The optimal immunosuppressive strategy for renal transplant recipients at high immunologic risk remains a topic of investigation. This prospective single arm pilot study was undertaken to evaluate the safety and efficacy of a combined tacrolimus and sirolimus regimen in recipients at immunological high risk and to compare outcomes with a contemporaneous control group received tacrolimus and mycophenolate mofetil. Patients that received a renal allograft between 2010 and 2011 at high risk (defined as panel reactive antibodies > 50%, 4 or more human leukocyte antigen mismatches, or retransplantation) were enrolled. All patients received basiliximab induction and corticosteroids. A total of 28 recipients treated with tacrolimus and sirolimus were enrolled in this study and 69 recipients were retrospectively reviewed as a control group. The sirolimus group showed a higher, but not statistically significant, incidence of biopsy proven acute rejection and a lower glomerular filtration rate than the control group. Furthermore, sirolimus group was associated with significant increases in BKV infection (P = 0.031), dyslipidemia (P = 0.004), and lymphocele (P = 0.020). The study was terminated prematurely due to a high incidence of adverse events. A de novo tacrolimus/sirolimus combination regimen may not be an ideal choice for recipients at high immunological risk.
Adult ; Drug Therapy, Combination/methods ; Female ; Graft Rejection/diagnosis/*etiology/*prevention & control ; Humans ; Immunocompromised Host ; Immunosuppressive Agents/administration & dosage/adverse effects ; Kidney Transplantation/*adverse effects ; Longitudinal Studies ; Male ; Middle Aged ; Sirolimus/*administration & dosage/adverse effects ; Survival Rate ; Tacrolimus/*administration & dosage/adverse effects ; Treatment Outcome

BACKGROUND/AIMS: The dose of mycophenolate mofetil (MMF) has been reduced in Asia due to side effects associated with the conventional fixed dose of 2-3 g/day. We aimed to determine the pharmacokinetics of a reduced dose of MMF and to validate its feasibility in combination with tacrolimus in living-donor liver transplantation (LDLT). METHODS: Two sequential studies were performed in adult LDLT between October 2009 and 2011. First, we performed a prospective pharmacokinetic study in 15 recipients. We measured the area under the curve from 0 to 12 hours (AUC0-12) for mycophenolic acid at postoperative days 7 and 14, and we performed a protocol biopsy before discharge. Second, among 215 recipients, we reviewed 74 patients who were initially administered a reduced dose of MMF (1.0 g/day) with tacrolimus (trough, 8-12 ng/mL during the first month, and 5-8 ng/mL thereafter), with a 1-year follow-up. We performed protocol biopsies at 2 weeks and 1 year post-LDLT. RESULTS: In the first part of study, AUC0-12 was less than 30 mgh/L in 93.3% of cases. In the second, validating study, 41.9% of the recipients needed dose reduction or cessation due to side effects within the first year after LDLT. At 12 months post-LDLT, 17.6% of the recipients were administered a lower dose of MMF (0.5 g/day), and 16.2% needed permanent cessation due to side effects. The 1- and 12-month rejection-free survival rates were 98.6% and 97.3%, respectively. CONCLUSIONS: A reduced dose of MMF was associated with low blood levels compared to the existing recommended therapeutic range. However, reducing the dose of MMF combined with a low level of tacrolimus was feasible clinically, with an excellent short-term outcome in LDLT.
Adult ; Aged ; Area Under Curve ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Gastrointestinal Diseases/etiology ; Graft Rejection/prevention & control ; Humans ; Immunosuppressive Agents/blood/*pharmacokinetics ; Leukopenia/etiology ; Liver/pathology ; Liver Failure/*therapy ; *Liver Transplantation ; Male ; Middle Aged ; Mycophenolic Acid/adverse effects/*analogs & derivatives/blood/pharmacokinetics ; ROC Curve ; Retrospective Studies ; Tacrolimus/therapeutic use ; Tissue Donors

