Adenine Phosphoribosyltransferase Deficiency: A Potentially Reversible Cause of CKD

Adenine phosphoribosyltransferase (APRT) enzyme deficiency is an important and potentially reversible cause of progressive chronic kidney disease. It is a rare, autosomal recessive disorder that was first described in 19741Simmonds H.A. Van Acker K.J. Cameron J.S. Snedden W. The identification of 2,8-dihydroxyadenine, a new component of urinary stones.Biochem J. 1976; 157: 485-487Crossref PubMed Scopus (52) Google Scholar with more than 40 known mutations2Runolfsdottir H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 3Bollée G. Dollinger C. Boutaud L. et al.Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency.J Am Soc Nephrol. 2010; 21: 679-688Crossref PubMed Scopus (85) Google Scholar and estimated prevalence of 1 in 50,000 to 100,000 persons.2Runolfsdottir H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 4Zaidan M. Palsson R. Meriequ E. et al.Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure.Am J Transplant. 2014; 14: 2623-2632Crossref PubMed Scopus (37) Google Scholar, 5Bollée G. Harambat J. Bensman A. et al.Adenine phosphoribosyltransferase deficiency.Clin J Am Soc Nephrol. 2012; 7: 1521-1527Crossref PubMed Scopus (64) Google Scholar The APRT enzyme is important for the conversion of adenine to adenosine monophosphate in the salvage purine pathway. Deficiency of this enzyme results in the metabolism of adenine into 2,8-dihydroxyadenine (DHA) by xanthine oxidase (xanthine dehydrogenase) (Figure 1a). DHA is highly insoluble in urine and will precipitate to cause either urolithiasis or crystal nephropathy. There are no known extrarenal manifestations and reasons for this remains unclear given the extensive tissue distribution of this enzyme. The typical appearances of DHA crystals on renal biopsy are of yellow-brown needle-shaped crystals, which are arranged in spherical, radial, or irregular aggregates and are birefringent under polarized light. Tubular injury, deposition, and obstruction can occur, and foreign body reaction with histiocytes can be seen surrounding some of the crystals. Left untreated, chronic crystal deposition in the kidney can lead to irreversible tubular atrophy and interstitial fibrosis. Crystalluria is characterized by birefringent yellow-brown crystals that are round in appearance and display a Maltese cross pattern on polarized light microscopy. Although it can present in any age group and stage of disease, it is most commonly diagnosed in adults (median age 36 years2Runolfsdottir H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), with up to 15% of patients diagnosed either in end-stage renal failure or following kidney transplantation.3Bollée G. Dollinger C. Boutaud L. et al.Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency.J Am Soc Nephrol. 2010; 21: 679-688Crossref PubMed Scopus (85) Google Scholar, 4Zaidan M. Palsson R. Meriequ E. et al.Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure.Am J Transplant. 2014; 14: 2623-2632Crossref PubMed Scopus (37) Google Scholar APRT deficiency also may be misdiagnosed, as other forms of renal stone disease, crystal nephropathy, or chronic kidney disease of unknown etiology.2Runolfsdottir H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar The diagnosis of APRT deficiency in patients with urolithiasis or crystal nephropathy is based on the following: (i) genetic mutation testing; (ii) absent or reduced APRT enzyme activity in red cell lysates; or (iii) confirmation of DHA crystal composition by infrared spectroscopy (Figure 1b). Reducing DHA production by xanthine oxidase inhibition is the cornerstone of pharmacological therapy for APRT deficiency. Allopurinol is the most used drug in this instance, whereas the addition or switch to febuxostat has been used in several cases.2Runolfsdottir H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 6Nanmoku K. Kurwosawa A. Shinzato T. et al.Febuxostat for the prevention of recurrent 2,8-dihydroxyadenine nephropathy due to adenine phosphoribosyltransferase deficiency following kidney transplantation.Intern Med. 2017; 56: 1387-1391Crossref PubMed Scopus (8) Google Scholar Supportive therapy includes low purine diet and high fluid intake. Urinary alkalinization is ineffective, as DHA remains insoluble at physiological urine pH ranges.5Bollée G. Harambat J. Bensman A. et al.Adenine phosphoribosyltransferase deficiency.Clin J Am Soc Nephrol. 