Reduced functional measure of cardiovascular reserve predicts admission to critical care unit following kidney transplantation

Background: There is currently no effective preoperative assessment for patients undergoing kidney transplantation that is able to identify those at high perioperative risk requiring admission to critical care unit (CCU). We sought to determine if functional measures of cardiovascular reserve, in particular the anaerobic threshold (VO2AT) could identify these patients. Methods: Adult patients were assessed within 4 weeks prior to kidney transplantation in a University hospital with a 37-bed CCU, between April 2010 and June 2012. Cardiopulmonary exercise testing (CPET), echocardiography and arterial applanation tonometry were performed. Results: There were 70 participants (age 41.7614.5 years, 60% male, 91.4% living donor kidney recipients, 23.4% were desensitized). 14 patients (20%) required escalation of care from the ward to CCU following transplantation. Reduced anaerobic threshold (VO2AT) was the most significant predictor, independently (OR = 0.43; 95% CI 0.27–0.68; p,0.001) and in the multivariate logistic regression analysis (adjusted OR = 0.26; 95% CI 0.12–0.59; p = 0.001). The area under the receiveroperating- characteristic curve was 0.93, based on a risk prediction model that incorporated VO2AT, body mass index and desensitization status. Neither echocardiographic nor measures of aortic compliance were significantly associated with CCU admission. Conclusions: To our knowledge, this is the first prospective observational study to demonstrate the usefulness of CPET as a preoperative risk stratification tool for patients undergoing kidney transplantation. The study suggests that VO2AT has the potential to predict perioperative morbidity in kidney transplant recipients

Steroids in kidney transplant patients

Any evaluation of steroids in kidney transplantation is hampered by individual variability in metabolism, the lack of clinically available steroid blood levels, and overall little attention to steroid exposure. Many feel that steroids were an essential part of chronic immunosuppression in past decades but may no longer be necessary in low-risk populations when our newer and more potent drugs are used. Potential differences in long-term outcome will be unapparent in short-term antibody induction studies in low-risk patients, particularly with low on steroid doses, as may have happened in the recent, well-done Astellas trial. In many studies, the evidence for the superiority of mycophenolate (MMF) and tacrolimus (TAC) was not as strong as the evidence for the benefit of steroids in the Canadian cyclosporine study. As the practice of steroid withdrawal has increased, we have not seen the improvement in long-term graft survival that many expected with our newer agents. Steroids have immunosuppressive effects even in doses that are low by historic standards, and side effects may not justify their abandonment

Prolonged Graft Survival in Older Recipient Mice Is Determined by Impaired Effector T-Cell but Intact Regulatory T-Cell Responses

Elderly organ transplant recipients represent a fast growing segment of patients on the waiting list. We examined age-dependent CD4+ T-cell functions in a wild-type (WT) and a transgenic mouse transplant model and analyzed the suppressive function of old regulatory T-cells. We found that splenocytes of naïve old B6 mice contained significantly higher frequencies of T-cells with an effector/memory phenotype (CD4+CD44highCD62Llow). However, in-vitro proliferation (MLR) and IFNγ-production (ELISPOT) were markedly reduced with increasing age. Likewise, skin graft rejection was significantly delayed in older recipients and fewer graft infiltrating CD4+T-cells were observed. Old CD4+ T-cells demonstrated a significant impaired responsiveness as indicated by diminished proliferation and activation. In contrast, old alloantigen-specific CD4+CD25+FoxP3+ T-cells demonstrated a dose-dependent well-preserved suppressor function. Next, we examined characteristics of 18-month old alloreactive T-cells in a transgenic adoptive transfer model. Adoptively transferred old T-cells proliferated significantly less in response to antigen. Skin graft rejection was significantly delayed in older recipients, and graft infiltrating cells were reduced. In summary, advanced recipient age was associated with delayed acute rejection and impaired CD4+ T-cell function and proliferation while CD4+CD25+FoxP3+ T-cells (Tregs) showed a well-preserved function

DRhigh+CD45RA−-Tregs Potentially Affect the Suppressive Activity of the Total Treg Pool in Renal Transplant Patients

Recent studies show that regulatory T cells (Tregs) play an essential role in tolerance induction after organ transplantation. In order to examine whether there are differences in the composition of the total CD4+CD127low+/−FoxP3+- Treg cell pool between stable transplant patients and patients with biopsy proven rejection (BPR), we compared the percentages and the functional activity of the different Treg cell subsets (DRhigh+CD45RA−-Tregs, DRlow+CD45RA−-Tregs, DR−CD45RA−-Tregs, DR−CD45RA+-Tregs). All parameters were determined during the three different periods of time after transplantation (0–30 days, 31–1,000 days, >1,000 days). Among 156 transplant patients, 37 patients suffered from BPR. The most prominent differences between rejecting and non-rejecting patients were observed regarding the DRhigh+CD45RA−-Treg cell subset. Our data demonstrate that the suppressive activity of the total Treg pool strongly depends on the presence of these Treg cells. Their percentage within the total Treg pool strongly decreased after transplantation and remained relatively low during the first year after transplantation in all patients. Subsequently, the proportion of this Treg subset increased again in patients who accepted the transplant and reached a value of healthy non-transplanted subjects. By contrast, in patients with acute kidney rejection, the DRhigh+CD45RA−-Treg subset disappeared excessively, causing a reduction in the suppressive activity of the total Treg pool. Therefore, both the monitoring of its percentage within the total Treg pool and the monitoring of the HLA-DR MFI of the DR+CD45RA−-Treg subset may be useful tools for the prediction of graft rejection

N-Octanoyl-Dopamine inhibits cytokine production in activated T-cells and diminishes MHC-class-II expression as well as adhesion molecules in IFN gamma-stimulated endothelial cells

IFN gamma enhances allograft immunogenicity and facilitates T-cell mediated rejection. This may cause interstitial fibrosis and tubular atrophy (IFTA), contributing to chronic allograft loss. We assessed if inhibition of T-cell activation by N-octanoyl dopamine (NOD) impairs adherence of activated T-cells to endothelial cells and the ability of activated T-cells to produce IFN gamma. We also assessed if NOD affects IFN gamma mediated gene expression in endothelial cells. The presence of NOD during T-cell activation significantly blunted their adhesion to unstimulated and cytokine stimulated HUVEC. Supernatants of these T-cells displayed significantly lower concentrations of TNF alpha and IFN gamma and were less capable to facilitate T-cell adhesion. In the presence of NOD VLA-4 (CD49d/CD29) and LFA-1 (CD11a/CD18) expression on T-cells was reduced. NOD treatment of IFN gamma stimulated HUVEC reduced the expression of MHC class II transactivator (CIITA), of MHC class II and its associated invariant chain CD74. Since IFTA is associated with T-cell mediated rejection and IFN gamma to a large extent regulates immunogenicity of allografts, our current data suggest a potential clinical use of NOD in the treatment of transplant recipients. Further in vivo studies are warranted to confirm these in vitro findings and to assess the benefit of NOD on IFTA in clinically relevant models