Hypercholesterolemia (HC) increases the risk of acute rejection (AR) and leads to chronic rejection (CR) through decreasing endothelial cell surface antigens and increasing both epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT)
B. Handan Ozdemir1, Alev Ok Atilgan1, Aydan Akyuz Ozdemir2, Ebru H. Ayvazoglu Soy3, Mehmet A. Haberal3.
1Pathology, Baskent University, Ankara, Turkey; 2Public Helath, Baskent University, Ankara, Turkey; 3Transplantation, Baskent University, Ankara, Turkey
Background: HC is a critical contributor to chronic allograft injury as a “non-immune” risk factor. HC believed to be an integral part of the CR process by the accumulation of oxidized LDL cholesterol in the kidney interstitium and arterial walls leading to interstitial fibrosis (IF) and transplant arteriosclerosis (TA). This study aimed to show the influence of HC on the risk of development of AR and CR.
Methods: The presence of HC (>200mg/dl) diagnosed according to the first six months mean total cholesterol levels after transplant. Among 170 patients, 75 (44%) had HC and 95 (56%) had normal cholesterol levels (NC). CD31, vWF, and VEGF expression of peritubular capillaries (PTCs) and vascular endothelium studied to show the presence or absence of EC surface antigens. Vascular and tubular F-actin and α-SMA expression evaluated to show the development of tubular EMT and vascular EndoMT. Angiogenesis highlighted with CD31 and VEGF. Both tubular and inflammatory cell TGF-β and TNF-α expression studied. Follow-up biopsies analyzed for the development of AR, TA, IF, and CR.
Results: The mean AR episodes, the degree of inflammation, the development of proteinuria, the degree of both tubular and inflammatory cell TGF-β and TNF-α expression were found significantly higher in HC group compared to NC group (p<0.001). The degree of the loss of EC surface antigens (CD31, vWF, VEGF) on PTCs and arteries and the degree of F-actin and α-SMA expression on both vasculature and tubules found to be highest in HC group compared to NC Group (p<0.01). The degree of angiogenesis noted lowest in HC group. The risk of the development of IF and TA during 18 months found higher in recipients with HC (P<0.001). The development of IF and TA showed a significant correlation with the loss of EC surface antigens and with the degree of F-actin and α-SMA expression on both vasculature and tubules (p<0.01). The mean graft survival was 91,8±34 and 70,8±39 months for patients with NC and HC respectively (p<0.001).
Conclusion: HC can activate the inflammatory response and lead to a series of pathological changes such as EMT and EndoMT in renal tissue. Thus both inflammatory factors and lipid dysmetabolism can aggravate damage in the kidney and cause early development of IF, TA, and CR. Because HC in the recipient increases the rate of AR and the risk of late graft loss, it is important to control cholesterol levels in kidney transplant recipients.
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