This study was designed to evaluate whether sirolimus (SRL) conversion effectively improves renal function and histopathology in calcineurin inhibitor (CNI)-treated renal recipients with mild to moderate renal insufficiency. SRL conversion from CNI was performed in patients who underwent kidney transplantation from 6 months to 5 yr prior to screening. Forty-five patients were enrolled. The effect of SRL conversion on graft function was evaluated, and protocol biopsies were performed preconversion and 1 yr after conversion. Overall graft function after SRL conversion gradually improved, and the improvement in renal function was closely associated with the shorter duration of CNI exposure. When we divided the patients by the duration of CNI exposure, the patients with less than 1 yr of CNI exposure demonstrated significant improvement, but patients with a greater than 1 yr CNI exposure did not exhibit significant improvement. In contrast, protocol biopsies demonstrated no significant improvements in the modified "ah" score or other Banff scores after SRL conversion. Furthermore, the duration of CNI treatment prior to SRL conversion was not associated with histological findings 1 yr after SRL conversion. SRL conversion improved graft function in renal recipients with mild to moderate renal insufficiency, but this effect is not accompanied by histological improvement.
Adult ; Calcineurin Inhibitors/*administration & dosage ; Drug Synergism ; Female ; Graft Rejection/*etiology/*prevention & control ; Graft Survival/drug effects ; Humans ; Immunosuppressive Agents ; Kidney Transplantation/adverse effects/*methods ; Male ; Renal Insufficiency/diagnosis/*therapy ; Republic of Korea ; Severity of Illness Index ; Sirolimus/*administration & dosage ; Transplantation Tolerance/drug effects ; Treatment Outcome

The purpose of the present study was to evaluate the difference in BMI pattern between patients with persistent new-onset diabetes after transplantation (P-NODAT) and without new-onset diabetes after transplantation (N-NODAT) in a retrospective matched case-control (1:3) analysis. Thirty-six patients who developed P-NODAT were identified among 186 adult renal transplant recipients with no evidence of pretransplant diabetes mellitus who underwent kidney transplantation from September 1997 to March 2008 and were treated with a triple regimen including tacrolimus. The controls were selected to match the patients for pretransplant BMI, age at transplantation (+/- 5 yr), and date of transplantation (+/- 12 months). Finally, 20 P-NODAT patients and 60 N-NODAT patients were selected. The pre- and posttransplant BMI data were collected every 16 weeks for up to 80 weeks. The clinical characteristics did not differ between the P-NODAT group and N-NODAT group. BMI increased faster in the P-NODAT group than in the N-NODAT group. The mixed-model analysis showed that patients with P-NODAT exhibited a faster increase in BMI. P-NODAT is associated with posttransplant weight gain. The risk of P-NODAT should be considered in patients with rapid weight gain after transplantation.
Adult ; Body Mass Index ; Case-Control Studies ; Diabetes Mellitus, Type 2/*etiology ; Female ; Graft Rejection/prevention & control ; Humans ; Immunosuppressive Agents/therapeutic use ; *Kidney Transplantation ; Male ; Middle Aged ; Retrospective Studies ; Tacrolimus/therapeutic use ; Time Factors ; *Weight Gain

Transplantation of islet cells into diabetic patients is a promising therapy, provided that the islet cells are able to evade host immune rejection. With improved islet viability, this strategy may effectively reverse diabetes. We applied 2% calcium alginate to generate small and large capsules to encapsulate porcine neonatal pancreatic cell clusters (NPCCs) using an air-driven encapsulator. After encapsulation, the viability was assessed at 1, 4, 7, 14 and 28 days and secretion of functional insulin in response to glucose stimulation were tested at days 14 and 28. Selective permeability of the small alginate capsules was confirmed using various sizes of isothiocyanate-labeled dextran (FITC-dextran). Encapsulation of NPCCs was performed without islet protrusion in the small and large capsules. The viability of NPCCs in all experimental groups was greater than 90% at day 1 and then gradually decreased after day 7. The NPCCs encapsulated in large capsules showed significantly lower viability (79.50 +/- 2.88%) than that of naive NPCCs and NPCCs in small capsule (86.83 +/- 2.32%, 87.67 +/- 2.07%, respectively) at day 7. The viability of naive NPCCs decreased rapidly at day 14 (75.67 +/- 1.75%), whereas the NPCCs encapsulated in small capsules maintained (82.0 +/- 2.19%). After 14 and 28 days NPCCs' function in small capsules (2.67 +/- 0.09 and 2.13 +/- 0.09) was conserved better compared to that of naive NPCCs (2.04 +/- 0.25 and 1.53 +/- 0.32, respectively) and NPCCs in large capsules (2.04 +/- 0.34 and 1.13 +/- 0.10, respectively), as assessed by a stimulation index. The small capsules also demonstrated selective permeability. With this encapsulation technique, small capsules improved the viability and insulin secretion of NPCCs without islet protrusion.
Alginates/chemistry/metabolism ; Animals ; Animals, Newborn ; Capsules/chemistry ; Cell Survival ; Diabetes Mellitus/pathology/*therapy ; Disease Models, Animal ; Glucuronic Acid/chemistry/metabolism ; Graft Rejection/etiology/*prevention & control ; Hexuronic Acids/chemistry/metabolism ; Humans ; Insulin/secretion ; Islets of Langerhans/*metabolism/pathology ; Islets of Langerhans Transplantation/*methods ; Postoperative Complications/etiology/*prevention & control ; *Swine

OBJECTIVETo identify the risk factors for cytomegalovirus (CMV) pneumonia after renal transplantation and investigate the early precaution measures.

