Time course of upregulation of fibrogenic growth factors in a rodent model of chronic renal allograft rejection

Upregulation of growth factors has been shown in CR but the time point at which this occurs in not known. The aim of this study was to examine the time course of upregulation of growth factors and correlate this with the macrophage and myofibroblast interstitial infiltrate. Methods: Using a rat model of CR (F344 kidney donor to Lewis recipient), infiltration by ED1+ macrophages and proliferation of α-smooth muscle actin (α-SMA) and desmin-expressing cells was examined using immunohistochemistry. In addition, expression of mRNA for interferon-γ (IFN-γ), transforming growth factor-β (TGF-β), basic-fibroblast growth factor (b-FGF) and vascular endothelial growth factor (VEGF) was studied using a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) technique. Native Lewis rat kidney and Lewis–Lewis isografts were used as controls. Results: Immunohistochemical staining of ED1+ cells showed a marked increase in the macrophage infiltrate of allografts compared to isografts at all time periods (P=0.0002) peaking at weeks 8–12 after transplantation. Expression of α-SMA was also increased in allografts (P=0.002). RT-PCR analysis showed that mRNA for TGF-β was maximally upregulated in allografts in comparison to isografts at week 8 after engraftment (P=0.05) and declined thereafter, although remained at elevated levels compared to controls. IFN-γ and b-FGF gene expression was increased in allografts late in the post-transplantation period. Conclusion: Early infiltration of macrophages and production of TGF-β1 was followed by later upregulation of fibrogenic growth factors and myofibroblasts associated with interstitial fibrosis and organ dysfunction

KHA-CARI guideline: KHA-CARI adaptation of the KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients

The latest Caring for Australians with Renal Impairment (CARI) guideline detailing renal transplant care, developed as a local modification of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines

TLR4 activation mediates kidney ischemia/reperfusion injury

Ischemia/reperfusion injury (IRI) may activate innate immunity through the engagement of TLRs by endogenous ligands. TLR4 expressed within the kidney is a potential mediator of innate activation and inflammation. Using a mouse model of kidney IRI, we demonstrated a significant increase in TLR4 expression by tubular epithelial cells (TECs) and infiltrating leukocytes within the kidney following ischemia. TLR4 signaling through the MyD88-dependent pathway was required for the full development of kidney IRI, as both TLR4–/– and MyD88–/– mice were protected against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. In vitro, WT kidney TECs produced proinflammatory cytokines and chemokines and underwent apoptosis after ischemia. These effects were attenuated in TLR4–/– and MyD88–/– TECs. In addition, we demonstrated upregulation of the endogenous ligands high-mobility group box 1 (HMGB1), hyaluronan, and biglycan, providing circumstantial evidence that one or more of these ligands may be the source of TLR4 activation. To determine the relative contribution of TLR4 expression by parenchymal cells or leukocytes to kidney damage during IRI, we generated chimeric mice. TLR4–/– mice engrafted with WT hematopoietic cells had significantly lower serum creatinine and less tubular damage than WT mice reconstituted with TLR4–/– BM, suggesting that TLR4 signaling in intrinsic kidney cells plays the dominant role in mediating kidney damage