2012; 7: 1521-1527Crossref PubMed Scopus (64) Google Scholar We present 3 cases (Tables 1 and 2) that highlight the diagnostic pitfalls and challenges in management, particularly in the transplantation setting. For further details to this article, please refer to the Supplementary Methods and Supplementary References.Table 1Baseline characteristics of the 3 patients, before transplantation in cases 1 and 2Patient characteristicsCase 1Case 2Case 3Age, yr, at diagnosis475223GenderMaleFemaleMaleRaceCaucasianLebaneseLebaneseComorbiditiesObesity, hypertension, atrial fibrillationGraves diseaseObesity, atrial flutterUrolithiasisNoNoYesFamily history of kidney diseaseNoNoNoCreatinine at presentation, μmol/l3562681020Proteinuria, g/24 h0.921.090.23Microscopic hematuriaNoNoNoNative kidney biopsyLM: 15/18 globally sclerosed glomeruli; tubular, epithelial and interstitial birefringent, brown crystal deposition with diffuse interstitial inflammation and fibrosis.IF: nondiagnosticEM: Needle-shaped crystals in some tubulesLM: 6 of 10 globally sclerosed glomeruli; golden brown, birefringent tubular crystals with associated diffuse interstitial fibrosis and inflammation.IF: nondiagnosticEM: nondiagnosticLM: 5 of 17 globally sclerosed glomeruli; yellow- brown, birefringent tubular crystals with associated diffuse interstitial fibrosis.IF: nondiagnosticEM: nondiagnosticProvisional diagnosisAPRT deficiencyChronic interstitial nephritisOxalate nephropathyTime from presentation to dialysis (modality)2 mo (hemodialysis)3 yr (peritoneal dialysis)<1 wk (hemodialysis)Time from native biopsy to APRT diagnosis10 wk6 yr10 moGenetic testingNot doneHomozygous c.188G>A (p.Gly63Asp)Homozygous c.188G>A (p.Gly63Asp)APRT enzyme activity, nmol/min per mg0.10.110.09Urine stone analysisNANAOrganic materialUrine 2,8-DHA28 mmol/molNot availableNot availableUrine biochemistryHypocitraturiaHypocitraturiaHyperoxaluriaUrine microscopyYes, but assessed only posttransplantBirefringent crystalsAPRT, adenine phosphoribosyltransferase; EM, electron microscopy; IF, immunofluorescence; LM, light microscopy; mo, month; NA, not applicable; wk, week; y, yr.Normal APRT enzyme activity > 0.15 nmol/min per mg and spot urine 2,8-DHA <13 mmol/mol. Open table in a new tab Table 2Post–kidney transplant course for patients 1 and 2Case 1Case 2TransplantationJanuary 2018May 2017APRT diagnosis before transplantationYesNoAllopurinol dose pretransplant150 mg (for 4.5 yr)NoDelayed graft functionYesYesImplantation biopsyAcute tubular injuryAcute tubular injuryTime from transplant to crystal detection, d1024Maximal allopurinol dose, mg600300Oxypurinol trough, mg/l21–3230–36Drug reaction with eosinophilia and systemic symptoms or ocular involvementNilNilFebuxostat40 mgNilCrystalluria posttransplantDetected 4 mo postNot detected 12 mo postTreatment for rejectionYes, pulse methylprednisoloneYes, methylprednisolone and 6 mg/kg antithymocyte globulin (day 24 for Banff grade 2A rejection: i1, t1, v1, ptc2, c4d-ve)Other complicationsInvasive CMV disease (graft CMV nephritis; colitis)BK virus–associated nephropathyShingles (reactivation of varicella zoster)CMV viremiaUrinary tract infectionsThree-mo posttransplant biopsyInvolved 15% of biopsy (less)No rejection: ci2, ct2, cv1, ah1No rejection: 15% crystals ci3, ct3, cv1, ah0Three-mo posttransplant GFR/DTPA, ml/min per 1.73 m25242Twelve-mo posttransplant biopsyNot availableNo rejection: 15% crystals ci3, ct3, cv1, ah0Last available creatinine level, μmol/l164 (6 mo post)145 (12 mo post)Maintenance immunosuppressionTacrolimus, mycophenolate, prednisoloneTacrolimus, mycophenolate, prednisoloneAPRT, adenine phosphoribosyltransferase; CMV, cytomegalovirus; DTPA, technetium-99m diethylene-triamine-pentaacetic acid; GFR, glomerular filtration rate; mo, month; yr, year. Open table in a new tab APRT, adenine phosphoribosyltransferase; EM, electron microscopy; IF, immunofluorescence; LM, light microscopy; mo, month; NA, not applicable; wk, week; y, yr. Normal APRT enzyme activity > 0.15 nmol/min per mg and spot urine 2,8-DHA <13 mmol/mol. APRT, adenine phosphoribosyltransferase; CMV, cytomegalovirus; DTPA, technetium-99m diethylene-triamine-pentaacetic acid; GFR, glomerular filtration rate; mo, month; yr, year. A 47-year-old Caucasian gentleman presented in 2013 for evaluation of renal impairment on a background of obesity, hypertension and atrial fibrillation. At the time of presentation, the serum creatinine (SCr) was 356 μmol/l (estimated glomerular filtration rate 17 ml/min per 1.73 m2) and subnephrotic proteinuria of 0.92 g/d without microscopic hematuria. This is compared with baseline SCr 119 μmol/l measured 5 years previously. The