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Due to its high sensitivity, the flow cytometry cross‐match (FCXM) has been described as valuable tool for identifying an optimal donor. We here focused on the impact of ABO incompatibility on FCXM results. We analyzed 29 ABO incompatible and 89 ABO compatible donor‐recipient pairs (73 and 175 datasets, respectively) prior to living donor kidney transplantation. In all patients, lymphocytotoxic cross‐matches for B and T cells were negative. Recipients with blood group O (A to O and B to O) displayed significantly (P <0.05) higher T‐FCXM results than those with blood group A and B (A to B, B to A and AB to A), respectively. Donor‐specific T‐FCXM responses (ΔMFI values) were significantly higher (P <0.05) in ABO incompatible vs. compatible pairs (ABO incompatible recipients with blood group O: 32 ± 6; with blood group A: 19 ± 7; with blood group B: 7 ± 4; recipients with ABO compatibility: 3 ± 2, respectively, data represent mean ± SEM). Consistent with the T‐FCXM results donor‐specific isohemagglutinins (IgG titers) were significantly higher in recipients with blood group O vs. A, both prior to rituximab treatment and plasmapheresis/immune adsorption (P =0.004) and immediately prior to transplantation, i.e., after rituximab and antibody‐depleting therapies (P =0.04). ABO incompatibility was associated with higher T‐FCXM responses, especially in recipients with blood group O. This finding has major impact on the interpretation of flow cross‐match results. Current cut‐off values need to be reassessed in the ABO incompatible setting. © 2016 International Clinical Cytometry Society

ZEUS study was an open-label, 12-month, multicenter study in which 300 de novokidney transplant recipients were randomized to continue receiving cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant. Five-year follow-up data were available for 245/269 patients (91.1%) who completed the core 12-month study (123 everolimus, 109 CsA). At 5 years, adjusted estimated GFR was 66.2 mL/min/1.73 m2with everolimus versus 60.9 mL/min/1.73 m2with CsA; the mean difference was 5.3 mL/min/1.73 m2in favor of everolimus (95% CI 2.4, 8.3; p < 0.001 [intent-to-treat population]). In a post hocanalysis of patients remaining on study drug at 5 years (everolimus 77, CsA 86), mean difference was 8.2 mL/min/1.73 m2(95% CI 4.3, 12.1; p < 0.001) in favor of everolimus. The cumulative incidence of biopsy-proven acute rejection postrandomization was 13.6% with everolimus versus 7.5% with CsA (p = 0.095), largely accounted for by grade I rejection (16/21 patients and 7/11 patients, respectively). Postrandomization, graft loss, mortality, serious adverse events and neoplasms were similar in both arms. In conclusion, conversion of kidney transplant patients to everolimus at 4.5 months posttransplant is associated with a significant improvement in renal function that is maintained to at least 5 years. The increase in early mild acute rejection did not affect long-term graft function.

Five‐year follow‐up data from the open‐label, 12‐month, multicenter ZEUS study, in which kidney transplant recipients were randomized to continue on cyclosporine or convert to everolimus posttransplant, show that a significant improvement in renal function in everolimus‐treated patients is maintained and that an increase in early acute rejection does not affect long‐term graft function.

The long‐term effect of conversion from calcineurin inhibitor (CNI) therapy to an mTOR inhibitor requires clarification. Following completion of the 12‐month, open‐label, multicenter ZEUS study, in which 300 kidney transplant recipients were randomized to continue cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant, outcomes were assessed at month 36 (n = 284; 94.7%). CNI therapy was reintroduced in 28.4% of everolimus patients by month 36. The primary efficacy endpoint, estimated glomerular filtration rate (Nankivell, ANCOVA) was significantly higher with everolimus versus the CsA group at month 24 (7.6 mL/min/1.73 m2, 95%CI 4.3, 11.0 mL/min/1.73 m2; p < 0.001) and month 36 (7.5 mL/min/1.73 m2, 95%CI 3.6, 11.4 mL/min/1.73 m2; p < 0.001). The incidence of biopsy‐proven acute rejection from randomization to month 36 was 13.0% in the everolimus arm and 4.8% in the CsA arm (p = 0.015). Patient and graft survival, as well as incidences of malignancy, severe infections and hospitalization, were similar between groups. Kidney transplant patients who are converted from CsA to everolimus at month 4.5 and who remain on everolimus thereafter may achieve a significant improvement in renal function that is maintained to 3 years. There was a significantly higher rate of rejection in the everolimus arm but this did not exert a deleterious effect by 3 years posttransplant.

