Early Recognition and Management of Rare Kidney Stone Disorders

Ross Goldstein, MD, MBA; David S. Goldfarb, MD


Urol Nurs. 2017;37(2):81-89. 

In This Article

Adenine Phosphoribosyltransferase Deficiency

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder of adenine metabolism. APRT catalyzes the synthesis of 5-adenosine monophosphate from adenine and 5-phosphoribosyl-1-pyrophosphate, the only metabolic pathway for adenine in humans. Absence or impairment of APRT, therefore, results in conversion of the 8-hydroxyadenine intermediate to the highly insoluble 2, 8-dihydroxyadenine (DHA) byproduct, which in turn results in stone formation and crystalline nephropathy. This conversion to DHA is catalyzed by xanthine dehydrogenase (XDH). The DHA crystals can precipitate in renal tubules and interstitium, leading to severe renal impairment. APRT deficiency often leads to irreversible renal failure, and the resulting nephropathy can recur even after transplant (Zaidan et al., 2014). About one-third of patients have decreased renal function, and about 10% have ESRD at the time of diagnosis (Bollée et al., 2010; Edvardsson, Palsson, Olafsson, Hjaltadottir, & Laxdal, 2001; Kamatani, Terai, Kuroshima, Nishioka, & Mikanagi, 1987).

Epidemiology of Adenine Phosphoribosyltransferase Deficiency

APRT deficiency is reported in all ethnic groups, but the majority of studies are from Japan, Iceland, and France. The estimated prevalence of APRT deficiency is 0.5 to 1 per 100,000 in the white population and 0.25 to 0.5 per 100,000 in the Japanese population. In Iceland, the estimated point prevalence is 8.9/100,000. This indicates there are at least 70,000 to 80,000 cases of APRT deficiency worldwide, suggesting that the condition may be seriously under-recognized and under-diagnosed (Bollée et al., 2012; Edvardsson et al. 2013).

Two types of APRT deficiency are recognized. In Type I disease, which affects primarily whites, APRT activity in red cell lysates is completely absent. In Type II APRT deficiency, which accounts for the majority of cases in Japan, enzyme activity is about 25% of normal values (Bollée et al., 2012).

Clinical Presentation of Adenine Phosphoribosyltransferase Deficiency

APRT deficiency can present at any age (Bollée et al., 2012). The most common manifestations of APRT deficiency are radiolucent kidney stones and crystalline nephropathy (Bollée et al., 2012). In children, the initial presentation is often acute kidney injury due to bilateral DHA calculi and urinary tract obstruction. Other clinical features include recurrent urinary tract infection, hematuria, and reddish-brown diaper stains (Edvardsson et al., 2013). In children, APRT deficiency is often characterized by progressive CKD with reduced GFR, whereas in adults, ESRD secondary to crystalline nephropathy is more common (Runolfsdottir, Palsson, Agustsdottir, Indridason, & Edvardsson, 2016). First stone presentation can be at any age. In studies from France and Japan, mean age at first onset of stone presentation ranged between 18 to 22 years, but some patients may be asymptomatic even in late adulthood (Bollée et al., 2010; Kamatani et al., 1987).

Diagnosis of Adenine Phosphoribosyltransferase Deficiency

A diagnosis of APRT deficiency should be considered in all children presenting with renal colic, recurrent radiolucent kidney stones, or acute kidney injury, and in infants presenting with reddish-brown diaper stains. Uric acid stones are radiolucent but usually associated with a low urine pH; therefore, radiolucent stones seen in conjunction with a high urine pH also support the diagnosis of APRT deficiency (Bollée et al., 2012; Edvardsson et al., 2013).

Microscopic examination of urine can yield diagnostic clues. Urine microscopy will usually show characteristic small and round, brown DHA crystals, which are pathognomonic of APRT deficiency. In addition, crystals will show a central Maltese cross-pattern on polarized light microscopy (see Figure 3) (Bollée et al., 2012; Edvardsson et al., 2013). Stone analysis using infrared spectroscopy or X-ray crystallography can distinguish DHA from uric acid or xanthine (Bollée et al., 2012).

Figure 3.

Characteristic Crystals of APRT Deficiency
Notes: (E) DHA crystals are round and brown and (F) show a central Maltese cross pattern on polarized light microscopy.
Source: reprinted with permission from Bollée et al., 2012.

Enzyme activity measurements help confirm the diagnosis; however, these assays may not be widely available. Patients with APRT deficiency Type I will have no APRT activity in red cell lysates and functionally significant mutations in both copies of the APRT gene. In Type II APRT deficiency, APRT activity will be 15% to 30% of normal (Bollée et al., 2012). The ability to assay urine for DHA is progressing in Iceland and should soon be a useful clinical test. Genotyping for an abnormal APRT gene is also available through the RKSC.

Treatment of Adenine Phosphoribosyltransferase Deficiency

Early recognition of APRT deficiency and prompt initiation of pharmacologic therapy can help stabilize renal function and prevent further renal damage. Allopurinol, an XDH inhibitor, is an effective and well-tolerated treatment for APRT deficiency. The recommended dose is 5 to 10 mg/kg/day in children (maximum suggested daily dose is 600 to 800 mg) taken as a single dose or divided into two doses. In adults, a dose of 200 to 300 mg/day prevents the formation of DHA crystals in most patients. Dosing is reduced when kidney function is impaired (Bollée et al., 2012). All patients with APRT deficiency, even if asymptomatic, receive allopurinol therapy because it can prevent stone formation, renal crystal deposition, and the development of kidney failure (Bollée et al., 2012). In patients who do not tolerate allopurinol, febuxostat, another XDH inhibitor, may be an option (Arnadóttir, 2014; Goldfarb, 2011).

Low purine diet and ample fluid intake provide adjunctive benefits to pharmacologic therapy (Bollée et al., 2012). Fluid intake should be increased to at least 2.5 L per day in adults, and patients should avoid purinerich foods. Urine alkalinization therapy is not necessary because DHA remains insoluble at pH less than 8.5 (Bollée et al., 2012).