Rodrigo E, López-Hoyos M, Escallada R, Fernández-Fresnedo G, Ruiz J C, Piñera C, Cotorruelo J G, Zubimendi J A, de Francisco A L, Arias M
Nephrology Unit, University Hospital Marqués de Valdecilla, Insalud, 39008 Santander, Spain.
Nephrol Dial Transplant. 2000 Dec;15(12):2041-5. doi: 10.1093/ndt/15.12.2041.
Chronic transplant nephropathy remains the major cause of graft loss after the first year post transplant, with the exception of death with functioning graft. The histological hallmark of chronic kidney rejection is progressive fibrosis in which extracellular matrix turnover plays an important role. This turnover is regulated by several systems of connective tissue proteases, the matrix metalloproteinases family being one of them. Every metalloproteinase exerts a different function over extracellular matrix proteins and can contribute to the pathogenesis of several diseases, such as rheumatoid arthritis and glomerulonephritis. The role of metalloproteinases in the pathogenesis of chronic transplant nephropathy and in kidney transplantation has not yet been addressed.
We measured the serum levels of proMMP-1, proMMP-2 and proMMP-3 by ELISA in 40 patients with chronic transplant nephropathy, 30 with acute rejection, 30 with stable graft function for a time equivalent to chronic transplant nephropathy, 30 with stable graft function for a time equivalent to acute rejection, and 30 healthy age-paired blood donors.
Serum proMMP-2 and proMMP-3 were significantly higher in patients with chronic transplant nephropathy than in patients with acute rejection, stable graft function and healthy donors. The most striking finding was the significant positive correlation observed between serum levels of proMMP-3 and serum creatinine, and between circulating levels of proMMP-2 and proteinuria. Serum concentration of proMMP-1 was increased in patients with acute rejection compared with those with stable graft function and healthy donors.
Serum proMMP-2 and proMMP-3 reflect the changes of glomerular and interstitial extracellular matrix in chronic transplant nephropathy, suggesting that they could play a role in the pathogenesis of this condition. Acute rejection is associated with increased levels of proMMP-1, which could be a reflection of the stimulation induced by a number of inflammatory cytokines produced in such a process.
除移植肾仍有功能的死亡情况外，慢性移植肾肾病仍是移植术后第一年移植物丢失的主要原因。慢性肾排斥反应的组织学特征是进行性纤维化，其中细胞外基质周转起重要作用。这种周转受结缔组织蛋白酶的多个系统调节，基质金属蛋白酶家族是其中之一。每种金属蛋白酶对细胞外基质蛋白发挥不同功能，并可导致多种疾病的发病机制，如类风湿性关节炎和肾小球肾炎。金属蛋白酶在慢性移植肾肾病发病机制及肾移植中的作用尚未得到研究。
我们采用酶联免疫吸附测定法（ELISA）检测了40例慢性移植肾肾病患者、30例急性排斥反应患者、30例移植肾功能稳定且时间与慢性移植肾肾病相当的患者、30例移植肾功能稳定且时间与急性排斥反应相当的患者以及30例年龄匹配的健康献血者血清中前基质金属蛋白酶-1（proMMP-1）、前基质金属蛋白酶-2（proMMP-2）和前基质金属蛋白酶-3（proMMP-3）的水平。
慢性移植肾肾病患者血清中的proMMP-2和proMMP-3显著高于急性排斥反应患者、移植肾功能稳定患者及健康献血者。最显著的发现是，血清proMMP-3水平与血清肌酐之间以及proMMP-2循环水平与蛋白尿之间存在显著正相关。与移植肾功能稳定的患者及健康献血者相比，急性排斥反应患者血清proMMP-1浓度升高。
血清proMMP-2和proMMP-3反映了慢性移植肾肾病中肾小球和间质细胞外基质的变化，表明它们可能在该病的发病机制中起作用。急性排斥反应与proMMP-1水平升高有关，这可能反映了该过程中产生的多种炎性细胞因子所诱导的刺激。
