Adenine Phosphoribosyltransferase Deficiency

Clinical characteristics.

Adenine phosphoribosyltransferase (APRT) deficiency is characterized by excessive production and renal excretion of 2,8-dihydroxyadenine (DHA), which leads to kidney stone formation and crystal-induced kidney damage (i.e., DHA crystal nephropathy) causing acute kidney injury episodes and progressive chronic kidney disease (CKD). Kidney stones, the most common clinical manifestation of APRT deficiency, can occur at any age; in at least 50% of affected persons symptoms do not occur until adulthood. If adequate treatment is not provided, approximately 20%-25% of affected individuals develop end-stage renal disease (ESRD), usually in adult life.

Diagnosis/testing.

The diagnosis of APRT deficiency is established in a proband by absence of APRT enzyme activity in red cell lysates or identification of biallelic pathogenic variants in APRT. The detection of the characteristic round, brown DHA crystals by urine microscopy is highly suggestive of the disorder.

Management.

Treatment of manifestations: Treatment with the xanthine oxidoreductase inhibitors (XOR; xanthine dehydrogenase/oxidase) allopurinol or febuxostat can improve kidney function, even in individuals with advanced CKD. The prescribed dose of allopurinol and febuxostat should not routinely be reduced in affected individuals who have impaired kidney function. Ample fluid intake is advised. Surgical management of DHA nephrolithiasis is the same as for other types of kidney stones. ESRD is treated with dialysis and kidney transplantation. Even after kidney transplantation, treatment with an XOR is recommended.

Surveillance: Measurement of eGFR and urinary DHA excretion (or urine microscopy for assessment of DHA crystalluria) every 6-12 months; routine follow up to facilitate adherence to pharmacologic treatment at least annually; periodic renal ultrasound examination should be considered to evaluate for new asymptomatic kidney stones.

Agents/circumstances to avoid: Azathioprine and mercaptopurine should not be given to individuals taking either allopurinol or febuxostat.

Evaluation of relatives at risk: It is recommended that sibs of an affected individual undergo APRT enzyme activity measurement or molecular genetic testing (if the pathogenic variants in a family have been identified) to allow early diagnosis and treatment and improve long-term outcome.

Pregnancy management: The safety of allopurinol and febuxostat in human pregnancy has not been systematically studied. Some post-transplantation immunosuppressive therapies can have adverse effects on the developing fetus. Ideally a thorough discussion of the risks and benefits of maternal medication use during pregnancy should take place with an appropriate health care provider prior to conception.

Genetic counseling.

APRT deficiency is inherited in an autosomal recessive manner. At conception, each sib 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. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Suggestive Findings

Adenine phosphoribosyltransferase (APRT) deficiency (also known as 2,8-dihydroxyadeninuria) should be suspected in individuals with the following clinical, radiographic, laboratory, and pathology findings [Balasubramaniam et al 2016, Runolfsdottir et al 2016, Garigali et al 2019, Runolfsdottir et al 2019a].

Clinical manifestations

• Kidney stone disease and renal colic
• Chronic kidney disease (CKD)
• Crystal nephropathy (confirmed by kidney biopsy; see Pathology)
• Reddish-brown diaper stain in infants and young children
• Allograft dysfunction following kidney transplantation

Radiographic findings

• Radiolucent kidney stones, detected by ultrasound or computed tomography (CT). Stones are not seen on a plain abdominal x-ray.
• Ultrasound examination frequently demonstrates increased echogenicity of the kidneys.

Laboratory findings

• Urine microscopy. The round and brown DHA crystals can usually be detected by urine microscopy (Figure 1A). Small and medium-sized DHA crystals display a central Maltese cross pattern when viewed by polarized light microscopy (Figure 1B), while larger crystal aggregates do not as they are impermeable to light.
  Note: (1) DHA crystals may be difficult to identify in individuals with advanced CKD, possibly due to reduced DHA clearance by the kidney [Bollée et al 2010, Edvardsson et al 2013]. (2) High urine pH in individuals with radiolucent stones provides an additional clue to the diagnosis of APRT deficiency because uric acid stones develop in acidic urine [Edvardsson et al 2013] (see Differential Diagnosis).
• Kidney stone analysis. Analysis of DHA crystals and kidney stone material using infrared or ultraviolet spectrophotometry (at both acidic and alkaline pH) and/or x-ray crystallography differentiates DHA from uric acid and xanthine, which also form radiolucent stones. Although stones in persons with APRT deficiency are predominantly composed of DHA, they may contain trace amounts of other minerals.
  • Kidney stone analysis using the above techniques is dependent on skilled personnel and, thus, cannot be used to establish a diagnosis of APRT deficiency (see Establishing the Diagnosis).
  • Stone analysis employing standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is not recommended.

