ABO-incompatible kidney transplantation (ABOi KT) was introduced to expand the donor pool and minimize shortage of kidneys for transplantation. Because improved outcomes of ABOi KT were reported in Japan in the early 2000s, the number of ABOi KTs has been increasing worldwide. In addition, a better understanding of immune pathogenesis and subsequent aggressive immunosuppression has helped to make effective desensitization protocols. Current strategies of ABOi KT consist of pretransplant antibody removal using plasmapheresis or immunoadsorption to prevent hyperacute rejection and potent maintenance immunosuppression, such as tacrolimus and mycophenolate mofetil, to inhibit antibody-mediated rejection. Recent outcomes of ABOi KT are comparable with ABO-compatible KT. However, there are still many problems to be resolved. Very high anti-ABO antibody producers are difficult to desensitize. In addition, ABOi KT is associated with an increased risk of infection and possibly malignancy due to aggressive immunosuppression. Optimization of desensitization and patient-tailored immunosuppression protocols are needed to achieve better outcomes of ABOi KT. This review provides an overview of the history, immune mechanism, immunosuppressive protocol, outcomes, current obstacles, and future perspectives in ABOi KT.
Blood Group Incompatibility ; Humans ; Immunosuppression ; Japan ; Kidney Transplantation* ; Kidney* ; Plasmapheresis ; Tacrolimus ; Tissue Donors

Pure red cell aplasia due to parvovirus B19 infection after renal transplantation has been rarely reported, and few have been described about pancytopenia due to parvovirus B19. We report a case of recurrent pancytopenia due to parvovirus B19 infection in a renal transplant recipient. Ten days after transplantation, the patient developed severe pancytopenia (WBC 400/mm3, platelet 29,000/mm3, hemoglobin 6.8 g/dL) and his blood sample was positive for parvovirus B19 DNA PCR. Two weeks after 5-day administration of IVIG 400 mg/kg/day, pancytopenia resolved and tacrolimus was converted to cyclosporine A for reducing immunosuppressant potency. However, recurrent pancytopenia developed two months after IVIG treatment. Both blood and bone marrow samples were positive again for parvovirus B19 DNA PCR. Although pancytopenia persisted after another 5-day administration of IVIG 400 mg/kg/day, excellent hematological response has been achieved with single dose of IVIG 1 g/kg/day. Our case suggested that parvovirus B19 infection should be considered in renal transplant recipients with unexplained severe pancytopenia. High dose IVIG would be an effective therapeutic option, if the infection is recurrent or refractory to the usual dose of IVIG.
Blood Platelets ; Bone Marrow ; Cyclosporine ; DNA ; Hemoglobins ; Humans ; Immunoglobulins, Intravenous ; Kidney Transplantation ; Pancytopenia ; Parvovirus ; Polymerase Chain Reaction ; Tacrolimus ; Transplants

BACKGROUND: Senile purpura is characterized by ecchymoses on the extensor surfaces of the forearms and the dorsa of hands in the elderly. The prevalence is around 10% in the eight and ninth decades. Its occurrence is secondary to the fragility of blood vessel walls caused by atrophy of dermal collagen bundles and solar elastosis due to intrinsic aging and photoaging. For prevention of senile purpura, sunscreens and barrier protection should be used. However, there has been no specific medical treatments developed for senile purpura. OBJECTIVE: The purpose of this study was to evaluate the clinical efficacy of a topical calcineurin inhibitor for the treatment of senile purpura. METHODS: Seven patients with senile purpura applied 1% pimecrolimus cream twice daily for 2 weeks. Efficacy was evaluated by the subject's assessment and by the objective findings using photographic assessment. RESULTS: There was an 8.5% reduction in the purpuric area compared with the initial lesion. When the Wilcoxon signed-rank test was used for determination of the purpuric area between the pre-treatment condition and the post-treatment condition, the therapeutic effect was statistically significant (p=0.004). Three of seven patients (42.9%) were satisfied with their treatment, and four of them (57.1%) were neither satisfied nor dissatisfied. No adverse events were observed during the treatment and follow up periods. CONCLUSION: This study shows that 1% pimecrolimus cream can be an effective and safe treatment modality for senile purpura.
Aged ; Aging ; Atrophy ; Blood Vessels ; Calcineurin ; Collagen ; Ecchymosis ; Follow-Up Studies ; Forearm ; Glycosaminoglycans ; Hand ; Humans ; Prevalence ; Purpura ; Sunscreening Agents ; Tacrolimus

