ImmunoCloak As A Paradigm Of The Biomaterial Approach to Immunomodulation: Where Regenerative Medicine Meets Organ Transplantation: Commentary to: Underlying Mechanisms of Protection Involved in ImmunoCloak.

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Bone Marrow Transplantation Under Regulatory T Cell Cover to Induce Donor-Specific Tolerance.

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Longitudinal Pharmacokinetics of Everolimus when Combined with Low-level of Tacrolimus in Elderly Renal Transplant Recipients.

Background: Although the proportion of elderly patients among renal transplant recipients has increased, pharmacokinetic (PK) studies of immunosuppressants rarely include older patients. Methods: We studied 12-hours everolimus (EVL) PK in 16 elderly renal transplant recipients (all caucasians; 10 males; mean age, 64+/-2 years, (61-71y), in 4 separate time-points (at 7, 30, 60 and 150 days) after EVL introduction, corresponding to a mean post renal-transplantation day: PK1 (43+/-4days), PK2 (65+/-7 days), PK3 (106+/-17 days) and PK4 (206+/-40 days). Patients received EVL (target trough level (Ctrough: 3-8 ng/mL), prednisone and tacrolimus (TCL) (target Ctrough: 2-5 ng/mL). Results: Mean TCL- Ctrough was 7.2+/-3.8, 4.9+/-2.2, 4.9+/-2.2, and 4.5+/-1.2 ng/mL at PK1, PK2, PK3 and PK4, respectively. There were no differences among time-points for mean EVL daily dose (data shown as PK3) (3.5+/-1.3 mg/day), Ctrough (4.7+/-2.5 ng/mL), AUC0-12h (106+/-51 ng*h/mL), Caverage (8.8+/-4.2 ng/mL), Cmax (19.2+/-9.7ng/mL), apparent Half-life (11.7+/-4.2 hours), estimated total body Clearance (0.39+/-0.27 L/hour), or Fluctuation (166+/-65%). Also, none of those PK parameters differed statistically when adjusted for body weight. EVL-Ctrough showed a very high correlation (r2 =0.849) with AUC0-12h. Conclusions: Our data indicate that elderly renal transplant recipients starting EVL 1 month after transplantation along with a steady-state TCL level, present stable EVL-PK parameters without significant changes in dose or exposure during the first 6 months after renal transplantation. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Inflammatory Markers and Outcomes in Kidney Transplant Recipients.

Background: Increased levels of TNF-Alpha and IL6 are associated with inflammation and cardiovascular disease among patients with normal kidney function. However, little is known about their association with outcomes in kidney transplant recipients. Methods: We collected socio-demographic, clinical and laboratory parameters, medical and transplant history from 977 prevalent kidney transplant recipients enrolled in the MINIT-HU study. Serum cytokine levels were measured at baseline. Associations between serum TNF-Alpha and IL6 values and death with a functioning graft over a 6-year follow-up period were examined in unadjusted and adjusted models. Results: The mean+/-SD age of the study population was 51+/-13 years, 57% were men, 21% were diabetics. Median serum TNF-Alpha and IL6 concentrations were significantly higher in patients who died with a functioning graft as compared to those who did not die during the follow-up period (TNF-Alpha: median[IQR]: 1.92[1.43-2.67] vs. 2.25[1.63-3.08, p

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Impact of Graft-versus-Graft Natural Killer Cell Alloreactivity on Single Unit Dominance After Double Umbilical Cord Blood Transplantation.

Background: Natural Killer (NK) cell alloreactivity is favored after double umbilical cord blood transplantation (dUCBT) in which cord blood (UCB) units and patients are often Human Leucocyte Antigen (HLA) class I mismatched. Generally, only 1 UCB unit persists after dUCBT. We hypothesize, that NK cell alloreactivity mediated by Killer cell Immunoglobulin-like Receptor (KIR) - HLA interactions may explain the dominance of 1UCB unit over the other after dUCBT. Methods: We investigated the impact of KIR+ NK cell alloreactivities on the dominance of 1 full UCB unit in 50 dUCBT. We analyzed the effects of the KIR/HLA genetic incompatibilities and studied cord blood cells at both the phenotypic and functional levels. Results: The genetic combination of KIR3DL1+ loser UCB unit/Bw4- winner UCB unit determined both the dominance of 1 UCB unit (Hazard Ratio=2.88[1.32-6.27], p=.0077) and correlated with an increased incidence of relapse (Hazard Ratio=4.91[1.39-17.3], p=.0134). It is interesting to note that cord blood cells exhibited extremely low HLA class I expression. Moreover, resting cord blood KIR3DL1+ NK cells exhibited a basal alloreactivity against Bw4- target cells that increased upon activation, thus triggering death by apoptosis. Conclusions: Our unicentric study suggests, for the first time, the significant impact of KIR+ NK cell alloreactivity in the determination of which UCB unit will dominate in dUCBT. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Poor Glycemic Control is Associated with Decreased Survival in Lung Transplant Recipients.

Background: Diabetes mellitus (DM) is associated with increased mortality following transplantation, but the effect of glycemic control on survival is unknown. We sought to determine the relationship between glycemic control (random (RBG) and fasting (FBG) blood glucose, HbA1c) and survival in all lung transplant (LTx) recipients and those with either persistent or no DM. Methods: All 210 LTx recipients from 1 August 2010 - 1 November 2013 were included (median observation 3.0 years). All underwent oral glucose tolerance tests pre and serially post-LTx. All glucose and HbA1c results from LTx until study end were included and hazard ratios were calculated. Results: Of 210 patients, 90 had persistent DM, and 84 had no DM. Overall mortality/repeat LTx was 31%. In the whole cohort, each 1 mM (18 mg/dl) increase in mean FBG and RBG and each 1% increase in mean HbA1c was associated with mortality increases of 18% (95%CI 5-32%, p=0.006), 38% (15-65%, p

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Incidence and Indications for Late Allograft Pancreatectomy while on Continued Immunosuppression.

Background: There are limited data about the incidence and indications for late allograft pancreatectomy while on continued immunosuppression for functional kidney allografts. Methods: We analyzed recipients of simultaneous pancreas and kidney (SPK) and pancreas after kidney (PAK) transplants between January 1994 and July 2013. Patients with functional kidney but failed pancreas allografts after 90 days were included. Results: Out of 1022 SPK or PAK recipients, 246 satisfied these criteria. Of these, 50 underwent allograft pancreatectomy (Px) and 196 did not (no-Px). Eleven of these pancreatectomies were performed at the time of repeat transplant and were analyzed separately. None of the basic recipient or donor characteristics differed significantly between the Px (n=39) and no-Px groups, except for a higher proportion of females in the Px group. The most common presentation in the Px group was abdominal pain. Histopathology of the pancreas varied widely with graft thrombosis as the most common finding. In univariate and multivariate Cox regression analysis, only female recipient was associated with higher risk for allograft pancreatectomy. Px was not associated with kidney allograft survival (p=0.16). Conclusion: Despite the ongoing presence of full immunosuppression for a functioning kidney allograft, the need for Px for symptoms and radiological findings is not rare (39/246, 15.8%). Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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