The long-term effect of conversion from calcineurin inhibitor (CNI) therapy to an mTOR inhibitor requires clarification. Following completion of the 12-month, open-label, multicenter ZEUS study, in which 300 kidney transplant recipients were randomized to continue cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant, outcomes were assessed at month 36 (n = 284; 94.7%). CNI therapy was reintroduced in 28.4% of everolimus patients by month 36. The primary efficacy endpoint, estimated glomerular filtration rate (Nankivell, ANCOVA) was significantly higher with everolimus versus the CsA group at month 24 (7.6 mL/min/1.73 m2, 95%CI 4.3, 11.0 mL/min/1.73 m2; p < 0.001) and month 36 (7.5 mL/min/1.73 m2, 95%CI 3.6, 11.4 mL/min/1.73 m2; p < 0.001). The incidence of biopsy-proven acute rejection from randomization to month 36 was 13.0% in the everolimus arm and 4.8% in the CsA arm (p = 0.015). Patient and graft survival, as well as incidences of malignancy, severe infections and hospitalization, were similar between groups. Kidney transplant patients who are converted from CsA to everolimus at month 4.5 and who remain on everolimus thereafter may achieve a significant improvement in renal function that is maintained to 3 years. There was a significantly higher rate of rejection in the everolimus arm but this did not exert a deleterious effect by 3 years posttransplant.

Definition of acute renal allograft rejection (AR) markers remains clinically relevant. Features of T-cell-mediated AR are tubulointerstitial and vascular inflammation associated with excessive extracellular matrix (ECM) remodeling, regulated by metzincins, including matrix metalloproteases (MMP). Our study focused on expression of metzincins (METS), and metzincins and related genes (MARGS) in renal allograft biopsies using four independent microarray data sets. Our own cases included normal histology (N, n 20), borderline changes (BL, n 4), AR (n 10) and AR IFTA (n 7). MARGS enriched in all data sets were further examined on mRNA andor protein level in additional patients. METS and MARGS differentiated AR from BL, AR IFTA and N in a principal component analysis. Their expression changes correlated to Banff t- and i-scores. Two AR classifiers, based on METS (including MMP7, TIMP1), or on MARGS were established in our own and validated in the three additional data sets. Thirteen MARGS were significantly enriched in AR patients of all data sets comprising MMP7, -9, TIMP1, -2, thrombospondin2 (THBS2) and fibrillin1. RT-PCR using microdissected glomerulitubuli confirmed MMP7, -9 and THBS2 microarray results; immunohistochemistry showed augmentation of MMP2, -9 and TIMP1 in AR. TIMP1 and THBS2 were enriched in AR patient serum. Therefore, differentially expressed METS and MARGS especially TIMP1, MMP7-9 represent potential molecular AR markers.

