The detrimental effect of donor-specific antibodies is irrespective of its level in highly-immunized living donor kidney transplant recipients: A case-control series.

Background: The impact of donor-specific antibodies (DSA) in (highly-) immunized living donor kidney transplant recipients is reported differentially in various patient cohorts. Methods: We have performed a retrospective analysis of all consecutive HLA-incompatible living donor kidney transplant recipients in our center between 2010-2019. Recipients who underwent plasmafiltration for a positive CDC-crossmatch were excluded. For each DSA+ recipient (DSA+), one immunized recipient without DSA (pPRA+) and two non-immunized recipients (pPRA-) were included. Patient and graft survival were analyzed and a subgroup analysis of DSA+ recipients was performed. Results: For 63 DSA+ recipients, 63 PRA+ and 126 PRA- recipients were included. 26 (41%) had class I, 24 (38%) class II and 13 (21%) combined HLA class I and II DSA. Death-censored graft survival was inferior in DSA+ recipients compared to pPRA+ (HR 2.38 [95% CI 1.00-5.70]) as well as to pPRA- (HR 3.91 [1.86-8.22]). In multivariate analysis, DSA remained of negative influence on death-censored graft survival. Flowcytometric crossmatch, MFI value, HLA class and origin of DSA were not of significant impact. Conclusion: In our cohort of (highly-) immunized recipients, pretransplant DSA led to inferior death-censored graft survival. There were no "safe" DSA characteristics since only DSA per se impacted death-censored graft survival.

Predictors of postoperative cardiovascular complications up to 3 months after kidney transplantation.

BACKGROUND: Renal transplant patients have a high peri-operative risk for cardiovascular events. Pre-operative screening for cardiac ischaemia might lower this risk, but there are no specific guidelines. METHODS: We conducted a chart review for all renal transplants performed between January 2010 and December 2013. We collected data about patient characteristics, pre-operative cardiac evaluation before referral, diagnostic tests and interventions. Logistic regression analyses were then applied to relate these factors to the composite endpoint of cardiac death, myocardial infarction, coronary revascularisation or admission for heart failure within 3 months after transplantation. RESULTS: A total of 770 kidney transplants were performed in 751 patients. In 750 cases (97%) a referral to the cardiologist was made. Non-invasive ischaemia detection by myocardial perfusion scintigraphy, exercise stress test or dobutamine stress echocardiography was carried out in 631 cases (82%). Coronary angiography was performed in 85 cases, which revealed significant coronary artery disease in 19 cases. Prophylactic revascularisation was done in 7 cases. The incidence of the study endpoint was 8.6%. In multivariable regression analysis, age at transplantation, pre-transplant myocardial infarction or heart failure, post-operative decrease in haemoglobin and positive non-invasive ischaemia testing were significantly associated with the study endpoint. However, when analysed separately, none of the different non-invasive ischaemia detection modalities were related to the study endpoint. CONCLUSION: Especially those renal transplant candidates with a cardiac history carry a high risk for a cardiovascular event post-transplantation. Uniformity in cardiac screening of renal transplant candidates and better pre-operative preparation might lower this post-operative risk. Besides, post-transplant anaemia should be prevented.

Sotrastaurin in calcineurin inhibitor-free regimen using everolimus in de novo kidney transplant recipients.

Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor-free regimen were evaluated in this two-stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300 mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200 mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300 mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200 mg, 300 mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300 mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy.

The effect of low and ultra-low dosages Thymoglobulin on peripheral T, B and NK cells in kidney transplant recipients.