METHODSA retrospective study was conducted in a group of 28 patients undergoing renal transplantation who were readmitted because of CMV pneumonia between Jan, 2005 and Dec, 2007. Chi-square test and multivariate logistic regression were used to identity the significant risk factors.

RESULTSSeven factors, namely recipient age, acute graft rejection, pre-transplantation dialysis, delayed graft function recovery, recipient peak PRA level, donor CMV positivity and the use of MMF were found to significantly correlate to post-transplant CMV pneumonia. Multivariate logistic regression further confirmed that donor CMV IgG positivity, acute graft rejection and pre-transplantation dialysis for over 6 months were independent factors to predict the occurrence of CMV pneumonia.

CONCLUSIONSAcute graft rejection control, appropriate donor selection and shortened dialysis before the transplantation can be crucial factors to reduce the incidence of CMV pneumonia after renal transplantation.

Age Factors ; Aged ; Cytomegalovirus Infections ; etiology ; prevention & control ; Female ; Graft Rejection ; Humans ; Kidney Transplantation ; adverse effects ; Male ; Middle Aged ; Multivariate Analysis ; Pneumonia, Viral ; etiology ; prevention & control ; Postoperative Complications ; etiology ; prevention & control ; Renal Dialysis ; Retrospective Studies ; Risk Factors

OBJECTIVETo analyze the clinical features of mid- and long-term acute cardiac allograft rejection to improve the long-term clinical outcomes of the patients.

METHODSFourteen recipients (11 males and 3 females) underwent orthotopic heart transplantation with standard immunosuppressive therapy protocols (3 cases) or induction therapy protocols (11 cases). Cyclosporine, azathioprine or mycophenolate mofetil, and prednisolone were applied as the maintenance immunosuppressive regimen. Acute graft rejection episodes occurred within 3 to 6 months in 1 case, within 6 months to 1 year in 3 cases, within 1 to 2 years in 3 cases, within 2 to 5 years in 6 cases, and above 5 years in 1 case.

RESULTSNo significant difference was found in the incidence of late heart rejection between the patients receiving the two immunosuppressive therapy protocols. Immunosuppressants were withdrawn or spared in 8 recipients due to different causes. Nine recipients with steroid-sensitive acute cardiac allograft rejection were treated with steroid-pulse therapy, while the other 5 were treated with a short course of polyclonal antithymocyte antibodies because of steroid-resistant acute rejection; in 11 cases, azathioprine was converted to mycophenolate mofetil. Four of the 5 late deaths occurred in the recipients with steroid-resistant rejection. The surviving recipients had a good quality of life, and no recurrent episodes of rejection or infection were observed in the follow-up period.

CONCLUSIONSLate acute cardiac allograft rejection is associated mainly with patient compliance but not with early immunosuppressive therapy protocols. The episodes are rather severe and should be timely treated with steroid pulses or polyclonal antithymocyte antibodies.

Adolescent ; Adult ; Cyclosporine ; Female ; Graft Rejection ; etiology ; prevention & control ; Heart Transplantation ; adverse effects ; Humans ; Immunosuppression ; methods ; Male ; Middle Aged ; Mycophenolic Acid ; analogs & derivatives ; Young Adult

OBJECTIVETo investigate the protective effects on allografts and the possible mechanism of adeno-associated heme-oxygenase-1 (AdHO-1) gene therapy against chronic rejection injury.

METHODSEx vivo AdHO-1 gene therapy was performed in vascular and renal transplantation models. The structure and function, the expression of therapeutic genes and proteins, and the immune modulation were analyzed.

RESULTSAdHO-1 gene therapy protected renal transplant against chronic rejection, but the effect was not as remarkable as that in vascular transplant. The transfected empty vehicle aggravated chronic rejection damage in renal transplantation. AdHO-1 decreased the infiltration of macrophages and CD4(+) T cells.

CONCLUSIONSAdHO-1 gene therapy can lessen damage of chronic rejection in allografts. It plays roles by protecting transplants, down-regulating immune response and inducing immune deviation.

