Cardiotrophin-1 Improves Kidney Preservation, Graft Function, and Survival in Transplanted Rats

Abstract

Background Cold ischemia-reperfusion injury is unavoidable during organ transplantation, and prolonged preservation is associated with poorer function recovery. Cardiotrophin-1 (CT-1) is an IL-6 family cytokine with cytoprotective properties. This preclinical study in rats tested whether CT-1 mitigates cold renal ischemia-reperfusion injury in the context of the transplantation of long-time preserved kidneys. Methods Kidneys were flushed with cold (4°C) University of Wisconsin solution containing 0.2 μg/mL CT-1 and stored for several periods of time at 4°C in the same solution. In a second approach, kidneys were first cold-preserved for 6 hours and then were perfused with University of Wisconsin solution containing CT-1 (0, 16, 32, or 64 μg/mL) and further cold-preserved. Organ damage markers were measured in the kidneys at the end of the storage period. For renal transplantation, recipient consanguineous Fischer rats underwent bilateral nephrectomy and received a previously cold-preserved (24 hours) kidney as described above. Survival and creatinine clearance were monitored over 30 days. Results Cardiotrophin-1 in perfusion and preservation fluids reduced oxidative stress markers (superoxide anion and inducible nitric oxide synthase), inflammation markers (NF-κB and tumor necrosis factor-α), and vascular damage (vascular cell adhesion molecule-1) and activated leukemia inhibitory factor receptor and STAT-3 survival signaling. Transplantation of kidneys cold-preserved with CT-1 increased rat survival and renal function (ie, lower plasma creatinine and higher creatinine clearance) and improved kidney damage markers after transplantation (ie, lower superoxide anion, tumor necrosis factor-α, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and higher NF-κB). Conclusions Cardiotrophin-1 represents a novel therapeutic strategy to reduce ischemia-reperfusion and cold preservation injury to rescue suboptimal kidneys and, consequently, to improve the clinical outcomes of renal transplantation.

Cardiotrophin‐1 therapy reduces disease severity in a murine model of glomerular disease

“…In conclusion, our study demonstrates that CT‐1 can maintain glomerular function and delay disease progression in mice with established glomerular disease. Together with previous studies demonstrating a renoprotective effect of CT‐1 in the context of acute (Garcia‐Cenador et al., 2013 , 2018 ; Quiros et al., 2013 , 2016 ) and chronic (Perretta‐Tejedor et al., 2019 ) kidney injury, CT‐1 is emerging as a promising therapeutic target in kidney disease.…”

“…With regard to kidney disease, CT‐1 administration is protective in rat models of acute kidney disease induced by either gentamicin (Quiros et al., 2016 ), contrast media (Quiros et al., 2013 ) or ischemia–reperfusion (Garcia‐Cenador et al., 2013 , 2018 ) resulting in improved renal function and lower levels of pro‐inflammatory cytokines and leukocyte‐adhesion molecules. In a mouse model of tubulointerstitial fibrosis induced by unilateral ureteral obstruction, lack of endogenous CT‐1 exacerbates tubular injury and fibrosis resulting in enhanced renal expression of adhesion molecules and macrophage markers indicating increased inflammation.…”

Renoprotective effects of cardiotrophin‐1 in a mouse model of chronic kidney disease

“…CT‐1 has since been associated with cytoprotective effects in various organ systems such as the central nervous system and the liver. The cytokine has also been suggested to have renoprotective effects in acute conditions such as ischaemia‐reperfusion injury in both transplanted and native kidneys and drug‐induced nephrotoxicity but has not previously been investigated in CKD. In the present study, Perretta‐Tejedor et al use the UUO model in mice with genetic deficiency of CT‐1 and show convincing data of aggravated renal damage in CT‐1‐deficient mice compared to wild‐type littermate controls.…”