OBJECTIVE: Evaluate effectiveness/safety of tacrolimus in patients in Korea with active rheumatoid arthritis (RA) and unsuccessful response to disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Open-label, single-arm, non-comparative, 24-week, Phase-IV study in patients with active RA who had taken DMARDs for >6 months. Following a washout period, tacrolimus was initiated (baseline-12 weeks; dose 2 mg/day and 1.5 mg/day in patients aged ≤65 and >65 years, respectively). After 12 weeks, dose could be adjusted (remaining between 1~3 mg); treatment continued to 24 weeks. Primary endpoint was American College of Rheumatology 20% improvement (ACR20) (baseline-Week 24). Secondary endpoints included ACR50/ACR70 response, disease-activity score in 28 joints (DAS28) erythrocyte sedimentation rate (ESR), number of tender/swollen joints, and bone mineral density (BMD) loss. Adverse events (AEs) were recorded. RESULTS: Overall, 121 patients were analysed. Mean±standard deviation tacrolimus dose baseline-Week 24 was 1.81±0.47 mg/day. After 24 weeks, 64.5%, 39.7%, and 19.0% of patients were ACR20, ACR50, and ACR70 responders, respectively. DAS28-ESR score decreased from 5.5±0.8 (baseline) to 3.7±1.5 (Week 24; p < 0.0001); number of tender/swollen joints decreased. Between screening and Week 24, change in BMD-T score in lumbar and femur regions was −0.06±0.38 (p=0.1550) and −0.04±0.28 (p=0.0936), respectively, with no significant change in International Society for Clinical Densitometry classification. Fifty-six (46.3%) patients experienced 93 AEs; 75.3% were mild. No unexpected safety signals identified. CONCLUSION: Tacrolimus therapy was associated with a high proportion of ACR responders, and improved DAS28-ESR score and physical joint function during the study. Tacrolimus may be a suitable therapy for DMARD-resistant patients with RA.
Antirheumatic Agents* ; Arthritis, Rheumatoid* ; Blood Sedimentation ; Bone Density ; Classification ; Densitometry ; Femur ; Humans ; Joints ; Korea ; Mass Screening ; Osteoporosis ; Rheumatology ; Tacrolimus*

BACKGROUND: Therapeutic drug monitoring (TDM) of tacrolimus is essential because of narrow therapeutic range and poor correlation of dose to blood concentration. Affinity Column Mediated Immunometric Assay (ACMIA) does not require a pretreatment steps in measurement of tacrolimus. In this study, we evaluated the performance of tacrolimus assay using ACMIA (Dimension RxL Max, Dade Behring). METHODS: The imprecision, the linearity and the detection limits and the interferences by bilirubin and chyle, and correlation with hematocrit for tacrolimus by ACMIA were evaluated according to Clinical and Laboratory Standards Institute guidelines EP5-A2, EP6-A, EP17-A, EP9-A2, and EP7-A2. Method comparison studies with microparticle enzyme immunoassay (MEIA) (IMx Tacrolimus II, Abbott Laboratories) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) (Waters 2795 Quattromicro API, Micromass) were also performed. RESULTS: The total imprecision for low, middle and high level was 12.8%, 9.0% and 6.7%, respectively. The range of tacrolimus from 3.1 ng/mL to 35.4 ng/mL showed a clinically relevant linearity. The limit of detection and the functional sensitivity were 0.24 ng/mL and 0.72 ng/mL, respectively. Tacrolimus concentration measurement (Tac-CM) with ACMIA did not show significant interferences with bile and chyle and also did not show significant correlation with hematocrit. In comparison study for Tac-CM with MEIA and LC-MS/MS, Tac-CM with ACMIA showed a good correlation with MEIA (r=0.950) and LC-MS/MS (r=0.946). CONCLUSIONS: The imprecision, linearity, detection limits, interference and correlation of Tac-CM with ACMIA were suitable for clinical use. Tac-CM with ACMIA could reduce turn around time and help clinicians to manage transplant patients on immunosuppressant therapy.
Bilirubin/chemistry ; Chromatography, Affinity ; Chyle/chemistry ; Drug Monitoring ; Humans ; Immunoassay/*methods ; Immunosuppressive Agents/*blood ; Limit of Detection ; Reagent Kits, Diagnostic ; Reproducibility of Results ; Tacrolimus/*blood

