Mechanisms of everolimus-induced glomerulosclerosis after glomerular injury in the rat

被引:47
作者
Daniel, C
Renders, L
Amann, K
Schulze-Lohoff, E
Hauser, IA
Hugo, C [1 ]
机构
[1] Univ Erlangen Nurnberg, Dept Hypertens & Nephrol, Erlangen, Germany
[2] Univ Erlangen Nurnberg, Dept Pathol, Erlangen, Germany
[3] Klinikum Koln Merheim, Med Clin 1, Cologne, Germany
[4] Goethe Univ Frankfurt, Dept Nephrol, D-6000 Frankfurt, Germany
关键词
anti-Thy1; model; glomerular regeneration; glomerular endothelial cell proliferation; rapamycin derivative everolimus; renal microvascular injury;
D O I
10.1111/j.1600-6143.2005.01120.x
中图分类号
R61 [外科手术学];
学科分类号
摘要
Despite the lack of nephrotoxicity, adverse effects of the new antiproliferative immunosuppressant everolimus have been reported. By varying time point and dose of everolimus treatment as well as the degree of glomerular injury, the specific conditions and potential mechanisms leading to adverse actions in the anti-Thy1 model have been determined. Only the combination of early and high-dose everolimus treatment (1-3 mg/kg bw) with a severe glomerular lesion ('full-dose' anti-Thy1 model) caused adverse effects with a high mortality rate, progressive apoptosis, crescent formation and glomerulosclerosis. In contrast, either later start or low-dose (0.3 mg/kg bw) therapy or treatment of a less severe lesion ('reduced dose' anti-Thy1 model) appeared to be relatively safe for the glomerular architecture. The adverse effects of everolimus were linked to its marked inhibition of endothelial cell, but not necessarily mesangial cell proliferation. In addition, everolimus markedly inhibited the angiogenic cytokine vascular endothelial growth factor in nephritic glomeruli in vivo. These experimental results suggest special caution regarding the use of everolimus in all situations of severe glomerular cell injury requiring extensive capillary repair, where at least adaption to a low dose needs to be considered.
引用
收藏
页码:2849 / 2861
页数:13
相关论文
共 38 条
  • [31] SDZ RAD, a new rapamycin derivative - Pharmacological properties in vitro and in vivo
    Schuler, W
    Sedrani, R
    Cottens, S
    Haberlin, B
    Schulz, M
    Schuurman, HJ
    Zenke, G
    Zerwes, HG
    Schreier, MH
    [J]. TRANSPLANTATION, 1997, 64 (01) : 36 - 42
  • [32] Sehgal S N, 1995, Curr Opin Nephrol Hypertens, V4, P482, DOI 10.1097/00041552-199511000-00004
  • [33] Shimizu A, 1997, AM J PATHOL, V151, P1231
  • [34] Shimizu A, 1996, CONTRIB NEPHROL, V118, P29
  • [35] Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use
    Smith, KD
    Wrenshall, LE
    Nicosia, RF
    Pichler, R
    Marsh, CL
    Alpers, CE
    Polissar, N
    Davis, CL
    [J]. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2003, 14 (04): : 1037 - 1045
  • [36] Apoptosis in glomerular sclerosis
    Sugiyama, H
    Kashihara, N
    Makino, H
    Yamasaki, Y
    Ota, Z
    [J]. KIDNEY INTERNATIONAL, 1996, 49 (01) : 103 - 111
  • [37] Effect of rapamycin and FK506 on mesangial cell proliferation
    Wang, W
    Chan, YH
    Lee, W
    Chan, L
    [J]. TRANSPLANTATION PROCEEDINGS, 2001, 33 (1-2) : 1036 - 1037
  • [38] Ziswiler R, 1998, J AM SOC NEPHROL, V9, P2055