Two birds one stone-two rare cases of adenine phosphoribosyl transferase deficiency

INTRODUCTION

Adenine phosphoribosyltransferase (APRT) deficiency is an inherited metabolic disorder that leads to the excessive formation and excretion of 2,8-dihydroxyadenine (DHA) in the urine.¹

DHA has poor solubility and it’s precipitation leads to the formation of urinary crystals and stones.¹ The presentation of APRT deficiency can be varied in the form of recurrent urolithiasis or nephropathy secondary to crystal precipitation into renal parenchyma (DHA nephropathy). APRT diagnosis requires stone or crystal analysis, genetic analysis and APRT activity measurement which helps to make the diagnosis easy to confirm when APRT deficiency is suspected.² However, the disease can present at any age, and the variability of symptoms can present a diagnostic challenge to many physicians. The early recognition and treatment of APRT deficiency are of crucial importance for preventing irreversible loss of renal function.

CASE REPORT

Case 1

A 52-year-old gentleman who was diagnosed with hypertension came to the outpatient department for a routine evaluation, his renal functions showed a creatinine of 4.2 mg/dl. On examination, he had no pedal edema, no history of haematuria or frothy urine. His urine analysis done showed no proteinuria and no active sediments. He did not have a baseline creatinine.

Ultrasound done showed normal sized kidneys and mildly increased echogenicities. It seemed like an interstitial pathology and in order to identify the etiology a renal biopsy was done which showed chronic interstitial nephritis with deposition of 2,8 DHA crystals. He was started on Febuxostat and reduce intake of purine rich food; he is currently stable with a creatinine in the range of 3-4 mg/dl.

Genetic analysis of case 1 done showed a novel mutation of autosomal recessive homozygous start loss in exon 1 of APRT gene on chromosome 16.

Case 2

A 54 year old female with no comorbidities was identified to have Chronic kidney disease in 2018 with a baseline creatinine of 2 mg/dl came with uremic symptoms and history of NSAID intake in June 2019. Her creatinine peaked to 7.9 mg/dl. Urine analysis displayed 1+ proteinuria with no active sediments. Her USG of the kidneys showed normal kidneys with increased echogenicities. She underwent Renal biopsy for etiology determination which showed Acute interstitial nephritis with deposition of 2,8 DHA crystals. Patient was initiated on hemodialysis, and currently continues to be dialysis dependant. Genetic analysis for case 2 showed a mutation of autosomal recessive homozygous in frame deletion in exon 5 of APRT gene on chromosome 16.

DISCUSSION

APRT deficiency is a rare inherited metabolic disorder that excess formation and excretion of 2,8-dihydroxyadenine (DHA) into urine¹. The APRT gene is located on chromosome 16q24 consisting 2.8 kb of DNA, contains five exons, and has a coding region of 540 bp with autosomal recessive inheritence.^2,3 APRT deficiency is a very rare disease, with most cases published from Japan, however its worldwide prevalence remains largely unknown. ⁴

The APRT enzyme is constitutively expressed. It can be detected in all tissues and provides the only pathway for the metabolic salvage of adenine resulting from polyamine biosynthesis and dietary sources.⁵ APRT is involved in the process of formation of 59-adenosine monophosphate and inorganic pyrophosphate from adenine and 5-phosphoribosyl-1-pyrophosphate, allowing adenine to be detected only at low levels in blood and urine. Those lacking functional APRT, adenine is converted to 8-hydroxyadenine, which is further metabolized to DHA by xanthine dehydrogenase (XDH), previously known as xanthine oxidase .^6,7 DHA has a high renal clearance, which may involve both filtration and tubular secretion. APRT deficiency therefore results in high urinary excretion of DHA. DHA is extremely insoluble in urine and forms crystals, which lead to formation of stones by the process of nucleation, aggregation and growth or precipitate in renal parenchyma, causing crystalline nephropathy.^8,9

Complete APRT deficiency often poses a diagnostic challenge not only because of variability of symptoms and age of onset but also lack of awareness. The disease can present with two types of clinical manifestations, which may occur together or separately: urolithiasis and crystalline nephropathy.¹⁰ The term “DHA nephropathy” is used for the crystalline nephropathy secondary to DHA precipitation. DHA nephropathy may have an acute presentation with Acute kidney injury developing over a few days or more frequently, develop insidiously and cause progressive decline of renal function over several years like chronic interstitial nephritis.⁵

Unfortunately, the diagnosis is often delayed by years after the onset of symptoms, and most patients would have already developed irreversible renal failure when adequate treatment is implemented. There is a crucial need for earlier recognition and better management of APRT deficiency. Studies in European and Japanese populations have highlighted that APRT deficiency can present at any age. The age at diagnosis varies from infancy to older than 70 years.¹¹

The diagnosis of APRT deficiency is primarily based on the identification of DHA, either by examination of crystals in urine or by stone analysis. Stones should be analyzed if available by the combination of morphologic examination under stereomicroscope.^12,13 Renal biopsy usually shows severe tubular injury and precipitation of crystals within tubular lumen and in renal interstitium. The crystals may lack the typical features of DHA and their presence in renal parenchyma should never be dismissed. The best method is to characterize crystals in renal biopsy using polarizing microscopy.^1,12 The mutations involved may be determined by sequencing of PCR-amplified DNA, which can be readily performed given the small size of APRT gene.⁶

