Ishimura T, Fujisawa M, Isotani S, Higuchi A, Iijima K, Arakawa S, Hohenfellner K, Flanders K C, Yoshikawa N, Kamidono S
Department of Urology, Kobe University School of Medicine, Kobe, Japan.
Clin Transplant. 2001 Jun;15(3):185-91. doi: 10.1034/j.1399-0012.2001.150307.x.
The main cause of late graft loss or declining long-term graft function is chronic allograft nephropathy (CAN), characterized by progressive interstitial fibrosis. Transforming growth factor (TGF)-beta1 plays a key role in fibrogenesis. We immunohistochemically investigated whether the degree of TGF-beta1 expression in early biopsy specimens routinely obtained from stable allografts at 100 d could predict fibrosis and graft dysfunction in the late phase. Patients were children with grafts from related donors. We immunohistochemically determined intracellular and extracellular expression of TGF-beta1 in the graft using LC antibody (LC) for intracellular TGF-beta1 and CC antibody (CC) for extracellular TGF-beta1. The change in creatinine clearance between 100 d and 3 yr after transplantation (DeltaCcr) was used as an index of long-term graft function. We also used image analysis to calculate the relative area involved by interstitial fibrosis in the trichrome-stained section of graft biopsy specimens at 100 d and 3 yr, designating the change as DeltaFI. DeltaCcr was -4.2+/-9.4 mL/min in subjects with minimal early immunoreactivity for CC and -20.5+/-15.9 mL/min in subjects with strong reactivity (p<0.05). DeltaCcr was -14.5+/-18.6 mL/min in subjects with minimal early immunoreactivity for LC and -11.7+/-12.8 mL/min in those with strong reactivity. DeltaFI in subjects with minimal CC reactivity (1.28+/-4.11%) tended to be lower than that in subjects with strong reactivity (8.45+/-15.47%). Neither fibrosis at 100 d nor DeltaFI differed between subjects with minimal and strong LC reactivity. Thus, strong extracellular TGF-beta1 expression in grafts at 100 d after transplantation is associated with a long-term decline in graft function and tends to be associated with increased graft fibrosis at 3 yr.
移植肾晚期丢失或长期移植肾功能下降的主要原因是慢性移植肾肾病（CAN），其特征为进行性间质纤维化。转化生长因子（TGF）-β1在纤维化形成过程中起关键作用。我们采用免疫组织化学方法研究了在移植100天时从稳定移植肾常规获取的早期活检标本中TGF-β1的表达程度是否能够预测晚期纤维化和移植肾功能障碍。患者为接受亲属供体移植肾的儿童。我们使用针对细胞内TGF-β1的LC抗体（LC）和针对细胞外TGF-β1的CC抗体（CC），通过免疫组织化学方法测定移植肾中TGF-β1的细胞内和细胞外表达。将移植后100天至3年期间肌酐清除率的变化（ΔCcr）用作长期移植肾功能的指标。我们还利用图像分析计算了移植肾活检标本在100天和3年时经三色染色切片中间质纤维化累及的相对面积，将其变化称为ΔFI。CC早期免疫反应最低的受试者的ΔCcr为-4.2±9.4 mL/分钟，而反应强烈的受试者的ΔCcr为-20.5±15.9 mL/分钟（p<0.05）。LC早期免疫反应最低的受试者的ΔCcr为-14.5±18.6 mL/分钟，而反应强烈的受试者的ΔCcr为-11.7±12.8 mL/分钟。CC反应最低的受试者的ΔFI（1.28±4.11%）往往低于反应强烈的受试者（8.45±15.47%）。LC反应最低和强烈的受试者之间，100天时的纤维化程度和ΔFI均无差异。因此，移植后100天时移植肾中强烈的细胞外TGF-β1表达与移植肾功能的长期下降相关，并且在3年时往往与移植肾纤维化增加相关。
