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BACKGROUND Current transplant immunosuppression regimens have numerous limitations. Recent evidence suggests histone deacetylase inhibitors (HDACis) may represent a class of drug with immunosuppressive properties. This study compares cyclosporin A (CyA) with the pan-HDACi suberoylanilide hydroxamic acid (SAHA) and a novel HDAC6-specific inhibitor (KA1010) in models of alloreactivity. METHODS Proliferation and mixed lymphocyte reaction (MLR)-based assays were used to determine the immunosuppressive effect of compounds, and a murine model of allogeneic skin transplantation was adopted to assess the in vivo effects of HDAC6 inhibition. RESULTS KA1010 displayed superior inhibitory effects on the activation of peripheral mononuclear cells using in vitro models of transplantation. In a 1-way MLR, KA1010 (5 μΜ) reduced parent cell proliferation from 92% to 64% (P = 0.001). A 2-way MLR, adopting IFN-γ production as a marker of alloresponse, resulting in up to 91% reduction. Dose-response curves revealed dose-dependent profiles with greater potency of HDACis over CyA (IC50 values of 82.0 nM and 13.4 nM for KA1010 and SAHA).Mice treated with KA1010 displayed no significant features of skin allograft rejection upon histological analysis at 70 days and graft survival of 80% in subjects treated with 160 mg/kg. Immunological assessment, revealed a significant increase in CD4CD25forkhead box P3 regulatory T cells (from 18% to 25%, P = 0.0002) and a corresponding reduction in CD4 T cells (from 58% to 42%, P = 0.0009). CONCLUSIONS HDAC6 may represent an optimal target for future immunosuppressant therapeutics with a particular role in transplantation. In this article, we have demonstrated a superior immunosuppressive effect of KA1010 over both CyA and SAHA, in the models of allotransplantation adopted.

Background. The early identification of kidney allografts at risk of later dysfunction has implications for clinical practice. Donor quality scoring systems (preoperative) and measures of early allograft function (first week postoperative) have previously shown practical utility. This study aimed to determine the optimal parameter(s) (preoperative and postoperative) with greatest predictive power for the development of subsequent allograft dysfunction. Methods. Consecutive deceased donor renal transplants (n=217) were studied. In each, the following measures were assessed: Preoperative donor quality scores: expanded criteria donor status; Deceased Donor Score (Nyberg et al., Am J Transplant 2003;3:715); Donor Risk Score (Schold et al., Am J Transplant 2005; 5(4 pt 1): 757); and delayed graft function (DGF) Nomogram (Irish et al., J Am Soc Nephrol 2003; 14:2967). Postoperative early function measures: dialysis requirement and duration; extended DGF definition (Boom et al., Kidney Int 2000; 58:859); creatinine at day 5 and day 7; creatinine reduction ratios at day 2 and day 7; and urine output posttransplantation. Primary outcome measures were creatinine at 12 months and the development of chronic kidney disease stage 4T. Results. Of donor scoring systems, Donor Risk Score was best associated with subsequent allograft function. Of early function measures: the extended definition of DGF, creatinine at day 5, and dialysis duration showed greatest predictive power in the patient population overall, those not requiring postoperative dialysis, and those requiring dialysis, respectively. No scores or early function measures were associated with change in creatinine between 6 and 12 months. Conclusions. This study validates and identifies the optimal early predictive parameter available for kidney transplant recipients, with implications for refining early postoperative management and potential utility in organ allocation policy.

Background. A reduction in acute rejection may reduce graft losses from chronic rejection, benefiting the recipient and helping ease the huge donor organ shortfall in the UK. The prediction of recipients at greater risk of acute rejection might justify the administration to them of more potent immunosuppression, but defining this group on clinical parameters has been largely unsuccessful. Events impacting on the kidney by the time of donation may, if detectable histologically, predict those kidneys more likely to undergo rejection. Methods. A prospective immunohistochemical analysis was undertaken to detect P-Selectin (PS), E-Selectin (ES), platelets, leukocyte common antigen, macrophages, T cells, and neutrophils in the pretransplant biopsies of 77 adult renal transplant recipients. Twenty-nine (38%) of this group rejected. Results. A significantly increased number of recipients rejected if the donor biopsy was PS positive (63 vs. 24%, P=0.0007), contained five or more leukocytes/ glomerulus (48 vs. 21%, P=0.03), contained >9.3 leukocytes/high power field (46.5 vs. 10.5%, P=0.006) or was both PS positive and contained >9.3 leukocytes/high power field (61.9 vs. 0.0%, P=0.0001). The PS was mostly of platelet origin and the majority of leukocytes were macrophages. Only previous CMV or any current infection in the donor correlated with the immunohistochemical changes. Conclusions. These immuno-histochemical changes are present before transplantation, which allows the prediction of recipients at both a higher and a lower risk of acute rejection, enabling the administration of recipient tailored immunosuppression, and supports the use of additional therapeutic intervention to reduce the injury response both within the recipient and the donor.

Indexed mitochondrial complex activities (MCA;) were determined in biopsies obtained from 52 donor kidneys at the end of cold ischemia (8-32 hr) to see if longer anoxia affected MCA i and accounted for the increased risk of delayed graft function (DGF) in recipients of grafts with longer cold ischemia time (CIT) or from non-heart-beating donors (NHBD). CITs were significantly different between those with and without DGF (P=0.02), being shorter in the latter, but MCA i were similar. CIT was correlated (r=0.43, P=0.003) with the time taken for creatinine concentration to fall to half the perioperative value (Cr t ½) but not with MCA i . Frequency of DGF, greater in NHBD, was significantly different from that of heart-beating donors (P= 0.04), but CIT and MCA i were similar. However, Cr t ½, was significantly different being longer in NHBD. Thus, the frequency of DGF increased and the speed of recovery diminished with longer CIT, whereas MCA, remained stable suggesting other factors determined tissue recovery.

Background. The microemulsion preconcentrate formulation of cyclosporine A (CsA) (Neoral) exhibits more uniform pharmacokinetics than the conventional formulation (Sandimmun; SIM). This randomized, open-label, U.K. multicenter study compared the efficacy, safety, and tolerability of Neoral and SIM in preventing acute rejection in de novo renal transplant recipients. Methods. Adult cadaveric kidney recipients (n=293) received Neoral or SIM twice daily for 12 months. Initially identical Neoral and SIM doses were titrated, maintaining trough CsA levels within locally defined therapeutic limits. Results. In the year after transplantation, acute rejection occurred in 34% of the Neoral and 47% of the SIM recipients (P=0.037). In the intent-to-treat population, fewer treatment failures (defined as acute rejection, graft loss, withdrawal, or death) occurred in the Neoral (45%) than the SIM recipients (58%) (P=0.015) and therapeutic CsA levels (≥250 μg/L) were reached faster with Neoral than SIM (P=0.0017). Antibody treatment of refractory rejection was used slightly less in the Neoral group (Neoral: 10%; SIM: 12%). One-year patient and graft survival rates (excluding deaths with functioning grafts) were 95% and 88%, respectively, for Neoral and 96% and 89% for SIM. Both formulations were well tolerated. No differences were observed between therapies in the nature, frequency, or severity of adverse events. Neoral use was not associated with increased nephrotoxicity or excessive immunosuppression. Conclusions. Neoral reduced the incidence of acute rejection compared with SIM, without significant increases in adverse events. This was achieved without altering existing SIM protocols and was attributed to improved absorption of CsA from Neoral and less variability in whole blood CsA concentrations.