Overview
Adenine phosphoribosyltransferase (APRT) deficiency is an underrecognized, autosomal recessive disorder of adenine metabolism, leading to 2,8-dihydroxyadeninuria that causes nephrolithiasis and kidney failure in a significant proportion of untreated patients. The disorder has been found in all ethnic groups and 24 functionally significant APRT mutations have been reported to date. Of more than 300 cases of APRT deficiency reported world-wide, more than 200 came from Japan, a substantial number of patients from France and Iceland, and about 15 cases have been reported in the US (personal communication A. Sahota). The estimated prevalence of APRT deficiency 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 estimated point prevalence is 8.9/100,000. Possible explanations for the apparently low prevalence in countries other than Iceland and Japan, include lack of awareness of this disorder, inadequate evaluation of patients with kidney stones, and erroneous diagnosis of 2,8-dihydroxyadenine (2,8-DHA) stones as uric acid or xanthine stones as all three of these types of stones are radiolucent.
Although the majority of patients with APRT deficiency present with kidney stone disease there is tremendous variability in the clinical expression of APRT deficiency, ranging from an asymptomatic condition to life-threatening kidney failure. In patients who have developed end-stage kidney failure the diagnosis of APRT deficiency has generally not been made prior to commencement of renal replacement thereapy and there are several reports in the literature of recurrent 2,8-DHA-induced nephropathy following kidney transplantation. In our experience and that of other investigators, occasional patients complain of eye discomfort but it is not clear if these symptoms are related to 2,8-DHA crystal deposition in ocular tissues such as the cornea (personal communication A. Sahota, D. Milliner).
Signs and Symptoms
APRT deficiency should be considered in any patient presenting with renal colic, radiolucent urolithiasis and tubulointerstitial nephropathy of unknown cause, as well as in infants with a history of reddish-brown diaper stain
Diagnosis
In our experience, 2,8-DHA crystals should be readily detected by routine urine microscopy in almost all patients with xanthine dehydrogenase. Occasionally, the crystals may be hard to identify, possibly due to decreased crystal clearance in some patients with severely reduced kidney function. The small and medium sized crystals have a central Maltese cross pattern on polarized light microscopy whereas the large crystals do not as they are impermeable to light.
Diagnosis of nephrolithiasis requires radiologic imaging techniques that can detect radiolucent calculi such as ultrasound or computerized tomography. Analysis of 2,8-DHA crystals and stone material with infrared and ultraviolet spectrophotometry and/or x-ray crystallography easily differentiates 2,8-DHA from uric acid [2, 3]. In contrast, stone analysis employing biochemical methods, such as colorimetric reaction and thermogravimetric analysis, does not distinguish 2,8-DHA from uric acid and has resulted in the erroneous diagnosis of uric acid nephrolithiasis.
Analysis of the residual APRT activity in red cell extracts is useful for the diagnosis of APRT deficiency but is not widely available in clical laboratories. The correct diagnosis from enzyme assays in red cell lysates can, however, be masked by a recent blood transfusion. Genetic testing, identifying mutations in both copies of the APRT gene, confirms the diagnosis and is a practical approach in populations where the predominant mutations have been defined. Kidney biopsy is rarely necessary except in cases of unexplained renal insufficiency when 2,8-DHA crystals are not detected or identified in the urine (See Figure 2 below).
Treatments
The purine analog allopurinol, a potent inhibitor of xanthine dehydrogenase, has successfully been used for the treatment of APRT deficiency for the last 30 years. Allopurinol administered in the dose of 5-10 mg/kg/day (maximum suggested daily dose 600-800 mg), effectively prevents 2,8-DHA crystalluria and new stone formation and significantly improves kidney function in most patients with renal insuffiency. Allopurinol appears to effectively prevent recurrent 2,8-DHA-induced nephropathy in the transplanted kidney. Allopurinol is generally well tolerated although approximately 5% of patients experience adverse effects leading to the discontinuation of the drug. 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, eosinophila and multiorgan involvement, including interstitial nephritis and hepatitis. Intolerance of allopurinol poses a serious problem for patients with APRT deficiency and, thus, alternative drug therapies are needed. Oxypurinol, an active metabolite of allopurinol, is also an inhibitor of xanthine dehydrogenase which has proven to be safe for the treatment of hyperuricemia and gout in patients allergic to allopurinol but approximately 40% of patients who are allergic to allopurinol develop similar reactions to oxypurinol. Additional xanthine dehydrogenase inhibitors are currently under study in animal models and humans. Ample fluid intake, in the range of 2 to 2.5 L per day in adults and mild to moderate dietary purine restriction should be recommended to all patients with 2,8-dihydroxyadeninuria. Approximately 30% of patients with 2,8-DHA kidney stones require intervention for stone removal which is similar to patients with other types of kidney stone disease. Extracorporeal shock-wave lithotripsy, lithotomy and endourological procedures are all effective for the treatment of acute stone episodes in patients with 2,8-DHA stones.