P0674DCR2,AS A SENESCENCE MARKER,IS ASSOCIATED WITH DISEASE SEVERITY AND PROGRESSION IN IGA NEPHROPATHY PATIENTS

Abstract

Abstract Background and Aims Accelerated senescence of renal tubular epithelial cells (RTECs) may contribute to the progression of IgA Nephropathy (IgAN). Our previous studies demonstrated that DcR2 may reflect senescence of RTECs in experimental models and patients with diabetic nephropathy. The objective of this study was to investigate the association of DCR2 with disease severity and progression in IgAN. Method We included a retrospective cohort of 105 patients with biopsy proven IgAN. 15 normal renal tissue specimens displaying insignificant alterations biopsied from patients with renal carcinoma were recruited as controls. Renal biopsies from all patients were scored according to Oxford classification (MEST-C score). We analysed the degree of expression and localization of DCR2 in biopsies from kidneys with IgAN, and correlated their immunostaining levels with various clinical and histological parameters at baseline. Cox regression was performed for the composite renal outcome defined as 30% reduction in initial estimated glomerular filtration rate (eGFR) and/or end-stage renal disease (ESRD), and for the individual components during a follow-up for 60 or more months. Results DCR2 was overexpressed in the cytoplasm of RTECs obtained from kidneys of patients with IgAN [male: 60.9%, age:39.5±13.0 years, mean arterial pressure (MAP): 95.2±18.0 mmHg, proteinuria: 1.9 (0.7, 3.7)g/day, Initial eGFR:89.8±37.2 ml/min/1.73 m2], and were elevated with the increasing T scores. At baseline, DCR2 protein levels in the RTECs was inversely correlated with eGFR (R=−0.597, P=0.000) and positively associated with 24h-proteinuria (R=0.379, P=0.000) and the T score (R=0.632, P = 0.000). During a median follow-up of 80 (60, 125) months, patients with ≥25% tubular DCR2 positive showed worse eGFR slopes (the rate of eGFR decline) than those<25% DCR2 positive group [4.35 (2.17, 5.53) versus 0.36 (-0.96, 1.19) ml/min per 1.73 m2 per year; P=0.000)]. Kaplan–Meier survival analysis revealed that renal survival for the composite outcome was significantly lower in the ≥25% DCR2 positive group than in the<25% DCR2 positive group (P=0.000). In Cox regression models, ≥25% tubular DCR2 positive expression independently associated with poor renal outcome (HR=2.02, P=0.001) after adjustment for multiple known risk factors for IgAN progression, including baseline proteinuria, hypertension, eGFR, Oxford scores, and steroids/immunosuppressive therapy. Moreover, tubular DCR2 expression showed the highest sensitivity and specificity (80.8% and 87.3%, respectively) at a cut-off value of 25.5% DCR2 positive expression over proteinuria and eGFR for the composite outcome. The area under the receiver operating characteristic curve (AUROC) of tubular DCR2 expression was 0.880. Conclusion DCR2 is associated with disease severity and prognosis in IgAN patients and may have additional prognostic value besides established risk markers.