High Weight Differences between Donor and Recipient Affect Early Kidney Graft Function—A Role for Enhanced IL-6 Signaling

Abstract

The frequency of delayed function of kidney transplants varies greatly and is associated with quality of graft, donor age and the duration of cold ischemia time. Furthermore, body weight differences between donor and recipient can affect primary graft function, but the underlying mechanism is poorly understood. We transplanted kidney grafts from commensurate body weight (L-WD) or reduced body weight (H-WD) donor rats into syngeneic or allogeneic recipients. Twenty-four hours posttransplantation, serum creatinine levels in H-WD recipients were significantly higher compared to L-WD recipients indicating impaired primary graft function. This was accompanied by upregulation of IL-6 transcription and increased tubular destruction in grafts from H-WD recipients. Using DNA microarray analysis, we detected decreased expression of genes associated with kidney function and an upregulation of other genes such as Cyp3a13, FosL and Trib3. A single application of IL-6 into L-WD recipients is sufficient to impair primary graft function and cause tubular damage, whereas immediate neutralization of IL-6 receptor signaling in H-WD recipients rescued primary graft function with 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 lowerweight donors could be used to improve primary graft function. † Both the authors contributed equally to this work.

Short-Term TNF-Alpha Inhibition Reduces Short-Term and Long-Term Inflammatory Changes Post-Ischemia/Reperfusion in Rat Intestinal Transplantation

“…The reduction of TNF>-induced IRI may not only improve short-and long-term graft survival; recent data suggest that IRI minimization may be a key element of tolerance induction (30,31).…”

LIF in the regulation of T-cell fate and as a potential therapeutic

“…58 A potential role of increased levels of IL-6 in human kidney graft rejection has been suggested 59 andgiven the opposing reciprocity between LIF and IL-6 as detailed later 34 -this may relate to the finding of a correlation between enhanced IL-6 signalling and poor primary kidney graft function in the clinic. 60 LIF delivered to CD4 þ cells via biodegradable PLGA nanoparticles guided the in vivo alloimmune response toward CD4 þ Foxp3 þ Treg, while treatment with anti-LIF had the opposite effect 34 demonstrating an allospecific, LIF-specific, effect. This places LIF at odds with IL-6 in terms of T-cell function, IL-6 being pro-inflammatory and a driver of TH17 lineage development in the presence of transforming growth factor-b.…”

Biomarkers for renal transplantation: where are we?

“…7,22 They may be caused by multiple factors, such as utilization of DBD, 22 donors from cardiac death (DCD), 7 or there may be a weight difference between the donor and recipient, resulting in acute tubular necrosis, post-transplantation oliguria, and even an increased risk of acute rejection episodes. 23 Indeed, post-transplantation renal allograft function of DCD recipients is comparable to that of DBD patients, although their influential mechanisms are different. 22,24 Therefore, early identification of DGF and PNF is of great value and interest for clinicians and researchers, which will benefit prognostic stratification of renal transplant patients and eventually improve transplant outcome.…”