hemoglobin A1c, autoimmune, and myeloma serology were all unremarkable. Computed tomography scan showed 8.5 cm kidneys without evidence of calculi or hydronephrosis. A native renal biopsy revealed global sclerosis in 15 of 18 glomeruli and multiple, yellow-brown tinged crystals in the tubular lumen, epithelial cytoplasm, interstitium, with associated giant cells, marked tubular atrophy, and diffuse interstitial fibrosis. The crystals ranged from needle to rod to rhomboid in shape and were birefringent under polarized light. Congo red was negative and immunofluorescence was nondiagnostic. Electron microscopy revealed unremarkable glomerular features, no evidence of electron-dense deposits, but noted needle-shaped crystals in some tubules. A 24-hour urine collection was unremarkable except for hypocitraturia (0.4 mmol/d). Given the unusual crystal appearance, APRT deficiency was suspected and subsequent testing confirmed this diagnosis with reduced APRT enzyme activity (0.1 nmol/min per mg; normal >0.15 nmol/min per mg) and elevated urinary 2,8-dihydroxyadenine (28 mmol/mol; normal < 13 mmol/mol). Despite treatment with allopurinol (100 mg/d), he progressed to be dialysis dependent 2 months after presentation. His allopurinol was increased to 150 mg daily when he received a deceased renal transplant in January 2018. He had delayed graft function and the implant biopsy showed acute tubular injury, and a repeat biopsy at day 10 demonstrated recurrence of crystal nephropathy with borderline rejection with interstitial inflammation and tubulitis. He received intravenous methylprednisolone (total of 1500 mg), and allopurinol was increased to 400 mg daily. Subsequent biopsy on day 21 showed similar findings (crystal nephropathy, borderline rejection) and he received further pulse methylprednisolone. His renal function improved, no longer needing dialysis at 3 weeks posttransplant, and reached a trough SCr 180 μmol/l. His allopurinol was up-titrated to a maximum tolerated dose of 600 mg daily (limited by diarrhea) and trough oxypurinol levels varied between 21 and 32 mg/l. Surveillance urine microscopy (Figure 2e and f) showed persistent crystalluria and 20 mg of feboxustat was introduced, in addition to allopurinol 600 mg daily. Four-months after transplantation, he developed invasive cytomegalovirus (CMV) disease and a repeat biopsy (Figure 2a–d) with SCr 270 μmol/l showed acute tubular injury, crystalline nephropathy, and CMV inclusions. His renal function improved to SCr 164 μmol/l following treatment of CMV disease and up-titration of feboxustat to 60 mg daily. He developed a facial rash, which was diagnosed as rosacea and resolved with a short course of doxycycline. Baseline characteristics of all 3 cases and the posttransplant course are summarized in Tables 1 and 2. A 52-year-old Lebanese woman was investigated for progressive kidney disease with SCr 97 μmol/l rising to 268 μmol/l (estimated glomerular filtration rate 54 and 17 ml/min per 1.73 m2, respectively) over 4 months. She had subnephrotic proteinuria (1.09 g/24 hours) without microscopic hematuria, and the renal ultrasound showed atrophic left kidney and 12.5 cm right kidney. The renal biopsy showed diffuse interstitial inflammation and fibrosis with the occasional golden brown, birefringent intratubular crystals, and this was attributed to ciprofloxacin-associated chronic interstitial disease, and she progressed onto peritoneal dialysis 3 years later. She received a deceased renal transplant and required 2 sessions of hemodialysis for delayed graft function. A biopsy day 3 posttransplant showed acute tubular injury and borderline rejection, which was treated with methylprednisolone. Her renal function improved to SCr 220 μmol/l but then deteriorated to SCr 262 μmol/l after a period of subtherapeutic tacrolimus levels. A biopsy at day 24 showed Banff grade 2A T-cell–mediated rejection (Banff scores: i1, t1, v1, ptc2), positive simian virus (SV40) stain, and tubular and interstitial crystal deposition.7Haas M. Loupy A. Lefaucheur C. et al.The Banff 2017 Kidney Meeting Report: revised diagnostic criteria for chronic active T cell–mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials.Am J Transplant. 