Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure

Abstract

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive enzyme defect of purine metabolism that usually manifests as 2,8-dihydroxyadenine (2,8-DHA) nephrolithiasis and more rarely chronic kidney disease. The disease is most often misdiagnosed and can recur in the renal allograft. We analyzed nine patients with recurrent 2,8-DHA crystalline nephropathy, in all of whom the diagnosis had been missed prior to renal transplantation. The diagnosis was established at a median of 5 (range 1.5-312) weeks following the transplant procedure. Patients had delayed graft function (n=2), acute-on-chronic (n=5) or acute (n=1) allograft dysfunction, whereas one patient had normal graft function at the time of diagnosis. Analysis of allograft biopsies showed birefringent 2,8-DHA crystals in renal tubular lumens, within tubular epithelial cells and interstitium. Fourier transformed infrared microscopy confirmed the diagnosis in all cases, which was further supported by 2,8-DHA crystalluria, undetectable erythrocyte APRT enzyme activity, and genetic testing. With allopurinol therapy, the allograft function improved (n=7), remained stable (n=1) or worsened (n=1). At last follow-up, two patients had experienced allograft loss and five had persistent chronic allograft dysfunction. 2,8-DHA nephropathy is a rare but underdiagnosed and preventable disorder that can recur in the renal allograft and may lead to allograft loss.

Keywords: Clinical research/practice; kidney (allograft) function/dysfunction; kidney disease; kidney transplantation/nephrology.

Figure 1. Metabolic pathways for the disposal of adenine in humans

Adenine phosphoribosyltransferase (APRT) deficiency causes 2,8-dihydroxyadenine (2,8-DHA) accumulation, leading to nephrolithiasis and crystalline nephropathy. In the absence of APRT activity, adenine cannot be converted to adenosine. Adenine is metabolized through an alternative pathway where it is oxidized by xanthine dehydrogenase (XDH) to 2,8-DHA via the generation of an intermediate compound, 8-hydroxyadenine. Because 2,8-DHA is insoluble at any physiological urine pH, it forms 2,8-DHA crystals eventually leading to 2,8-DHA nephrolithiasis and/or crystalline nephropathy. ADA, adenosine deaminase; AMP, adenosine monophosphate; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; IMP, inosine monophosphate; PNP, purine nucleoside phosphorylase; PRPP, 5-phosphoribosyl-1-pyrophosphate.

Figure 2. Renal allograft biopsy findings viewed by conventional light microscopy

Low magnification view showing focal deposition of crystals in the allograft parenchyma together with diffuse inflammatory interstitial infiltrates and varying degrees of interstitial fibrosis and tubular atrophy (A). Deposits of 2,8-DHA crystals within tubular lumens forming spherical aggregates, causing tubular obstruction with foreign-body type reaction (B). Small needle-shaped and irregular crystals located within the tubular epithelial cells (C). Small spherical to large crystal aggregates in the tubular lumen and within tubular epithelial cells (D).

Figure 3. Renal allograft biopsy findings viewed by polarized light microscopy

The crystals are highly birefringent and of variable size and appearance. Crystals precipitates within the tubular lumens (A), forming spherical and irregular aggregates. Very small needle-shaped crystal deposits located within the tubular epithelial cells (A, arrows). Crystals exhibiting a typical birefringent Maltese cross pattern are rarely observed within the tubular lumens (A, inset). Spherical (B) and ring-like (C) crystal aggregates composed of radially-oriented crystals. Lower magnification showing small birefringent crystals in only some foci of the graft parenchyma, and very small crystals diffusely interspersed within the renal interstitium yielding a stardust-like appearance (D).

Figure 4. Evolution of graft function from diagnosis to last follow-up

Each dot (○) represents the value of a measured serum creatinine. ◆ indicates the need for hemodialysis.