Practices for Supporting and Confirming Decision-Making Involved in Kidney and Liver Donation by Related Living Donors in Japan: A Nationwide Survey.

This nationwide survey investigated the actual practices for supporting and confirming the decision-making involved in related living-organ donations in Japan, focusing on organ type and program size differences. Answers to a questionnaire survey were collected from 89 of the 126 (71%) kidney and 30 of the 35 (86%) liver transplantation programs in Japan that were involved in living-donor transplantations in 2013. In 70% of the kidney and 90% of the liver transplantation programs, all donors underwent "third-party" interviews to confirm their voluntariness. The most common third parties were psychiatrists (90% and 83%, respectively). Many programs engaged in practices to support decision-making by donor candidates, including guaranteeing the right to withdraw consent to donate (70% and 100%, respectively) and prescribing a set "cooling-off period" (88% and 100%, respectively). Most donors were offered care by mental health specialists (86% and 93%, respectively). Third parties were designated by more of the larger kidney transplant programs compared with the smaller programs. In conclusion, the actual practices supporting and confirming the decision to donate a living organ varied depending on the organ concerned and the number of patients in the program.

Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system.

The CD40/CD154 co-stimulatory pathway is crucial in alloimmune response. We developed a novel small interfering RNA (siRNA) delivery system with a poly-dA extension at the 5'-end of the siRNA sense strand that was stably incorporated into 1,3-ß-glucan (schizophyllan, SPG). This was captured and incorporated into dendritic cells (DCs) through its receptor, Dectin-1, specifically silencing CD40 genes (siCD40) to exert immunoregulatory activity. siCD40/SPG-treated CBA mice permanently accepted B10 fully mismatched cardiac allografts. Consistent with graft survival, the infiltration of CD4(+), CD8(+) T cells into the graft was lower, and that the numbers of CD40(low)CD11c(+) DCs cells and CD4(+)Foxp3(+)cells were increased in both the graft and in the recipient spleen. In addition, naive CBA recipients given an adoptive transfer of splenocytes from the primary recipients with siCD40/SPG accepted a heart graft from donor-type B10, but not third-party Balb/c mice. In conclusion, the treatment with siCD40/SPG targeting DCs could generate antigen-specific Tregs, resulting in the permanent acceptance of mouse cardiac allografts. These findings have important implications for clarifying the mechanism underlying the induction of tolerance in DCs, and also highlight the potential of immunomodulation and the feasibility of siRNA-based clinical therapy in the transplantation field.

Anti-huCD20 antibody therapy for antibody-mediated rejection of renal allografts in a mouse model.

We have reported that B6.CCR5(-/-) mice reject renal allografts with high serum donor-specific antibody (DSA) titers and marked C4d deposition in grafts, features consistent with antibody-mediated rejection (AMR). B6.huCD20/CCR5(-/-) mice, where human CD20 expression is restricted to B cells, rejected A/J renal allografts by day 26 posttransplant with DSA first detected in serum on day 5 posttransplant and increased thereafter. Recipient treatment with anti-huCD20 mAb prior to the transplant and weekly up to 7 weeks posttransplant promoted long-term allograft survival (>100 days) with low DSA titers. To investigate the effect of B cell depletion at the time serum DSA was first detected, recipients were treated with anti-huCD20 mAb on days 5, 8, and 12 posttransplant. This regimen significantly reduced DSA titers and graft inflammation on day 15 posttransplant and prolonged allograft survival >60 days. However, DSA returned to the titers observed in control treated recipients by day 30 posttransplant and histological analyses on day 60 posttransplant indicated severe interstitial fibrosis. These results indicate that anti-huCD20 mAb had the greatest effect as a prophylactic treatment and that the distinct kinetics of DSA responses accounts for acute renal allograft failure versus the development of fibrosis.

Graft-derived CCL2 increases graft injury during antibody-mediated rejection of cardiac allografts.