2017; 18: 293-307Crossref Scopus (634) Google Scholar She received antithymocyte globulin (total 6 mg/kg) with improvement from peak SCr 327 μmol/l to SCr 243 μmol/l. Oxalate nephropathy was suspected, but 24-hour urine metabolic screen was unremarkable except for hypocitraturia (<2 mmol/d). With the experience in case 1, we tested for and confirmed APRT deficiency with reduced APRT enzyme activity (0.11 nmol/min per mg). Genetic testing confirmed homozygous c.188G>A; p.Gly63Asp mutation (an identified pathogenic APRT gene mutation). Urine DHA testing was now unavailable. The patient was commenced on allopurinol at 5 weeks posttransplant, tolerating 300 mg/d (corresponding trough oxypurinol levels 35–36 mg/l), again, limited by Despite the positive stain, and urine reaction testing for and virus were negative and not A repeat biopsy 2 weeks showed persistent crystals and positive in 2 and negative and urine virus on she was treated with intravenous with improvement of SCr to to 150 μmol/l. The glomerular filtration rate of ml/min per 1.73 diethylene-triamine-pentaacetic and biopsy was from rejection, but had of tubular crystal deposition with the she developed CMV of varicella and recurrent urinary tract Her biopsy no crystalluria on polarized light showed no evidence of rejection or but birefringent crystals on the were in the tubular epithelial and and associated with tubular atrophy and interstitial fibrosis. She also developed a facial this the allopurinol was reduced to mg daily (corresponding oxypurinol 24 with the of feboxustat 40 mg daily. The results of the serum crystal and tissue distribution at time of transplant and biopsy of cases 1 and 2 are presented in The of patients showed similar in the disease DHA and crystal most crystals are seen in the allopurinol was a progressive in the of crystals seen in the with more in the epithelial and interstitial A of Lebanese 1 of urolithiasis in presented with acute kidney injury with SCr μmol/l (12 months with SCr The patient commenced acute hemodialysis given no reversible were identified and the renal biopsy showed global sclerosis in 5 of 17 in the and birefringent tubular crystals with associated tubular atrophy and interstitial fibrosis. The had this stone and of this revealed urine testing revealed g/24 no hematuria, and borderline elevated urine < was genetic testing of and and no were detected on further clinical this patient had the as 2 not and the suspected APRT deficiency. The diagnosis was confirmed with low enzyme activity nmol/min per mg) and a homozygous genetic mutation was confirmed Crystalluria also was detected in this patient on polarized light microscopy. cases highlight in of APRT particularly given the of clinical limited to and in levels of of disease and to The was in cases 2 and as chronic interstitial and nephropathy. case the diagnosis was only after of recurrence of crystals in the allograft and again, this was to be nephropathy. This 2 with (i) native renal in the of disease may be due to and (ii) it may be as other forms of crystal nephropathy and of the to between the to the rare of the disease, is a low of clinical that the to APRT deficiency findings of tubular interstitial of crystalline and negative to for other more of crystalline et nephropathy due to an cause of irreversible renal Transplant. 2010; PubMed Scopus Google Scholar to testing also may be a for urinary DHA was not available after the first case years and stone with infrared spectroscopy is also not available and been particularly for case stone was as APRT enzyme activity measured in red cell are absent or but a of rare pathogenic that disease but not red cell APRT enzyme L. M. et urolithiasis in a patient with adenine phosphoribosyltransferase activity in cell but with in of PubMed Scopus Google Scholar of therapy is to systemic DHA production by purine most production is salvage and inhibition of xanthine oxidase xanthine dehydrogenase) with allopurinol or febuxostat There is no for of DHA or urinary is in as it is and any on dialysis be to up with the high rate of production given the of the purine salvage pathway. The of allopurinol is not of H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google M. Palsson R. Meriequ E. et al.Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure.Am J Transplant. 2014; 14: 2623-2632Crossref PubMed Scopus (37) Google et nephropathy due to an cause of irreversible renal Transplant. 