Chronic kidney disease and reduced renal COX2 expression in xanthinuria: a case-control study

Background Xanthinuria is a rare inherited metabolic disorder caused by xanthine dehydrogenase (XDH) deficiency, leading to excessive urinary xanthine excretion. It is associated with kidney stones and, in exceptional cases, renal failure. To date, no kidney biopsy findings have been reported in cases of xanthinuria. We present the first documented biopsy from such a patient, revealing a reduction in cyclooxygenase-2 (COX2) expression. Case presentation A 38-year-old man of Afghan origin presented with flank pain and a staghorn calculus in the right kidney. Laboratory tests revealed impaired renal function with serum creatinine at 192 µmol/L. Percutaneous nephrolithotomy was performed to remove the stone, and infrared analysis confirmed its 100% xanthine composition. Genetic sequencing identified two pathogenic variants in the XDH gene, confirming type I xanthinuria. Despite stone removal, renal function progressively declined during the following months, with serum creatinine reaching 238 µmol/L and significant albuminuria. Imaging revealed no residual stones or atrophy of the right kidney, while the left kidney remained free of lithiasis. A biopsy of the left kidney demonstrated advanced chronic kidney disease with fibrosis, without crystal deposits or stones. As the etiology of nephropathy remained unclear, we assessed COX2 expression, an enzyme involved in prostaglandin synthesis, in the left kidney tissue. Compared with healthy controls and biopsies from other advanced chronic kidney disease cases, the xanthinuria biopsy showed considerably reduced tubular COX2 expression. The patient ultimately developed end-stage renal failure at age 41 and underwent successful kidney transplantation, achieving excellent graft function 32 months post-transplant. Conclusions This case provides the first histopathological evidence of chronic kidney disease in xanthinuria without crystal deposition and identifies reduced tubular COX2 expression as a potential pathogenic mechanism. These findings support hypotheses from animal models suggesting that xanthine dehydrogenase deficiency may impair prostaglandin synthesis, contributing to kidney fibrosis and possibly abnormal nephrogenesis. Further investigation of similar cases could improve our understanding of rare metabolic disorders and inform strategies to preserve kidney function.