the last 30 years. The recommended dose of allopurinol is 300-600 mg or 5-10 mg/kg/day, either once daily or in two divided doses. In treated adults these doses can be moderated, and doses also need to be reduced if the patient has CKD. This regime has been shown to minimise 2,8-DHA crystalluria, stone formation, crystal deposition in the kidney, and the development of kidney failure (Edvardsson et al 2001; Bollee et al 2010).

Treatment with allopurinol can even dissolve 2,8-DHA kidney stones and improve kidney function in individuals with advanced CKD as well as preventing recurrent 2,8-DHA-induced nephropathy in transplanted kidneys (Edvardsson et al 2001; Eller et al 2004; Bollee et al 2010).

Allopurinol treatment and dosing is monitored by clinical evaluation and urine microscopy with the absence of urinary 2,8-DHA crystals indicative of adequate therapy. Allopurinol is generally well tolerated although approximately 5% of patients experience adverse effects leading to the discontinuation of the drug (Wortmann 2005). In most cases these side effects are relatively mild and limited to gastrointestinal intolerance and skin rash. However, approximately 0.4% of patients develop allopurinol hypersensitivity syndrome which is characterized by fever, cutaneous manifestations, eosinophilia and multiorgan involvement, including interstitial nephritis and hepatitis (Takano et al 2005; Gutierrez-Macias et al 2005).

Another XDH inhibitor, febuxostat, may be an alternative treatment option for affected individuals who are allergic to or intolerant of allopurinol (Becker et al 2005). No data have been published on the use of febuxostat in individuals with APRT deficiency. However, using a daily febuxostat dose of 80 mg the authors observed a significant reduction in 2,8-DHA crystalluria in one adult with APRT deficiency who is allergic to allopurinol (unpublished observation).

Ample fluid intake, in the range of 2 to 2.5 L per day in adults should be recommended to all patients with 2,8-dihydroxyadeninuria. In addition patients should adhere to a low purine diet (Bollee et al 2012), which consists of moderating dietary protein sources especially shellfish, beer and red meats.

Poster presented at UK Kidney Week, 2017 – APRT Deficiency – A Rare disease that should not be forgotten in renal failure of unknown cause, Lowe, M. & Lipkin, G.

Abstract presented at Renal Association Meeting, 2014 – Adenine Phosphoribosyltransferase Deficiency: Two Novel Genetic Mutations and United Kingdom Experience, Balasubramaniam, G. et al.

Thorsteinsdottir M et al (2016). Quantitative UPLC–MS/MS assay of urinary 2,8-dihydroxyadenine for diagnosis and management of adenine phosphoribosyltransferase deficiency. Journal of Chromatography B, Volumes 1036–1037, pages 170–177.

The Rare Kidney Stone Consortium APRT Deficiency Support Network APRT Deficiency on OrphaNet