Expression of hypoxia-inducible factor-1α (HIF-1α) in infiltrating inflammatory cells is associated with chronic allograft dysfunction and predicts long-term graft survival

Abstract

In chronic kidney failure, a hypoxic state, infiltrating inflammatory cells play a crucial role in the progression to end-stage renal disease. No studies have evaluated the influence of hypoxia and infiltrating inflammatory cells on chronic allograft dysfunction. Renal transplant recipients who underwent renal allograft biopsy with interstitial fibrosis/tubular atrophy (IF/TA) were enrolled and renal allograft tissue sections were processed for immunohistochemical staining including hypoxia-inducible factor-1α (HIF-1α), nitrotyrosine, α-smooth muscle actin and e-cadherin. Patients with total renal tissue HIF score ≥1 were defined as positive for HIF-1α. To assess the phenotype of the infiltrating cells, dual staining of HIF-1α with CD45, CD68 and CD3 was performed. The correlation between HIF-1α score and Banff's score was analysed. Clinical parameters including renal survival among patients with or without an expression of HIF-1α were compared. Out of 55 patients enrolled, 23 patients (41.8%) had an HIF-1α score ≥1 (Group B). Compared with Group A (total renal HIF score <1), Group B had a significantly higher Banff score of interstitial infiltrates (i) (P = 0.029), vascular fibrous intimal thickening (cv) (P = 0.007) and arteriolar hyaline thickening (ah) (P = 0.026). Clinically, patients with an HIF-1α score were associated with a poor graft survival. Significantly inferior allograft survival was noted in Group B. HIF scores had an adjusted hazard ratio of 3.25 (95% confidence inteval: 1.71-6.16, P = 0.0003) in allograft failure. We first demonstrated the expression of HIF-1α protein among infiltrating inflammatory cells in areas with IF/TA in patients with chronic allograft dysfunction.