Figure 1.

Urinary 2,8-dihydroxyadenine (DHA) crystals from an individual with adenine phosphoribosyltransferase deficiency. These crystals have a characteristic appearance and polarization pattern. A. Conventional light microscopy shows the typical brown DHA crystals. (more...)

Pathology. Renal histopathologic findings in persons with APRT deficiency and CKD or acute allograft dysfunction are characterized by diffuse tubulointerstitial DHA crystal deposits accompanied by inflammation and fibrosis (see Figure 2), which may be observed even in individuals without a history of kidney stones [Nasr et al 2010, Zaidan et al 2014, Agrawal et al 2015, Lusco et al 2017].

Figure 2.

Kidney biopsy findings from an individual with adenine phosphoribosyltransferase deficiency and kidney failure due to 2,8- dihydroxyadenine crystal nephropathy A. 2,8-dihydroxyadenine crystals are seen within tubular lumens (arrows). Significant tubular (more...)

Note: It is important not to confuse the histopathologic manifestations of DHA crystal nephropathy with those of other crystal nephropathies, particularly those caused by oxalate (particularly primary hyperoxaluria) and uric acid deposits [Nasr et al 2010].

Establishing the Diagnosis

The diagnosis of APRT deficiency is established in a proband with absent APRT enzyme activity in red cell lysates or biallelic pathogenic variants in APRT identified by molecular genetic testing (see Table 1). See Figure 3 for a diagnostic algorithm [Edvardsson et al 2013].

Figure 3.

Algorithm for diagnostic evaluation of adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadeninuria From Edvardsson et al [2013]. Used with permission.

Note: Kidney stone analysis suggesting APRT deficiency is not reliable enough to establish the diagnosis.

Clinical Description

More than 400 individuals with adenine phosphoribosyltransferase (APRT) deficiency have been reported in the medical literature [Bollée et al 2010, Bollée et al 2012, Harambat et al 2012, Balasubramaniam et al 2014, Zaidan et al 2014, Runolfsdottir et al 2016, Huq et al 2018, Runolfsdottir et al 2019a, Runolfsdottir et al 2019b].

Age at presentation. APRT deficiency may present at any age; there is no typical age of clinical onset. However, in at least 50% of affected individuals, symptoms do not occur until adulthood.

• The age at diagnosis among individuals in the APRT Deficiency Registry of the Rare Kidney Stone Consortium (RKSC) ranged from six months to 72 years (median age: 37 years) [Runolfsdottir et al 2016].
• Approximately 35% of persons with APRT deficiency are diagnosed before age 18 years.
• In a significant number of asymptomatic individuals, a diagnosis of APRT deficiency has been suggested by the detection of DHA crystals on routine urine microscopy or through the screening of sibs of affected individuals and subsequently confirmed by enzyme activity or genetic testing.

Of note, abdominal ultrasound and CT examinations performed for other reasons may identify kidney stones in individuals with APRT deficiency who may be otherwise asymptomatic [Huq et al 2018].

Kidney stone disease. Between 60% and 90% of affected individuals have already developed kidney stones at diagnosis. In the absence of pharmacotherapy (see Management, Table 4), the majority of those untreated symptomatic persons experience stone recurrence [Runolfsdottir et al 2019a], abdominal pain, and/or lower urinary tract symptoms (e.g., straining, hesitancy, dribbling, incomplete bladder emptying).

Chronic kidney disease (CKD) secondary to DHA crystal nephropathy is present in more than 50% of individuals at diagnosis [Runolfsdottir et al 2016]. As many as 15% of affected individuals have progressed to end-stage renal disease (ESRD) at the time of diagnosis of APRT deficiency [Harambat et al 2012, Runolfsdottir et al 2016].

• In some of these individuals, the diagnosis was not made until after kidney transplantation had been performed.
• The relatively frequent occurrence of advanced CKD and even ESRD at the time of diagnosis is concerning and suggests a lack of familiarity with this easily treatable condition [Runolfsdottir et al 2019a].

ESRD. Approximately 20%-25% of affected individuals develop ESRD, usually in adult life, if adequate treatment is not provided.