2010; PubMed Scopus Google to 600 mg) and febuxostat K. Kurwosawa A. Shinzato T. et al.Febuxostat for the prevention of recurrent 2,8-dihydroxyadenine nephropathy due to adenine phosphoribosyltransferase deficiency following kidney transplantation.Intern Med. 2017; 56: 1387-1391Crossref PubMed Scopus (8) Google Scholar been required to inhibition of DHA at also the APRT also used a of mg allopurinol and mg febuxostat in some are than the dose for patients with renal impairment or on to of allopurinol or drug reaction with eosinophilia and systemic This also in the of been of febuxostat used in patients with chronic kidney stage 5 to mg and transplant patients in the of With in is required for therapy of either with to drug reaction with eosinophilia and systemic or is the active of allopurinol and is when creatinine is but levels been used to the of trough levels mg), but no levels for APRT We this can be a to in patients, particularly to for with and renal function than a or allopurinol dose We measured oxypurinol levels in transplant patients and high levels in the case 1 on 600 mg daily with trough levels 21 to 32 and case 2 on 300 mg daily with trough levels the maximum allopurinol dose in patients was limited by patients described facial on 1 was treated for rosacea without in therapy and in case the resolved with of allopurinol on renal biopsy is the to this is limited by the and the of crystal crystal deposition of Urine microscopy and DHA are the only to of crystals under and polarized microscopy confirmation with infrared has been used as a for of urine DHA is an as it is more of and can be used with allopurinol or feboxustat but this is measured only A of 10 patients with APRT deficiency demonstrated marked of urine DHA and when treated with allopurinol or febuxostat and will be a and more The group is also into of DHA in which will be in the of levels are not for APRT deficiency levels < in of disease after transplantation is a and been to for patients with APRT deficiency. the case et M. Palsson R. Meriequ E. et al.Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure.Am J Transplant. 2014; 14: 2623-2632Crossref PubMed Scopus (37) Google patients with renal transplantation, the to diagnosis was 5 weeks after and allopurinol or feboxustat of patients developed chronic allograft nephropathy or graft case et et nephropathy due to an cause of irreversible renal Transplant. 2010; PubMed Scopus Google a patient treated with and allopurinol before transplantation, with no evidence of but with failure from and patient treated with allopurinol from recurrence of disease. described the of allopurinol or feboxustat is unclear and a in renal transplant given the of chronic graft and Although patient in case 1 was on allopurinol before transplantation, he was for and given the active was the posttransplant is high of acute graft from a with of systemic DHA into the urine by the new allograft kidney. The of tubular crystal is in the of or low and patients were to crystal and deposition is associated with acute tubular injury, tubular foreign body and tubulitis. It was to inflammation on the was due to crystalline disease or was or and interstitial but not Banff for Given from delayed graft inflammation on the was treated with intravenous and 1 patient progressed to Banff grade 2A This is not a and the clinical will to be to the of graft of rejection or to crystalline disease the of patients case 1 with invasive and case 2 with nephropathy, varicella CMV and recurrent urinary tract We the posttransplant of patients and that in the disease crystals were seen in the tubules. With the of allopurinol was at no further in crystal with over several months for in transplant patients tolerated showed to the distribution of crystal We based on the results presented in and and and following deposition, the crystals are then also into the tubular epithelial by either or of new of epithelial This is then by atrophy or of the tubular and deposition of crystals into the interstitial (Figure crystal deposition an to chronic tubular atrophy and interstitial fibrosis and is an important to the progressive chronic tubular and interstitial Banff in patients (Figure and Genetic testing in of a patient diagnosed with APRT deficiency on pathogenic in the The of will by rare may pathogenic that may be by or in other particularly may then the known APRT enzyme activity or urinary purine be more dependent on and Genetic be to of patients with APRT deficiency on either genetic or testing in There is a of disease, as some cases in H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google whereas some are detected only when patients are to chronic kidney disease in It is to all patients of particularly allopurinol is a but it may be to renal function and urinary or DHA to to allopurinol is APRT deficiency is an important to in patients with crystal nephropathy or It is potentially but the treatment are from and this has on graft in transplant