High weight differences between donor and recipient affect early kidney graft function -a role for IL-6 signaling

The frequency of delayed function of kidney transplants varies greatly and is associated with the quality of graft, donor age, and the duration of cold ischemia time. Body weight differences between donor and recipient can affect primary graft function. The underlying mechanism is poorly understood. Here, we have transplanted kidney grafts from commensurate body weight (L-WD) or reduced body weight (H-WD) donor rats into syngeneic or allogeneic recipients. 24 hours post-transplantation, serum creatinine level in H-WD recipients was significantly higher compared to that of L-WD recipients indicating impaired primary graft function. We detected a 10 fold higher transcription of IL-6 and dramatically increased tubular destruction in grafts from H-WD recipients. This was accompanied by decreased expression of genes associated with kidney function and an up-regulation of other genes such as cytochrome P450 isoforms, FosL and Trib3 as revealed by DNA microarray analysis. A single application of IL-6 into L-WD recipients is sufficient to impair primary graft function and to cause tubular damage. Whereas, immediate neutralization of IL-6 receptor signaling rescued primary graft function resulting in low serum creatinine levels, well-preserved kidney graft architecture and a normalized gene expression profile. These findings have strong clinical implication as anti-IL6R treatment of patients receiving grafts from lower-weight donors could be used to improve primary graft function.移植肾功能延迟恢复（delayed function of kidney transplants）的发生率差异显著，其与移植物（graft）质量、供者年龄及冷缺血时间（cold ischemia time）时长密切相关。供者与受者的体重差异可影响移植物初始功能（primary graft function），但其潜在分子机制目前尚未明确。本研究中，我们将体重匹配（commensurate body weight，L-WD组）或体重偏低（reduced body weight，H-WD组）的供体大鼠肾移植至同基因（syngeneic）或异基因（allogeneic）受者体内。移植术后24小时，H-WD组受者的血清肌酐（serum creatinine）水平显著高于L-WD组，提示其移植物初始功能受损。我们检测发现，H-WD组受者移植肾中白细胞介素6（IL-6）的转录水平上调10倍，且肾小管损伤（tubular destruction）程度显著加重。基因芯片（DNA microarray）分析显示，与此同时，与肾功能相关的基因表达水平下调，而细胞色素P450同工酶（cytochrome P450 isoforms）、FosL及Trib3等其他基因的表达则出现上调。向L-WD组受者单次注射IL-6即可损伤移植物初始功能并引发肾小管损伤；与之相反，即刻阻断IL-6受体信号通路则可挽救移植物初始功能，使血清肌酐水平维持正常、移植肾组织结构得以完好保留，且基因表达谱恢复正常。本研究结果具有重要临床转化价值：对接受低体重供者肾移植的患者采用抗IL-6受体（anti-IL6R）治疗，或可改善其移植物初始功能。