Adenoviridae ; genetics ; Animals ; Blood Vessels ; transplantation ; CD4 Lymphocyte Count ; Chronic Disease ; Genetic Therapy ; methods ; Genetic Vectors ; Graft Rejection ; etiology ; prevention & control ; Graft Survival ; Heme Oxygenase-1 ; genetics ; Kidney Transplantation ; adverse effects ; methods ; Macrophages ; pathology ; Male ; Rats ; Rats, Inbred Lew ; Transfection ; Transplantation, Homologous

OBJECTIVE: To observe the effect of FTY720 and ICAM-1 mAb mono and combination therapy in mouse-to-rat cardiac xenotransplantation. METHODS: Cardiac xenotransplantation was performed in abdominal site with micro-surgical technique. Recipients with xenografts were treated with different doses of FTY720 and/or ICAM-1 mAb. Graft survival, histopathology, infiltration of CD4+, and CD8+ T cells and levels of serum IL-2, IFN-gamma, IL-4, and IgM were investigated. RESULTS: Survival time of xenografts was (2.75+/- 0.43)d in the controls, survival of grafts treated with ICAM-1 mAb did not significantly improve. Treatment with large dose FTY720 led to a survival of (4.25+/- 0.71)d (P<0.01). Combination therapy with large dose FTY720 and ICAM-1 mAb achieved a significant prolongation of graft survival with (10.25+/- 2.12)d (P<0.01). Levels of serum IL-2, IFN-gamma and rat-anti-mouse IgM decreased in the combined therapy group. Pathologic lesion and infiltration of T cells in xenografts showed mitigated in the large dose combined therapy group. There was a significant negative correlation between the antibody level and the graft survival time (R=-0.754, P<0.01). CONCLUSION The combined therapy of FTY720 and ICAM-1 mAb can achieve a significant effect in the prolongation of heart xenograft survival and inhibition of xenoantibodies.
Animals ; Antibodies, Monoclonal ; therapeutic use ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Fingolimod Hydrochloride ; Graft Rejection ; blood ; etiology ; prevention & control ; Graft Survival ; drug effects ; Heart Transplantation ; adverse effects ; methods ; Immunoglobulin M ; blood ; Immunosuppressive Agents ; therapeutic use ; Intercellular Adhesion Molecule-1 ; immunology ; Interferon-gamma ; blood ; Interleukin-2 ; blood ; Interleukin-4 ; blood ; Mice ; Mice, Inbred BALB C ; Propylene Glycols ; therapeutic use ; Rats ; Rats, Wistar ; Sphingosine ; analogs & derivatives ; therapeutic use ; Time Factors ; Transplantation, Heterologous

OBJECTIVETo investigate the efficacy and safety of half-dose Zenapax for prevention of acute rejection after renal transplantation.

METHODSAccording to the immunosuppressive regimen and renal function after transplantation, patients were divided into 4 groups, namely groups A, B, C, and D of 90, 73, 11 and 13 patients, respectively. Blood creatinine measured 1 week after operation was <176.6 micromol/L in groups A and B, and was >353 micromol/L in groups C and D. Patients in groups A and C were given 25 mg Zenapax (0.5 mg/kg) and MMF 0.75 g before operation, and those in groups B and D had only MMF of 0.75 g. All patients were given Pred, CsA and MMF after operation, and the rejection episodes, the time of acute rejection onset, the rate of rejection reversal and complications were analyzed in the time period of 6 months after operation.

RESULTSAfter the operation, 13 patients (14.4%) developed acute rejection in group A, 18 (24.6%) in group B, 6 (54.5%) in group C and 7 (53.8%) in group D (P<0.01). The incidence of acute rejection in group B was significantly lower than that in groups C and D groups (P<0.01), and the latter two groups had similar incidence. The time of acute rejection onset ranged from 3 to 9 days postoperatively (mean 6.2-/+3.2 days) in group A, significantly delayed as compared with that in group B (range 2-8 days, mean 4.7-/+3.1 days), group C (range 2-7 days, mean 4.3-/+4.2 days) and group D group (range 2-9 days, mean 3.9-/+3.5 days), but the time was similar between groups B, C, and D (P>0.05). All acute rejection cases in group A was reversed, and the rate of reversal was 88.9% (16/18) in group B, 83.3% in group C, and 71.4% in group D. No significant differences were noted in such complications as infection, vascular injuries or gastrointestinal reactions between the 4 groups (P>0.05).

CONCLUSIONZenapax at the dose of 25 mg can safely decrease the risk of acute rejection in patients with good postoperative renal function recovery, but dose not seem effective in patients with delayed graft function recovery.

Acute Disease ; Adolescent ; Adult ; Antibodies, Monoclonal ; administration & dosage ; Antibodies, Monoclonal, Humanized ; Creatinine ; blood ; Female ; Follow-Up Studies ; Graft Rejection ; etiology ; prevention & control ; Humans ; Immunoglobulin G ; administration & dosage ; Immunosuppressive Agents ; administration & dosage ; Kidney Transplantation ; adverse effects ; methods ; Male ; Middle Aged ; Postoperative Complications ; etiology ; prevention & control ; Treatment Outcome