PURPOSE: Management of cardiovascular risk factors is of major importance in renal transplant recipients to determine long-term outcomes. While calcineurin inhibitors improve the clinical course after kidney transplantation, they have been implicated in contributing to increased cardiovascular risk. This study investigated the influence of conversion from cyclosporine to tacrolimus on cardiovascular risks and graft function in renal allograft recipients with hyperlipidemia. METHODS: Twenty three adult renal recipients who were receiving cyclosporine-based regimen for more than one year after transplantation and had hyperlipidemia (serum total cholesterol > or =200 mg/dL) were enrolled. The effect of conversion from cyclosporine to tacrolimus was evaluated with blood pressure, fasting lipid profile, glucose and HbA1c. They were measured at baseline and at 1, 3, 6 and 12 months after conversion. The change in estimated glomerular filtration rate (eGRF) was also compared between before and after conversion. RESULTS: Though conversion from cyclosporine to tacrolimus did not cause significant differences in the serum triglyceride level, there was a noticeable decline in total cholesterol level (213.78+/-16.28 to 185.96+/-38.62 mg/dL, p<0.01). Conversion did not trigger new onset or worsening of diabetes mellitus with no meaningful differences in fasting blood glucose and HbA1c levels. The eGFR stabilized with Tacrolimus in comparison with the cyclosporine (-2.9+/-13.4 mL/min vs. -7.3+/-13.8 mL/min). CONCLUSION: Conversion to tacrolimus would be preferable to cyclosporine for maintenance immunesuppression in renal recipient with hyperlipidemia, as it meliorates hyperlipidemia and leads to stabilization of allograft function.
Adult ; Blood Glucose ; Blood Pressure ; Calcineurin ; Cardiovascular Diseases ; Cholesterol ; Cyclosporine ; Diabetes Mellitus ; Dyslipidemias ; Fasting ; Glomerular Filtration Rate ; Glucose ; Humans ; Hyperlipidemias ; Kidney Transplantation ; Risk Factors ; Tacrolimus ; Transplantation, Homologous ; Transplants

This study is to establish an artificial neural network (ANN) for predicting blood tacrolimus concentration in liver transplantation recipients. Tacrolimus concentration samples (176 samples) from 37 Chinese liver transplantation recipients were collected. ANN established after network parameters were optimized by using momentum method combined with genetic algorithm. Furthermore, the performance of ANN was compared with that of multiple linear regression (MLR). When using accumulated dose of 4 days before therapeutic drug monitoring (TDM) of tacrolimus concentration as input factor, mean prediction error and mean absolute prediction error of ANN were 0.02 +/- 2.40 ng x mL(-1) and 1.93 +/- 1.37 ng x mL(-1), respectively. The absolute prediction error of 84.6% of testing data sets was less than 3.0 ng x mL(-1). Accuracy and precision of ANN are superior to those of MLR. The correlation, accuracy and precision of ANN are good enough to predict blood tacrolimus concentration.
Adult ; Aged ; Drug Monitoring ; methods ; Female ; Humans ; Immunosuppressive Agents ; blood ; Linear Models ; Liver Transplantation ; Male ; Middle Aged ; Neural Networks (Computer) ; Tacrolimus ; blood

OBJECTIVETo investigate the in vitro effects of immune inhibitor tacrolimus on platelet function.

METHODSFresh venous blood was collected from healthy volunteers at ages of 18-25 years old, who are not taking antiplatelet drugs within two weeks. The platelets were isolated from the blood and incubated with different concentrations of tacrolimus (0.06, 0.6, 6, 60, 120, 240 μmol/L) at 37 °C for 2 hours, and then the changes of mitochondrial membrane potential and P-selection of platelets were detected by flow cytometry, the expression of apoptosis related protein by Western Blot, and the change of the platelet aggregation function by platelet aggregation analyzer.