Definition of acute renal allograft rejection (AR) markers remains clinically relevant. Features of T-cell– mediated AR are tubulointerstitial and vascular inflammation associated with excessive extracellular matrix (ECM) remodeling, regulated by metzincins, including matrix metalloproteases (MMP). Our study focused on expression of metzincins (METS), and metzincins and related genes (MARGS) in renal allograft biopsies using four independent microarray data sets. Our own cases included normal histology (N, n = 20), borderline changes (BL, n = 4), AR (n = 10) and AR + IF/TA (n = 7). MARGS enriched in all data sets were further examined on mRNA and/or protein level in additional patients.METS andMARGS differentiated AR from BL, AR + IF/TA and N in a principal component analysis. Their expression changes correlated to Banff t- and iscores. Two AR classifiers, based on METS (including MMP7, TIMP1), or on MARGS were established in our own and validated in the three additional data sets. Thirteen MARGS were significantly enriched in AR patients of all data sets comprising MMP7, -9, TIMP1, -2, thrombospondin2 (THBS2) and fibrillin1. RT-PCR using microdissected glomeruli/tubuli confirmed MMP7, -9 and THBS2 microarray results; immunohistochemistry showed augmentation of MMP2, -9 and TIMP1 in AR. TIMP1 and THBS2 were enriched in AR patient serum. Therefore, differentially expressed METS and MARGS especially TIMP1, MMP7/ -9 represent potential molecular AR markers.

FTY720 is a novel immunomodulator investigated in de novorenal transplantation and other therapeutic areas including multiple sclerosis. This 1-year multicenter, randomized, phase III study in 668 de novorenal transplant patients compared FTY720 2.5 mg plus full-dose cyclosporine (FDC) or FTY720 5.0 mg plus reduced-dose cyclosporine (RDC), with mycophenolate mofetil (MMF) plus FDC. The primary efficacy endpoint was the composite incidence of first treated biopsy-proven acute rejection (BPAR), graft loss, death or premature study discontinuation at month 12. Primary efficacy with FTY720 2.5 mg and MMF (32.4 and 30.2; p NS), plus mortality and BPAR incidence, were comparable. Patients receiving FTY720 5.0 mg plus RDC were discontinued from treatment due to increased risk of acute rejection (primary endpoint incidence 47.3). FTY720 was associated with lower creatinine clearance (month 12: 53.1, 56.0 vs. 65.1 mLmin; p < 0.001) and more macular edema cases (2.2 and 1.3 vs. 0), whereas cytomegalovirus infections were higher with MMF (6.2 and 10.6 vs. 18.1 p < 0.0001 and p 0.0139, respectively). FTY720 2.5 mg provided comparable rejection prophylaxis over 12 months versus MMF; however, FTY720 5.0 mg did not support a 50 reduction in cyclosporine exposure. The cause of macular edema cases and lower creatinine clearance with FTY720 in de novotransplantation needs further investigation.

FTY720 is a novel immunomodulator investigated in de novorenal transplantation and other therapeutic areas including multiple sclerosis. This 1-year multicenter, randomized, phase III study in 668 de novorenal transplant patients compared FTY720 2.5 mg plus full-dose cyclosporine (FDC) or FTY720 5.0 mg plus reduced-dose cyclosporine (RDC), with mycophenolate mofetil (MMF) plus FDC. The primary efficacy endpoint was the composite incidence of first treated biopsy-proven acute rejection (BPAR), graft loss, death or premature study discontinuation at month 12. Primary efficacy with FTY720 2.5 mg and MMF (32.4% and 30.2%; p = NS), plus mortality and BPAR incidence, were comparable. Patients receiving FTY720 5.0 mg plus RDC were discontinued from treatment due to increased risk of acute rejection (primary endpoint incidence 47.3%). FTY720 was associated with lower creatinine clearance (month 12: 53.1, 56.0 vs. 65.1 mL/min; p < 0.001) and more macular edema cases (2.2% and 1.3% vs. 0%), whereas cytomegalovirus infections were higher with MMF (6.2% and 10.6% vs. 18.1% p < 0.0001 and p = 0.0139, respectively). FTY720 2.5 mg provided comparable rejection prophylaxis over 12 months versus MMF; however, FTY720 5.0 mg did not support a 50% reduction in cyclosporine exposure. The cause of macular edema cases and lower creatinine clearance with FTY720 in de novotransplantation needs further investigation.

Key words: Gemella morbillorum; magnetic resonance imaging; renal transplantation; spondylodiscitis