Underlying Causes and Risk Factors of Chronic Renal Allograft Dysfunction Among Renal Transplant Recipients

Objective: Dialysis or renal transplantation are the two treatment options for end-stage renal disease patients. Renal transplantation from an appropriate donor increases survival and quality of life compared to treatment with dialysis. Recent advances in immunosuppressive therapy have significantly improved the success in 1-year graft survival. However, the long-term graft survival remains the same. Therefore, we aimed to determine the underlying causes and risk factors of chronic allograft dysfunction in renal transplant recipients. Materials and Methods: From 2000 to 2012, all consecutive renal transplant recipients followed in our tertiary referral center who underwent renal biopsy due to an increase in serum creatinine level were enrolled. Etiologies of chronic allograft dysfunction were assessed according to pathologic results of renal biopsy specimens and laboratory findings. The immunological and non-immunological risk factors of chronic allograft dysfunction were screened and recorded retrospectively. Results: Eighty (80) renal transplant recipients with a mean age of 38±10 years were included in the study. Delayed graft function (p=0.007), history of acute rejection (p<0.001), positive panel reactive antibody (p=0.033) (Class I (p=0.013), Class II (p=0.006)), positive donor specific antibodies (p=0.001), number of recurrent acute rejections (p<0.001), number of human leukocyte antigens mismatches (p=0.051), cold ischemia time (p=0.001) were found to be risk factors for chronic allograft dysfunction. The donor specific antibodies positivity (p<0.001) and the panel reactive antibody positivity (Class I (p=0.003), Class II (p=0.001)) were significantly higher in patients with antibody mediated rejection than patients without antibody mediated rejection (p=0.002). Conclusion: Delayed graft function, presence and the number of acute rejections, increased cold ischemia time, panel reactive antibody positivity, donor specific antibodies positivity, and the number of human leukocyte antigens mismatches were risk factors for chronic allograft dysfunction.

Cyclophilin A/CD147 Induces the Epithelial-to-mesenchymal Transition and Renal Fibrosis in Chronic Allograft Dysfunction by Regulating MAPK Signaling

Objectives: Our study was designed to explore the role of Cyclophilin A (CyPA)/CD147 interactions in renal allograft fibrosis and chronic allograft dysfunction (CAD). Methods and materials: A rat renal transplant model with significant CAD was successfully identified. Renal allograft tissues and blood samples were collected. HE, Masson and immunohistochemistry staining were performed. Then human HK-2 cells were intervened by certain concentrations of CyPA, and total protein and mRNA were extracted. Western blot assay and PCR were performed to explore the protein and mRNA expression of CyPA, CD147 and epithelial-to-mesenchymal transition (EMT)-related biomarkers. CD147 siRNA and specific inhibitor of MAPK were used to explore the involved cellular mechanism.Results: We have successfully established and identified a 20-weeks renal transplant CAD model. We observed significant distributed and expressed CyPA and CD147 in the renal allograft fibrosis tissues. We also found the significant expression of CD147 and EMT-related markers in the HK-2 cells stimulated by CyPA. The CD147 siRNA confirmed the previous results in vitro. The selective inhibition of MAPK suggested the notable role of MAPK signaling pathway in the CyP/CD147 interactions involved in renal allograft fibrosis.Conclusions: Our study reported the positive relationship of CyPA/CD147 interactions with the renal allograft dysfunction. In vitro study suggested that CyPA could bind to CD147 and then induce the development of EMT process by MAPK signaling, thus contributing to the renal allograft fibrosis and CAD.

A novel biomarker of chronic allograft dysfunction in renal transplant recipients (serum calreticulin and CD47)

Background Chronic allograft dysfunction (CAD) is considered the leading cause of late allograft loss. The cluster of differentiation 47 (CD47) and calreticulin (CRT) are involved in many and diverse cellular processes. The present study was designed to study the role of the pro-phagocytic CRT and anti-phagocytic CD47 signals in patients with renal transplantation in relation to graft function. Thirty renal transplantation recipients (RTR) for more than 6 months [15 with stable renal function and 15 with chronic allograft dysfunction (CAD)] and 15 healthy controls were enrolled in the study. Quantification of CRT, CD47, and high-sensitivity C-reactive protein (hsCRP) levels in serum was done using standardized enzyme-linked immunosorbent assay (ELISA) kits. Measurement of renal function and urinary alkaline phosphatase (U.ALP) was done. Renal interstitial fibrosis (IF) was graded in renal biopsies of CAD. Results Serum CRT and urinary ALP levels were statistically significant higher (P < 0.001) while serum CD47 level was statistically significant lower (P < 0.001) in patients with CAD than patients with stable graft function and controls. There was statistically insignificant difference between controls and patients with stable graft function. Serum CRT and serum CD47 levels were positively correlated with each other and with worsening renal and tubular function, serum hsCRP in RTR and with degree of renal IF in patients with CAD (P < 0.05). Conclusions The activation and dysregulation of CRT and CD47 could play a role in the development of CAD and could be a potential biomarker for renal allograft dysfunction.