• Importantly, individuals with APRT deficiency who are diagnosed and treated early with allopurinol or febuxostat have a much more favorable renal outcome [Runolfsdottir et al 2019a] (see Management, Table 4).
• Timely diagnosis and institution of pharmacologic therapy appears to reduce stone burden and retard or possibly prevent CKD progression to ESRD, even in severely affected individuals.

APRT deficiency is not known to affect organs other than the kidney; however, the authors and other investigators have encountered occasional individuals with APRT deficiency complaining of eye discomfort [Neetens et al 1986; Author, personal observation], which merits further study.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been established; clinical features are known to vary greatly among individuals with the same pathogenic variants [Bollée et al 2010, Runolfsdottir et al 2016].

Nomenclature

Originally, two types of APRT deficiency with identical clinical manifestations were described, based on the level of residual APRT activity in cell extracts (erythrocyte lysates) [Sahota et al 2001]. However, this distinction is of historic interest only, as APRT enzyme activity in intact cells has been shown to be less than 1% in both types [Kamatani et al 1985] (see APRT Enzyme Activity).

Prevalence

The estimated heterozygote frequency in different populations ranges from 0.4% to 1.2% [Hidaka et al 1987, Sahota et al 2001], suggesting that the prevalence of a homozygous state is at least 1:50,000 to 1:100,000.

If this holds true, at least 70,000-80,000 individuals should be affected worldwide, of whom 40,000 would be expected to be in Asia, 9,000 in Europe, and 8,000 in the Americas, including at least 3,000 affected individuals in the US alone. Most of these individuals are currently unrecognized, and thus not benefitting from medical therapy.

Evidence suggests that APRT deficiency may be a seriously underrecognized cause of kidney stones and crystal nephropathy, progressing over time to ESRD in a significant proportion of untreated individuals [Zaidan et al 2014].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with adenine phosphoribosyltransferase (APRT) deficiency, the evaluations in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Prevention of Primary Manifestations

Adequate treatment of APRT deficiency with allopurinol or febuxostat prevents kidney stone formation and the development of CKD in most, if not all, individuals with the disorder [Edvardsson et al 2001, Bollée et al 2010, Harambat et al 2012] (see Table 4).

Surveillance

No consensus surveillance guidelines have been established.

Agents/Circumstances to Avoid

Azathioprine and mercaptopurine should be avoided by individuals taking XOR inhibitors (allopurinol or febuxostat). Inhibition of xanthine oxidase may cause increased plasma concentrations of azathioprine or mercaptopurine, leading to toxicity.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Approximately 15% of individuals with APRT deficiency may be asymptomatic [Bollée et al 2010, Runolfsdottir et al 2016]; these individuals are usually identified during family screening.

Evaluations can include the following:

• Molecular genetic testing if the pathogenic variants in the family are known. Further investigations, including assessment of renal function and urinalysis, are warranted in individuals with biallelic pathogenic variants.
• APRT enzyme activity measurements, particularly if the pathogenic variants in the family are not known

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The safety of allopurinol and febuxostat in human pregnancy has not been systematically studied.

Animal studies using high doses of allopurinol have revealed evidence of adverse fetal effects in mice but not in rabbits or rats; it is not clear if these effects are a result of direct fetal toxicity or maternal toxicity. Thus, allopurinol should only be prescribed during pregnancy when the benefit of treatment is believed to outweigh the risk. Treatment with allopurinol during pregnancy should be considered in women with APRT deficiency who have CKD with reduced glomerular filtration rate (GFR) or who have undergone kidney transplantation.

Animal studies using high doses of febuxostat in rats and rabbits have not supported a teratogenic effect. However, very high doses in pregnant rats have been associated with neonatal loss and low pup birthweight.

Some post-transplantation immunosuppressive therapies can also have adverse effects on the developing fetus.

A thorough discussion of the risks and benefits of maternal medication use during pregnancy should ideally take place with an appropriate health care provider prior to conception.

See MotherToBaby for further information on medication use during pregnancy.

Therapies and Assays Under Investigation

Urinary DHA measurements. The authors' group has recently developed a urinary DHA assay using ultra-high-performance liquid chromatography – tandem mass spectrometry (UPLC-MS/MS) [Thorsteinsdottir et al 2016], which is expected to facilitate both the clinical diagnosis and monitoring of pharmacotherapy of individuals with APRT deficiency [Edvardsson et al 2018]. Further clinical studies to examine the sensitivity and specificity of the assay are currently under way.

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