The pathogenic role of macrophages in antibody-mediated rejection (AMR) remains unclear. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic factor for monocytes and macrophages. The current studies used a murine model of AMR to investigate the role of graft-derived CCL2 in AMR and how macrophages may participate in antibody-mediated allograft injury. B6.CCR5−/−/CD8−/− recipients rejected MHC-mismatched WT A/J allografts with high donor-reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. In contrast, A/J.CCL2−/− allografts induced low donor-reactive antibody titers and C4d deposition at Day 7 posttransplant. Decreased donor-reactive CD4 T cells producing interferon gamma were induced in response to A/J.CCL2−/− versus WT allografts. Consequently, A/J.CCL2−/− allograft survival was modestly but significantly longer than A/J allografts. Macrophages purified from WT allografts expressed high levels of IL-1ß and IL-12p40 and this expression and the numbers of classically activated macrophages were markedly reduced in CCL2-deficient allografts on Day 7. The results indicate that allograft-derived CCL2 plays an important role in directing classically activated macrophages into allografts during AMR and that macrophages are important contributors to the inflammatory environment mediating graft tissue injury in this pathology, suggesting CCL2 as a therapeutic target for AMR.

Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions.

A consensus meeting was held in Vienna on September 8-9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney-centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new-onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion-based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion-based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM.

PD-1/B7-H1 interaction contribute to the spontaneous acceptance of mouse liver allograft.

The programmed death-1 (PD-1)/B7-H1 pathway acts as an important negative regulator of immune responses. We herein investigated the role of the PD-1/B7-H1 pathway in establishing an immunological spontaneous tolerance status in mouse liver allografting. B7-H1 is highly expressed on the donor-derived tissue cells and it is also associated with the apoptosis of infiltrating T cells in the allografts. Strikingly, a blockade of the PD-1/B7-H1 pathway via anti-B7-H1mAb or using B7-H1 knockout mice as a donor led to severe cell infiltration as well as hemorrhaging and necrosis, thus resulting in mortality within 12 days. Furthermore, the expression of the FasL, perforin, granzyme B, iNOS and OPN mRNA in the liver allografts increased in the antibody-treated group in comparison to the controls. Taken together, these data revealed that the B7-H1 upregulation on the tissue cells of liver allografts thus plays an important role in the apoptosis of infiltrating cells, which might play a critical role of the induction of the spontaneous tolerance after hepatic transplantation in mice.

[Sarcomatoid carcinoma of the thymus which caused acute epicarditis].

Thymic carcinoma is rare. Particularly sarcomatoid carcinoma of the thymus is a very rare disease it has been reported in only 15 patients to date. The prognosis is very poor and diagnosis and treatment have not yet been established. We report a case of 63-year-old man who was initially diagnosed with acute pericarditis and was finally found to be sarcomatoid carcinoma of the thymus. He underwent surgery and the tumor was completely resected. However, 6 months after surgery, local recurrence was noted. The patient was treated by radiotherapy followed by paclitaxel monotherapy. Partial remission was achieved transiently with paclitaxel, but the tumor again recurred. He died 33 months after surgery. The possibility of diseases like this tumor must be kept in mind for a patient with chest symptoms. Paclitaxel monotherapy is likely to be effective in treating sarcomatoid carcinoma of the thymus.

Prevalence of the metabolic syndrome in kidney transplantation.

OBJECTIVES: We investigated the prevalence of the metabolic syndrome (MS) in kidney transplantation patients and assessed its development based on plasma adiponectin levels and the results of an oral glucose tolerance test (OGTT). METHODS: We performed a cross-sectional study of 94 recipients with stable graft function who underwent kidney transplantation between January 1999 and October 2008. The presence of MS was determined using National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria with body mass index (BMI) used in place of waist circumference. In addition, we measured plasma adiponectin level and performed a 75-g oral GTT. RESULTS: Fourteen (14.9 %) recipients suffered from MS for a mean period of 46.7 months (range, 1-106) after transplantation. BMI at the time of transplantation was significantly greater in the MS group (23.4 +/- 3.24 vs 20.1 +/- 2.50; P < .0001), whereas plasma adiponectin level was significantly lower (11.95 +/- 5.13 vs 17.71 +/- 8.47; P = .0158). The insulinogenic index values were similar, whereas the homeostatic model assessment of insulin resistance was greater in the MS group (2.598 +/- 1.918 vs 1.340 +/- 0.934; P = .0002). CONCLUSION: The level of adiponectin, which was lower in kidney transplant recipients who developed MS, was negatively correlated with insulin sensitivity. We concluded that a low adiponectin level may correlate with the prevalence of MS in kidney transplantation in association with impaired insulin sensitivity.

Bcl-2 protects tubular epithelial cells from ischemia/reperfusion injury by dual mechanisms.