INTRODUCTION: Rabbit Anti-Thymocyte Globulin (r-ATG) is a polyclonal antibody preparation, used to prevent and treat acute rejection episodes after organ transplantation. However, despite more than 40 years of clinical use, the optimal dose of r-ATG is still not defined. To find a better balance between efficacy and infectious complications, we embarked on a controlled study and monitored the effect of low and ultra-low dosages Thymoglobulin (Genzyme) on peripheral T, B, and NK cells. PATIENTS AND METHODS: Kidney transplant recipients received either 0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg on the first 3 consecutive days post-transplantation. Thus, total doses were 1.5 mg/kg, 3.0 mg/kg and 6.0 mg/kg. A total of 40 patients were enrolled, including 11 controls. All patients were treated with Prednisolon, Advagraf (Astellas) and Mycophenolate Mofetil (Roche). T (CD3+), B (CD19+) and NK (CD3-CD16+56+) cells were analyzed by flow cytometry. Baseline cell counts were compared to forty age and sex matched healthy persons. Post-transplantation cell counts of the 3 Thymoglobulin groups were compared to the 11 control patients, who received no induction therapy. RESULTS: Absolute numbers of T, B, and NK cells were comparable in all patients pre-transplantation, but T and B cells were lower than in healthy persons (p=0.007 and p=0.0003, Mann Whitney test). In the first week, T cells and NK cells were significantly lower in all Thymoglobulin groups compared to controls. B cells were not affected. One month after Thymoglobulin NK cells had returned to control numbers in all groups, while T cells had already recovered to control counts in the 1.5 mg/kg group. During follow-up, T cells in the 3.0mg/kg group also returned to control values, but at one year the patients in the 6.0 mg/kg group still had significantly lower T cells (p=0.03). Patient and graft survival, rejection and infection incidence and renal function did not differ between groups. CONCLUSION: Patients with end stage renal disease have significantly lower peripheral T and B cell counts than healthy persons. (Ultra-) low Thymoglobulin schedules deplete peripheral lymphocytes in a dose dependent way. Knowledge of the duration of this depletion contributes to finding the optimal immunosuppressive strategy for kidney transplant recipients.

The calcineurin inhibitor tacrolimus allows the induction of functional CD4CD25 regulatory T cells by rabbit anti-thymocyte globulins.

Rabbit anti-thymocyte globulins (rATG) induce CD4(+)CD25(+)forkhead box P3 (FoxP3(+)) regulatory T cells that control alloreactivity. In the present study, we investigated whether rATG convert T cells into functional CD4(+)CD25(+)FoxP3(+)CD127(-/low) regulatory T cells in the presence of drugs that may hamper their induction and function, i.e. calcineurin inhibitors. CD25(neg) T cells were stimulated with rATG or control rabbit immunoglobulin G (rIgG) in the absence and presence of tacrolimus for 24 h. Flow cytometry was performed for CD4, CD25, FoxP3 and CD127 and the function of CD25(+) T cells was examined in suppression assays. MRNA expression profiles were composed to study the underlying mechanisms. After stimulation, the percentage CD4(+)CD25(+)FoxP3(+)CD127(-/low) increased (from 2% to 30%, mean, P < 0.01) and was higher in the rATG samples than in control rIgG samples (2%, P < 0.01). Interestingly, FoxP3(+)T cells were also induced when tacrolimus was present in the rATG cultures. Blockade of the interleukin (IL)-2 pathway did not affect the frequency of rATG-induced FoxP3(+) T cells. The rATG tacrolimus-induced CD25(+) T cells inhibited proliferative responses of alloantigen-stimulated effector T cells as vigorously as rATG-induced and natural CD4(+)CD25(+)FoxP3(+)CD127(-/low) T cells (67% +/- 18% versus 69% +/- 16% versus 45% +/- 20%, mean +/- standard error of the mean, respectively). At the mRNA-expression level, rATG-induced CD25(+) T cells abundantly expressed IL-10, IL-27, interferon (IFN)-gamma, perforin and granzyme B in contrast to natural CD25(+) T cells (all P = 0.03), while FoxP3 was expressed at a lower level (P = 0.03). These mRNA data were confirmed in regulatory T cells from kidney transplant patients. Our findings demonstrate that tacrolimus does not negatively affect the induction, phenotype and function of CD4(+)CD25(+) T cells, suggesting that rATG may induce regulatory T cells in patients who receive tacrolimus maintenance therapy.