2,8-Dihydroxyadenine Crystal Nephropathy and Mediators of Kidney Injury in Adenine Phosphoribosyltransferase Deficiency

Background: Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder leading to accumulation of 2,8-dihydroxyadenine (DHA) in the kidneys, causing urinary stones and progressive chronic kidney disease. This study aimed to characterize the renal histological changes in APRT deficiency, and immunohistochemical expression of selected potential mediators of kidney injury. Methods: Kidney biopsy (n=3) and nephrectomy specimens (n=2) from five patients with APRT deficiency, along with three control nephrectomy specimens were included in the study. All kidney tissue samples, obtained from the Landspitali University Hospital Biobank, were assessed for DHA crystal localization, degree of inflammation and/or fibrosis, and other indicators of tissue damage. Tissue samples were classified as DHA high and DHA low based on DHA crystal tissue burden. The expression of APRT, xanthine oxidoreductase, E-cadherin, N-cadherin, CD44, NGAL, KIM-1 and collagen I and III was assessed by immunohistochemistry (IHC). Results: Kidney tissue from patients with APRT deficiency showed birefringent DHA crystals within tubular lumina, inside tubular epithelial cells, and in the interstitium. DHA high samples displayed marked inflammation and tubular atrophy, with interstitial fibrosis, whereas DHA low samples exhibited only localized injury around the limited crystal deposits. No crystals, inflammation, or fibrosis were observed in the control tissue. IHC confirmed absent APRT, reduced N-cadherin in DHA high samples, and increased collagen III expression in all samples, suggesting early fibrotic remodeling. CD44 expression tended to be higher in kidney sections from patients with APRT deficiency, consistent with crystal-induced inflammation. Conclusions: DHA crystal deposits were seen in renal tubular lumina, within epithelial cells, and in the interstitial space. The degree of inflammation and fibrosis noted in kidneys of individuals with APRT deficiency was associated with the burden of DHA crystal deposits observed. The IHC findings, together with previously published data, support a likely pathobiological chain of events mediating DHA crystal-induced kidney injury in APRT deficiency .