Crystalline nephropathy due to adenine phosphoribosyl transferase deficiency as a cause of renal allograft dysfunction

Adenine Phosphoribosyl Transferase (APRT) defi ciency is an inherited condition presenting from infancy to late adulthood. A common feature is recurrent kidney and urinary tract stones and obstructive symptoms. It presents as radiolucent nephrolithiasis or Tubular crystal deposition can occur associated with marked interstitial fi brosis. The stones are characteristically radiolucent and they can recur following renal transplant. 2,8 Dihydroxy adenine (DHA) formation is blocked by Xanthine Oxidase blocker allopurinol reduces interstitial fi brosis [1]. DHA-induced nephropathy may recur in the allograft and it is diagnosed only when the allograft failure has been investigated more carefully. We here report a unique case of recurrence of crystalline nephropathy due to APRT defi ciency causing renal allograft dysfunction.

Citation: Hegde  is blocked by Xanthine Oxidase blocker allopurinol reduces interstitial fi brosis [1]. DHA-induced nephropathy may recur in the allograft and it is diagnosed only when the allograft failure has been investigated more carefully. We here report a unique case of recurrence of crystalline nephropathy due to APRT defi ciency causing renal allograft dysfunction.
At the age of 20 years, he was initiated on HD through right IJV DLC in view of uremic convulsion. Later left RC AVF was constructed which had primary failure and then left BC AVF which was his access when he came to our hospital. He was detected to be hepatitis C positive (Genotype 3) with normal liver function so he was treated with injection. Interferon thrice per week for 12 months. His X ray KUB didn`t show any stone but CT KUB showed bilateral small kidneys with multiple soft calcifi c density foci in renal parenchyma ( Figure   1) In view of history of stone disease, he underwent 24-hour urinary metabolic evaluation which was not suggestive of hyperuricosuria. As the stone was radiolucent, oxalosis was excluded and genetic work up was deferred. His 55-year-old father come forward as prospective donor and found suitable for kidney donation. He underwent ABO compatible live renal transplant with triple immunosuppressant comprising of prednisolone, mycophenolate mofetil and cyclosporine without induction. There was immediate graft function and the Creatinine decreased to 1.57 mg/dl on the fourth day.
However, there was rise in Creatinine to 1.78 mg/dl with cyclosporine level of 120ng/ml. His Cyclopsorine dose was increased. However, in view of rising Creatinine, graft biopsy was done on 12 th post-operative day, which showed borderline rejection (interstitial infl ammation with occasional Tubulitis).
Inj. Methylprednisolone 250mg each was given for 3 days. His    [5]. 15% of the patients develop End stage renal failure [6] and they are diagnosed APRT defi ciency only after renal transplantation. 15-20% of people with APRT defi ciency present no symptoms. Although APRT defi ciency has no known extrarenal manifestations, in some patients suggested partial APRT defi ciency could contribute to hyperuricemia and gout. Although the worldwide prevalence of APRT defi ciency is largely unknown, it has been estimated to be 1/100,000 in Caucasian population, 1: 27000 people in Japan, rarer in Europe 1: 50000-100000 people [7]. Inheritance is autosomal recessive typically involving Chromosome 16q24 and has presently 24 functional known mutations [7].
APRT defi ciency may present at any age ranging from infancy to more than 70 years of age. In a French series only 37% of individuals with APRT defi ciency were diagnosed before age 16 years. Median age is 37 years. Common feature is recurrent kidney and urinary tract stones and obstructive symptoms. In infancy presents as tiny ravel of reddish brown material in baby diapers. Renal functions affected by early to late adulthood. 60-75% patients are affected in adulthood.
The presenting symptoms are stones, urinary tract infections, hematuria, abdominal pains and nausea and vomiting, nearly 10% fi nally progress towards ESRD before the diagnosis.
More than 400 subjects with APRT defi ciency have been reported in the medical literature including case reports, case series, and registry data [6]. A study of 67 patients from 56 families by Irène Ceballos-Picot etal [8] from Necker Universitary Hospital, Paris, identifi ed complete APRT defi ciency 73% presented with recurrent nephroloithiasis and due to misdiagnosis, 20% cases developed irreversible loss of renal function. In a registry data consisting of 53 patients by Runolfsdottir HL, et al. [9] with APRT defi ciency were followed up for median duration of 10.3 years. At the end of the study 42% patients were in CKD 3-5 stage. There was slower fall in the median eGFR -0.38 mL Vs -5.74/ml/min/1.73m 2 per year in patients receiving treatment with Allopurinol compared to those not treated prior to the development of stage 5 CKD. In another study by Runolfsdottir HL, et al. showed that if the therapy is initiated early in the course the eGFR is maintained at higher range (children -114 (70-163) Vs adults -62 (10-103) mL/min/1.73 m 2 ) [10].
In renal transplantation the absence of prophylactic treatment, 2,8-DHA crystalline nephropathy can recur in the renal allograft, leading to allograft loss in more than 25% of cases. Recurrence of nephrolithiasis has also been reported but is less common in transplant than in native kidneys. 2,8-DHA crystals can be detected in the urine within the fi rst few days after renal transplantation, leading to delayed graft function and primary graft non-function. The factors underlying variable presentation are unclear. The environmental factors such as fl uid intake, acute episodes of dehydration, and purine intake infl uence the phenotypic variability. A study of recurrence after transplant by Zaidan M, et al. [11] Consisting of 9 patients with recurrent 2,8-DHA crystalline nephropathy,5 had acute on chronic graft dysfunction, 1 acute graft dysfunction and 1 had delayed graft dysfunction at the timer of diagnosis. With Allopurinol therapy graft function improved in 7 patients, stabilized in 1 and worsened in one patient. In our patient also had acute on chronic graft dysfunction and stabilized with allopurinol therapy.
There are 2 types of defi ciencies in enzyme: APRT 1 defi ciency: Absent enzyme levels (complete defi ciency in Vivo and in Vitro), usually found in Caucasians populations with 0.4-1.1% distribution in general population. APRT 2 defi ciency: Decreased levels of enzyme by less than 30% (complete defi ciency in vivo but partial defi ciency in vitro) usually found in the Japanese with 05-1.2% distribution in general population amounts to 70% of the cases.

Detection of APRT defi ciency
The identifi cation of DHA in stone or urine is pathognomonic of APRT defi ciency. The diagnosis of APRT defi ciency disease in our patient was confi rmed by: (i) the absence of APRT enzyme activity in erythrocyte lysates by High Performance Liquid Fabuxostat, a recent XDH inhibitor may be used as an alternative therapy. Increased fl uid intake is advisable. DHA crystal formation can be minimized by purine-poor diet to reduce adenine accumulation and by xanthine oxidase inhibition to prevent the alternative metabolism of adenine to DHA [3].
Urinary alkalization is not benefi cial. Dialysis is ineffective in preventing DHA, as it is usually protein bound, and any removal on dialysis would be unable to keep up with the high rate of production [3]. Crystalluria can be used for monitoring