Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to ischemia/reperfusion

Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to ischemia/reperfusion.BackgroundIschemia/reperfusion (I/R) injury after organ transplantation is a major cause of delayed graft function. Following I/R, locally produced CXC chemokines attract and activate granulocytes, which in turn promote graft damage.MethodsWe examined the involvement of granulocyte recruitment via the CXCR2 pathway in a rat model of 4 hours cold ischemia followed by kidney transplantation. Serum creatinine and intragraft granulocyte infiltration were monitored in the early phase posttransplant. A CXCR2 inhibitor, repertaxin, was given to recipients before transplantation (at -24 hours or -8 hours or -2 hours), immediately before reperfusion and 2 hours later.ResultsAn increase of granulocyte chemoattractant CINC-1/interleukin-8 (IL-8) mRNA expression after I/R both in syngeneic and allogeneic transplantation was associated with a marked infiltration of granulocytes in renal tissue. In syngeneic transplantation, Lewis rats given 15 mg/kg repertaxin 24 hours before surgery had granulocyte graft infiltration and serum creatinine levels significantly reduced in respect to vehicle-treated animals. Intermediate effects were observed with 5 mg/kg, whereas the dose of 30 mg/kg had toxic effects. We found that reducing the pretreatment time to 8 hours before surgery was still effective. Prevention of granulocyte infiltration and serum creatinine increase was also obtained in allogeneic transplantation, when Brown Norway recipients of Lewis kidneys were given 15 mg/kg repertaxin starting 8 hours before surgery.ConclusionRepertaxin treatment of the recipient animal was effective in preventing granulocyte infiltration and renal function impairment both in syngeneic and in allogeneic settings. The possibility to modulate I/R injury in this rat model opens new perspectives for preventing posttransplant delayed graft function in humans

ACE inhibition limits chronic injury of kidney transplant even with treatment started when lesions are established

ACE inhibition limits chronic injury of kidney transplant even with treatment started when lesions are established.BackgroundInhibition of the renin-angiotensin system (RAS) prevents development of chronic allograft dysfunction in experimental animals. Whether this therapeutic approach is effective even if started when signs of allograft nephropathy are already manifested has not been investigated.MethodsTo address this issue, we studied the effect of a late treatment with the angiotensin-convertine enzyme (ACE) inhibitor trandolapril in the Fisher 344 to Lewis rat kidney transplant model. Seven months after transplant a renal biopsy was done for graft histology examination. Thereafter rats received either no treatment (allograft-none) or trandolapril until sacrifice at month 13.ResultsAll animals were alive at the end of the study with the exception of a rat in the untreated group that died of renal insufficiency at day 292. Despite the fact that the grafts had already signs of structural injury and function impairment at the time treatment was stated, trandolapril completely restored renal function to baseline pretransplant values. Trandolapril also halted the progression of glomerular damage and suppressed intragraft T-lymphocyte infiltration and reduced the expression of the chemokine monocyte chemoattractant protein-1 (MCP-1). However, trandolapril had no direct effect on T cell function, since in vivo treatment did not modify recipient T-cell alloreactivity against donor antigens.ConclusionThese findings provide the basis for a novel treatment intervention with RAS blockade that, together with pharmacologic inhibition of the immune response, could interrupt progression of chronic allograft dysfunction and injury

Predicting respiratory failure in patients infected by SARS-CoV-2 by admission sex-specific biomarkers

Background: Several biomarkers have been identified to predict the outcome of COVID-19 severity, but few data are available regarding sex differences in their predictive role. Aim of this study was to identify sex-specific biomarkers of severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19. Methods: Plasma levels of sex hormones (testosterone and 17β-estradiol), sex-hormone dependent circulating molecules (ACE2 and Angiotensin1-7) and other known biomarkers for COVID-19 severity were measured in male and female COVID-19 patients at admission to hospital. The association of plasma biomarker levels with ARDS severity at admission and with the occurrence of respiratory deterioration during hospitalization was analysed in aggregated and sex disaggregated form. Results: Our data show that some biomarkers could be predictive both for males and female patients and others only for one sex. Angiotensin1-7 plasma levels and neutrophil count predicted the outcome of ARDS only in females, whereas testosterone plasma levels and lymphocytes counts only in males. Conclusions: Sex is a biological variable affecting the choice of the correct biomarker that might predict worsening of COVID-19 to severe respiratory failure. The definition of sex specific biomarkers can be useful to alert patients to be safely discharged versus those who need respiratory monitoring

Imaging of the Porous Ultrastructure of the Glomerular Epithelial Filtration Slit

The ultrastructure of the glomerular filtration slit is still controversial. In the last 30 years, observations from transmission electron microscopy (TEM) and theoretical analysis of solute clearance produced conflicting results. Here, we used scanning EM with a high-sensitivity detector to image the deepest regions of the filtration slits and report a previously undescribed organization of the slits' ultrastructure. In contrast to previous TEM imaging, we observed circular and ellipsoidal pores in the podocyte junctions mainly located in the central region of the slit diaphragm. The normal mean pore radius estimated by digital morphometric analysis had a log-normal distribution, with an average value of 12.1 nm. In proteinuric pathologic conditions, the mean pore radius values were also log-normally distributed with the presence of some very large pores, exceeding the sizes observed in normal conditions. Our morphologic analysis suggests that the filtration slit is a heteroporous structure instead of the previously proposed zipper-like structure. Selective changes in the ultrastructural organization of the pores may be responsible for the increased filtration of plasma proteins in glomerular disease

Effects of Rituximab on Morphofunctional Abnormalities of Membranous Glomerulopathy

Background and objectives: In idiopathic membranous nephropathy (IMN), CD20 B-cell depletion by rituximab may induce nephrotic syndrome (NS) remission. Whether this is associated with kidney function restoration and regression of the glomerular pathology was evaluated