Wednesday September 16, 2020 - 14:30 to 15:15
Rapamycin prevents interstitial fibrosis through decreasing peritubular capillary (PTC) VEGF expression and angiogenesis while inducing glomerular sclerosis and proteinuria through decreasing glomerular VEGF expression
B. Handan Ozdemir1, F. Nurhan Ozdemir2, Eda Akcay1, Alev Ok Atilgan1, Aysegul Yucel Polat1, Aydincan Akdur3, Mehmet A. Haberal3.
1Pathology, Baskent University, Ankara, Turkey; 2Nephrology, Baskent University, Ankara, Turkey; 3Transplantation, Baskent University, Ankara, Turkey
Background: Rapamycin (Rp) is known to decrease VEGF synthesis, making it an option for recipients who develop malignant diseases. Anti-angiogenic and anti-proliferative properties of Rp also promote their usage in transplant to delay the development of allograft vasculopathy. Whereas Rp use may be complicated by the development of proteinuria and glomerulosclerosis (GS) in renal allografts. Because VEGF plays a crucial role in the glomerular function and vascular remodeling, we aimed to understand the effect of Rp on renal VEGF expression and, therefore on renal allograft prognosis.
Methods: Of 102 patients, 53 was under Rp therapy (Group R) and 49 was under calcineurin inhibitor therapy (Group C). Glomerular and interstitial leukocyte, lymphocyte and macrophage infiltration graded. Glomerular and PTC expression of VEGF and tubular and interstitial cell expression of TGF-β examined. The microvessel density (MVD) highlighted by CD31 immunostaining. Follow-up biopsies analyzed for the development of focal segmental glomerulosclerosis (FSGS), GS (> 30% of total glomeruli), and interstitial fibrosis (IF).
Results: The expression of VEGF in both glomeruli and PTCs was found significantly lower in Group R compared to Group C (P<0.001). A significant negative correlation found between the glomerular VEGF and the development of proteinuria, FSGS and GS (P<0.001). Group R showed higher incidence of FSGS (30%), GS (51%) and proteinuria (66%) compared to Group C (8,2%, 20,4%, and 40,8% respectively) (p<0.01). Also, the development of FSGS, GS and proteinuria was found early in Group R than Group C (p<0.001). Compared to Group C, Group R showed lower degrees of PTC-VEGF and tubulointerstitial TGF-β expression (p<0.001). The degree of MVD, interstitial leukocyte, lymphocyte and macrophage infiltration were found lower in Group R than Group C (p<0.01). Group R showed a lower incidence of IF development than Group C (P<0.001).The development of IF found to decrease with decreasing degree of PTC-VEGF expression, angiogenesis, inflammation, and tubulointerstitial TGF-β expression (p<0.001).
Conclusion: Rp treated patients showed a lower incidence of IF and the possible mechanism of this might be explained by the anti-proliferative, anti-VEGF and anti-angiogenic effect of Rp. The prevention of these processes will decline the density of cells that were secreting fibrotic mediators such as TGF-β. Whereas the anti-VEGF property of Rp, which is useful in preventing IF, causes early GS and proteinuria. Thus because of this detrimental effect, the patient must closely be monitored for proteinuria and early GS.