A Rare Case of APRT Deficiency with End-stage Renal Failure and Successful Renal Transplant

Clinical presentation

APRT deficiency can present as urolithiasis and crystalline nephropathy. Although APRT deficiency occurs in all cells, no extra-renal symptom has been reported in affected individuals. APRT deficiency can present at any age from infancy to older than 70 years.[7910] In the setting of familial screening, it is not unusual to detect complete APRT deficiency in individuals who are totally asymptomatic even as adults.[710] The first urolithiasis episode may occur during the first few months after childbirth as well as later than the fifth decade.[7899] Reddish-brown diaper stains may be observed in infants.[10] Delayed diagnosis is less frequent when symptoms begin to show in children. In adults, confusion occurs between DHA and uric acid stones, which are radiolucent such as DHA stones. DHA stones may contain calcium salts, making them sometimes radiopaque.[11].

DHA crystals can precipitate in renal tubules and interstitium and severely impair renal function leading to crystalline nephropathy known as DHA nephropathy.[12] DHA nephropathy can present as an acute disease leading to renal failure (RF) in a few days or weeks or more frequently develop insidious and progressive decline of renal function in several years. Acute RF may be triggered by dehydration, which causes oliguria, urine supersaturation, and massive precipitation of DHA. Decreased renal function was observed in about one-third of patients at the time of diagnosis. Nearly 10% of patients had reached ESKD before diagnosis.[7910] DHA nephropathy can recur after renal transplantation if APRT deficiency remains unrecognized, which often leads to loss of allograft function within a few weeks.[51013] Factors such as fluids and purine intake are likely to account for variability in presentation.

Earlier reported cases of APRT deficiency from India include two cases in early childhood and one case in a young female.[141516] Both children (3 years and 2 years) presented with radiolucent stone with acute kidney injury in one and urinary tract infection in another. The only adult reported case was in a 24-year-old female, who presented with crystal nephropathy and rapidly progressive RF but had no stones. Our case also had crystal nephropathy without stones but was detected late in chronic kidney disease stage, who underwent transplant, which is reported for the first time.

Diagnosis

Stones should be analyzed by the combination of morphologic examination under a stereomicroscope and infrared spectroscopy which allows identification of DHA in all cases.[17] The biochemical stone analysis fails to differentiate DHA from uric acid and cannot be relied on for the diagnosis of APRT deficiency. Crystalluria examination by light and polarizing microscopy is a very useful, noninvasive, and inexpensive tool.[17] It is best performed in the first voided morning urine sample. Quantification can be done by counting the number of crystals per volume unit, which is high in untreated patients.[17] Infrared spectrophotometry should also be performed when DHA crystals are suspected. Crystalluria is very sensitive and specific, allowing the identification of homozygotes in 100% of cases. False-negative results have been rarely reported.[10].

As an invasive procedure, renal biopsy is theoretically not required. However, it often leads to the diagnosis in cases of DHA nephropathy as an unexpected finding in most cases.[13] Our case also was diagnosed following clues from the renal biopsy. The renal biopsy usually shows severe tubular injury and precipitation of crystals within tubular lumen and in renal interstitium. The best method is to characterize crystals in renal biopsy using polarizing microscopy and Fourier transform infrared microscopy.[18] If latter is not available, crystalluria and measurement of APRT activity assay may lead to diagnosis.

Measurement of APRT activity in erythrocyte lysates can be done by high-performance liquid chromatography (HPLC) and urinary adenine can be measured by UV detection.[19] APRT enzymatic activity is not mandatory but is useful when available. The mutations involved may be determined by the sequencing of PCR-amplified DNA which can be readily performed given the small size of APRT gene.[6] However, 10% of mutations remain unidentified.[7].

The possibility of APRT deficiency should be considered in

1. All cases of urolithiasis in children,

2. Recurrent urolithiasis (especially if stones are radiolucent),

3. Urolithiasis associated with renal dysfunction of uncertain cause.

In such cases, adequate stone analysis should be performed whenever possible. Crystalluria is very useful, especially if the stone is not available for analysis.[13] APRT activity assay is useful when no stone is available and crystalluria cannot be studied in a patient with crystalline nephropathy (e.g., anuria). APRT activity should be systematically measured in patients with ESRD awaiting renal transplantation who have a history of urolithiasis.[13] We could not do APRT enzyme activity, as this test is not available as of now in any part of the country. But, with the biopsy picture and pathogenic mutation identified on NGS, it is highly likely to be diagnostic of APRT deficiency.

Management

No treatment has been shown to increase APRT activity.

1. Allopurinol: It acts by blocking xanthine dehydrogenase. The possibility of renal function recovery depends on the degree of acute tubular necrosis and chronic tubulointerstitial changes when treatment is initiated. Complete APRT deficiency even asymptomatic should be treated by allopurinol, given the risk for acute or insidious DHA nephropathy. The usual dosage of allopurinol is 200–300 mg/day in adults and 5–10 mg/kg/day in children. The treatment is monitored by clinical evaluation and urine microscopy. The absence of urinary DHA crystals is indicative of adequate therapy

2. Febuxostat: Another xanthine dehydrogenase inhibitor represents a potential alternative in allopurinol intolerant patients.20 The usual dose is 80 mg/day

3. High fluid intake of at least 2.5 L of water per day in adults

4. Avoidance of purine-rich food should also be advised. Alkalization does not have to be recommended because DHA remains very insoluble at pH values below 8.5. Decrease of crystalluria usually should be considered as an adequate response to treatment.[7] Stones may recur in a minority of patients despite treatment.[7] Lack of adherence to treatment or insufficient dosing of allopurinol should be suspected in such situations or if crystalluria persists

5. Surgical management of DHA kidney stones is the same as for the management of other types of stones including ESWL

6. Treatment of ESKD: Treatment of end-stage kidney disease remains the same as dialysis or kidney transplantation.

All individuals with APRT deficiency require treatment with allopurinol or febuxostat for at least 6 weeks prior to transplant surgery, whenever possible. The unrecognized disease may lead to graft failure because of the recurrence of crystal nephropathy. Lifelong therapy with allopurinol or febuxostat after kidney transplantation is required to prevent DHA crystal nephropathy in transplant kidney.

Surveillance

All individuals with APRT deficiency should be followed up every 6–12 months to monitor:

1. Kidney function,

2. Assess urinary excretion of DHA crystals,

3. Medications compliance,

4. Periodic ultrasound of kidney for new kidney stones.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.