RESULTSTacrolimus at concentration of 0.06 μmol/L could promote collagen induced platelet aggregation, inhibit thrombin induced platelet aggregation, have no effect on ristocetin and vWF induced platelet aggregation function. Tacrolimus at concentration of 120 μmol/L and 240 μmol/L could reduce the platelet mitochondrial membrane potential and induce the expression of apoptosis protein caspase-3.

CONCLUSIONIn vitro experimental results showed that high concentration of tacrolimus could lead to platelet apoptosis. But the current therapeutic dose of tacrolimus at 0.06 μmol/L (which is equivalent to 50 ng/ml blood concentration) could have different effects on platelet aggregation function according to different stimulating agents.

Adolescent ; Adult ; Blood Coagulation Tests ; Blood Platelets ; drug effects ; Caspase 3 ; Humans ; In Vitro Techniques ; Platelet Aggregation ; Tacrolimus ; pharmacology ; Thrombin ; Young Adult

OBJECTIVETo investigate the effect of FK506 on cytokine secretions in whole blood from healthy individuals.

METHODSBlood samples collected from healthy volunteers were co-cultured with different concentrations of FK506 and stimulated with PMA and IONO. The concentrations of 8 cytokines including IL-2, IL-6, IL-12, IL-17, IFN-gamma, TNF-alpha, GM-CSF and G-CSF were detected by Bio-Plex suspension system.

RESULTSCompared with the control group, high-concentration FK506 (20 ng/ml) significantly inhibited the secretions of IL-2, IL-6, IL-12, IL-17, IFN-gamma, TNF-alpha, GM-CSF and G-CSF. At a moderate concentration (5 ng/ml), FK506 inhibited the secretion of GM-CSF significantly.

CONCLUSIONFK506 effectively inhibits the secretion of proinflammatory cytokines including IL-6, IFN-gamma and TNF-alpha and also the secretion of IL-2, IL-12, IL-17, GM-CSF and G-CSF. FK506 might play the role of immunosuppression by inhibiting the production of these cytokines by the immune cells. Monitoring the levels of these cytokines might be a potential method for evaluating the adequacy of FK506 doses administered.

Adult ; Cytokines ; blood ; secretion ; Down-Regulation ; drug effects ; Female ; Humans ; Immunosuppressive Agents ; pharmacology ; Interferon-gamma ; blood ; secretion ; Interleukin-6 ; blood ; secretion ; Male ; Tacrolimus ; pharmacology ; Tumor Necrosis Factor-alpha ; blood ; secretion ; Young Adult

PURPOSE: Liver transplantation (LT) can cure abnormality of glucose metabolism, but cause altered glucose metabolism with immunosuppressive treatment. Up to now, almost all studies have been performed in cadaveric donor liver transplantation (CDLT). We underwent study in CDLT and also living donor liver transplantation (LDLT) recipients. METHODS: Among 397 adult-to-adult LT recipients between January 1994 and August 2001, we selected 81 patients who could be followed more than 12 months by using the table of random sampling numbers. We reviewed the change of blood glucose and risk factors, complications and survival retrospectively between post-transplantation diabetes mellitus (PTDM) and no PTDM patients. RESULTS: Clinical data showed 34 : 47 in frequency of PTDM to no PTDM. Age, family history of DM, preoperative DM history over 6 months had a significant risk of PTDM. There was no difference of PTDM frequency between CDLT and LDLT and its subgroup. The worse post-transplant graft function causes the more incidence of PTDM (P=0.051). FK506 had higher relation with PTDM than cyclosporine and mycophenolate mofetile (P=0.058). The incidence of DM after operation has been decreased by 6 months, but thereafter no further. There were 18 of De Novo DM among 34 PTDM patients, and only 1 preoperative DM patient improved after LT. Between PTDM and no PTDM group, there were no significant difference of complication rate and 5-year survival rate. CONCLUSIONS: The types of graft would not affect the incidence of PTDM if the graft function were preserved. Other clinical data showed similar results to previous reports.
Blood Glucose ; Cadaver ; Cyclosporine ; Diabetes Mellitus* ; Glucose ; Humans ; Incidence ; Liver Transplantation* ; Liver* ; Living Donors ; Metabolism ; Retrospective Studies ; Risk Factors ; Survival Rate ; Tacrolimus ; Tissue Donors ; Transplants