Primary hyperoxaluria type 2 presenting with febuxostat-associated acute tubular injury in a kidney transplant recipient: a case report

Background Febuxostat, a non-purine selective xanthine oxidase inhibitor, is increasingly used for managing hyperuricemia in kidney transplant recipients. While generally considered safe in this population, emerging post-marketing data raise concerns about potential nephrotoxicity. Primary hyperoxaluria type 2 (PH2) is a rare autosomal recessive disorder caused by mutations in the GRHPR gene, leading to oxalate overproduction, recurrent nephrolithiasis, and progressive renal failure. Isolated kidney transplantation in PH2 patients carries a high risk of recurrent oxalate nephropathy, which can lead to rapid allograft failure. However, PH2 is often diagnosed late or missed entirely. Case summary A 67-year-old woman with end-stage renal disease secondary to bilateral nephrolithiasis underwent deceased-donor kidney transplantation. Post-transplant recovery was initially uneventful, with serum creatinine declining to a nadir of 116.4 μmol/L. She developed hyperuricemia and was started on febuxostat 40 mg daily approximately two months after transplantation. About five months after febuxostat initiation, she presented with progressive, unexplained creatinine elevation from baseline to a peak of 327.9 μmol/L (~ 2.8 times the baseline). Comprehensive diagnostic work-up excluded T cell-mediated rejection, antibody-mediated rejection, BK virus nephropathy, and calcineurin inhibitor toxicity. The first renal allograft biopsy showed acute tubular injury with crystalline material suggestive of drug or phosphate/oxalate deposition; the second biopsy suggested extensive calcium oxalate crystal deposition on polarized light microscopy. Von Kossa staining was positive in both biopsies, implicating calcium phosphate deposition and supporting a mixed calcium oxalate/calcium phosphate crystal composition. Febuxostat was discontinued, and renal function stabilized temporarily but subsequently declined. Metabolic evaluation revealed markedly elevated urinary oxalate excretion. Genetic testing identified a homozygous likely pathogenic splice-site variant c.599-1G>C in the GRHPR gene, confirming the diagnosis of PH2. Conclusion This case highlights that PH2 can present as recurrent oxalate nephropathy after kidney transplantation. Febuxostat may have contributed to the clinical presentation, but its causal role remains unproven. Clinicians should consider PH in kidney transplant recipients with unexplained allograft dysfunction and calcium oxalate crystal deposition on biopsy, particularly those with a history of nephrolithiasis of unclear etiology. Early recognition and genetic confirmation are essential to guide appropriate management, including metabolic therapy and consideration of combined liver-kidney transplantation.