APRT activity cannot be increased by any therapy. Treatment of APRT deficiency relies on allopurinol therapy, which acts by blocking Xanthine dehydrogenase.¹⁴ In patients with DHA nephropathy, allopurinol therapy usually allows renal function to stabilize or improve and prevents recurrence after renal transplantation. The possibility of renal function recovery largely depends on the degree of acute tubular necrosis and chronic tubulointerstitial changes when treatment is initiated. All individuals with complete APRT deficiency, even asymptomatic, should be treated by allopurinol, given the risk for acute or insidious DHA nephropathy. Allopurinol dosage is 200-300 mg/d in adults and 5-10 mg/kg per day in children.¹⁴

Febuxostat, another XDH inhibitor, is an alternative in allopurinol-intolerant patients. Dietary modifications in the form of high fluid intake (at least 2.5 L of water per day in adults) and avoidance of purine-rich food should be advised. Alkalization does not have to be recommended because DHA remains very insoluble at pH values below 8.5. ^14-16 One should also be cautious during transplantation as the disease can recur on transplantation and this is why determination of native kidney disease is important. ^15,16

CONCLUSION

APRT deficiency represents a unique example of a disease that potentially leads to renal failure but can be easily treated by taking a pill each day. Physicians should therefore leave no stone unturned when it comes to caring for patients with urolithiasis or renal disease. There is a need to make diagnostic tools, especially APRT activity assay, more available.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

REFERENCES

1. 1. Guillaume Bollée, Jérôme Harambat, Albert Bensman, Bertrand Knebelmann, Michel Daudon and Irène Ceballos-Picot, CJASN. 2012;7(9):1521-7.
2. 2. Cartier P, Hamet M, Hamburger J. A new metabolic disease: The complete deficit of adenine phosphoribosyltransferase and lithiasis of 2,8-dihydroxyadenine. C R Acad Hebd Seances Acad Sci D. 1974;279(10):883-6.
3. 3. Van Acker KJ, Simmonds HA, Potter C, Cameron JS: Complete deficiency of adenine phosphoribosyl transferase. Report of a family. N Engl J Med. 1977;297:127-32.
4. 4. Kamatani N, Terai C, Kuroshima S, Nishioka K, Mikanagi K: Genetic and clinical studies on 19 families with adenine phosphoribosyl transferase deficiencies. Hum Genet. 1987;75:163-8.
5. 5. Runolfsdottir HL, Palsson R, Agustsdottir IM, Indridason OS, Edvardsson VO. Kidney Disease in Adenine Phosphoribosyltransferase Deficiency. Am J Kidney Dis. 2016;67(3):431-8.
6. 6. Bolle´e G, Dollinger C, Boutaud L, Guillemot D, Bensman A, Harambat J et al. Phenotype and genotype characterization of adenine phosphoribosyl transferase deficiency. J Am Soc Nephrol. 2010;21:679-88.
7. 7. Edvardsson V, Palsson R, Olafsson I, Hjaltadottir G, Laxdal T. Clinical features and genotype of adenine phosphoribosyl transferase deficiency in iceland. Am J Kidney Dis. 2001;38:473-80.
8. 8. Sahota A. APRT deficiency and 2,8-DHA urolithiasis. In: Metabolic and Molecular Bases of Inherited Disease, 8^th ed, edited by Scriver CR, New York, McGraw-Hill. 2001;2571-84.
9. 9. Ericson A, Groth T, Niklasson F, de Verdier CH. Plasma concentration and renal excretion of adenine and 2,8- dihydroxyadenine after administration of adenine in man. Scand J Clin Lab Invest. 1980;40:1-8.
10. 10. Fye KH, Sahota A, Hancock DC, Gelb AB, Chen J, Sparks JW et al. Adenine phosphoribosyltransferase deficiency with renal deposition of 2,8-dihydroxyadenine leading to nephrolithiasis and chronic renal failure. Arch Intern Med. 1993;153:767-70.
11. 11. Kamatani N, Takeuchi F, Nishida Y, Yamanaka H, Nishioka K, Tatara K et al. Severe impairment in adenine metabolism with a partial deficiency of adenine phosphoribosyltransferase. Metabolism. 1985;34:164-8.
12. 12. Hesse A, Miersch WD, Classen A, Thon A, Doppler W: 2,8-Dihydroxyadeninuria: Laboratory diagnosis and therapy control. Urol Int. 1988;43:174-8.
13. 13. Estepa-Maurice L, Hennequin C, Marfisi C, Bader C, Lacour B, Daudon M. Fourier transform infrared microscopy identification of crystal deposits in tissues: Clinical importance in various pathologies. Am J Clin Pathol. 1996;105:576-82.
14. 14. Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353:2450-61.
15. 15. Glicklich D, Gruber HE, Matas AJ, Tellis VA, Karwa G, Finley K et al. 2,8-dihydroxyadenine urolithiasis: Report of a case first diagnosed after renal transplant. Q J Med. 1988;68:785-93.
16. 16. Cheng Y, Guo L, Wang M, Chen J, Wang R. Recurrence of 2,8-dihydroxyadenine Crystalline Nephropathy in a Kidney Transplant Recipient: A Case Report and Literature Review. Intern Med. 2021;60(16):2651-7.