Activin inhibition limits early innate immune response in rat kidney allografts-a pilot study.

Activins are members of the transforming growth factor-beta (TGF-ß) superfamily of cytokines. They play critical roles in the onset of acute and chronic inflammatory responses. The aim of this study was to investigate how activin inhibition affects acute kidney injury and inflammation after transplantation. The study was carried out in kidney transplantation and renal ischemia-reperfusion models in the rat. Soluble activin type 2 receptor (sActRIIB-Fc) was used to inhibit activin signaling. Transplantation groups were as follows: (i) cyclosporine A (CsA) (ii) CsA + sActRIIB-Fc, (iii) CsA+ inactive protein control Fc-G1. IRI groups were as follows: (i) no treatment, (ii) sActRIIB-Fc. Serum activin B concentration was significantly elevated after transplantation and IRI, whereas activin A was produced locally in renal allografts. Activin inhibition efficiently limited neutrophil, macrophage, and dendritic cell infiltration to the allografts measured 72 h after transplantation. In addition, sActRIIB-Fc treatment modulated serum cytokine response after transplantation and reduced the early accumulation of fibroblasts in the graft interstitium. In conclusion activin inhibition reduces the innate immune response early after renal transplantation in the rat. It also limits the accumulation of fibroblasts in the graft suggesting that activins may be involved in the fibrogenic signaling already early after kidney transplantation.

Intensive perioperative simvastatin treatment protects from chronic kidney allograft injury.

BACKGROUND/AIMS: Ischemia-reperfusion injury (IRI) and innate immune response augment adaptive immunity and may also trigger repair processes that lead to uncontrolled fibrosis and atherosclerosis as seen in chronic allograft injury. Simvastatin has been shown to protect from renal IRI in several experimental studies. The aim of this study was to examine the effect of donor simvastatin pretreatment and early initiation of recipient simvastatin treatment on chronic kidney allograft injury. METHODS: A rat renal transplantation model was used. Simvastatin was administered perorally for donor (5 mg/kg) and/or for recipient (2 mg/kg) 2 hours before transplantation and/or as daily treatment starting on the first postoperative day (2 mg/kg/day). The study included 5 groups: (1) no simvastatin, (2) donor pretreatment, (3) daily recipient treatment, (4) donor pretreatment + daily recipient treatment and (5) donor pretreatment + recipient pretreatment + daily recipient treatment. The grafts were recovered at day 90 for histopathological and immunohistochemical analysis. Kidney function was followed weekly with serum creatinine, and 24-hour urine protein was measured 60 and 90 days after transplantation. RESULTS: We found that donor and recipient simvastatin pretreatment combined with daily recipient treatment reduced graft inflammation and chronic allograft injury. Treatment using only statins started after transplantation reduced inflammation to some extent, but did not affect chronic kidney allograft injury. Pretreatment using only donor statins impaired graft function and increased proteinuria. CONCLUSION: Our data suggest that perioperative recipient statin treatment reduces inflammation and may protect the graft in the long term.

Sirolimus inhibits lymphangiogenesis in rat renal allografts, a novel mechanism to prevent chronic kidney allograft injury.

Lymphangiogenesis occurs in renal allografts and it may be involved in the maintenance of the alloreactive immune response and thus participate in the development of chronic kidney allograft injury. Sirolimus (SRL) has been shown to inhibit lymphangiogenesis. The aim of this study was to describe lymphangiogenesis and its regulation during the development of chronic kidney allograft injury and to investigate the effect of SRL on allograft lymphangiogenesis and chronic kidney allograft injury. A rat renal transplantation model was used. Allografts treated with cyclosporine A or with SRL were analyzed in various time points. Syngenic transplantations were used as controls. Kidney function was followed with serum creatinine. Histology was analyzed by Chronic Allograft Damage Index (CADI). Immunohistochemistry was used to detect lymphatic vessels, VEGF-C and VEGFR-3. In cyclosporine-treated allografts VEGF-C/VEGFR-3 pathway was strongly upregulated leading to extensive lymphangiogenesis 60 days after transplantation. Lymphangiogenesis correlated positively with the CADI score. Sirolimus efficiently inhibited lymphangiogenesis, improved graft function and attenuated the development of chronic kidney allograft injury when compared with cyclosporine. In conclusion, lymphangiogenesis is associated with chronic kidney allograft injury and SRL is a potent inhibitor of lymphangiogenesis in renal allografts. Inhibition of lymphatic proliferation could mediate the nephroprotective properties of SRL.