Ischemia/reperfusion (I/R) injury, which induces extensive loss of tubular epithelial cells, is associated with delayed graft function following kidney transplantation. Recent reports have suggested that cell death by I/R injury occurs by autophagy, a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, as well as by apoptosis. Recently, we demonstrated that overexpression of the anti-apoptotic factor, Bcl-2, inhibited tubular apoptosis and subsequent tubulointerstitial damage after I/R injury. Autophagy is also observed in cells undergoing cell death in several diseases. Therefore, we hypothesized that increased Bcl-2 protein may protect tubular epithelial cells by suppressing autophagy and inhibiting apoptosis. In the present study, a transgenic mouse model (LC3-GFP TG) in which autophagosomes are labeled with LC3-GFP and Bcl-2/LC3-GFP double transgenic mice (Bcl-2/LC3-GFP TG) were used to examine the effect of Bcl-2 on I/R-induced autophagy. I/R injury, which is associated with marked disruption of normal tubular morphology, promoted the formation of LC3-GFP dots, representing extensively induced autophagosomes. On electron microscopy, the autophagosomes contained mitochondria in I/R-injured tubular epithelial cells. In contrast, Bcl-2 augmentation suppressed the formation of autophagosomes and there was less tubular damage. In conclusion, Bcl-2 augmentation protected renal tubular epithelial cells from I/R injury by suppressing autophagosomal degradation and inhibiting tubular apoptosis.

Relationship Between Stress Coping Mechanisms and Depression in Kidney Transplant Recipients.

BACKGROUND: It has been reported that transplant recipients are exposed to physical and psychosocial stresses even after transplant surgery and exhibit psychological disorders such as depression. PURPOSE: In this study, we extracted trends concerning how recipients of kidney transplants cope with stress, and we also examined how they cope with depression and its countermeasures. METHOD: We administered questionnaire surveys to 109 kidney transplant recipients. These included items on personal attributes, medical information, depression, and stress-coping type scales. Statistical analysis was performed using factor analysis and multiple regression analysis. RESULTS: Fifteen out of 109 (13.8%) were found to be high-risk patients for depression based on responses to the questionnaire using the depression scale. We extracted 2 factors of stress-coping type, namely Factor 1, "Directly coping with the problem," of patients who try to directly resolve the problem in a positive manner and Factor 2, "Stress-release while avoiding the problem," for those who relieve their feelings in response to the stress without resolving the problem itself. When multiple regression analysis was conducted with the depression scale as the dependent variable and the stress-coping factor as the independent variable, Factor 1 tended to be associated with reduced depression and Factor 2 with increased depression. CONCLUSIONS: Results showed that to improve the mental health of those who receive kidney transplants, it is necessary to examine the depression and stress-coping types of such patients at an early stage and carry out education on stress-coping, focusing on resolving the actual problem.

Superagonistic CD28 antibody induces donor-specific tolerance in rat renal allografts.

The ultimate goal of organ transplantation is to establish graft tolerance where CD4+CD25+FOXP3+ regulatory T (Treg) cells play an important role. We examined whether a superagonistic monoclonal antibody specific for CD28 (CD28 SA), which expands Treg cells in vivo, would prevent acute rejection and induce tolerance using our established rat acute renal allograft model (Wistar to Lewis). In the untreated or mouse IgG-treated recipients, graft function significantly deteriorated with marked destruction of renal tissue, and all rats died by 13 days with severe azotemia. In contrast, 90% of recipients treated with CD28 SA survived over 100 days, and 70% survived with well-preserved graft function until graft recovery at 180 days. Analysis by flow cytometry and immunohistochemistry demonstrated that CD28 SA induced marked infiltration of FOXP3+ Treg cells into the allografts. Furthermore, these long-surviving recipients showed donor-specific tolerance, accepting secondary (donor-matched) Wistar cardiac allografts, but acutely rejecting third-party BN allografts. We further demonstrated that adoptive transfer of CD4+CD25+ Treg cells, purified from CD28 SA-treated Lewis rats, significantly prolonged allograft survival and succeeded in inducing donor-specific tolerance. In conclusion, CD28 SA treatment successfully induces donor-specific tolerance with the involvement of Treg cells, and thus the therapeutic value of this approach warrants further investigation and preclinical studies.

Treatment adherence in renal transplant recipients: a questionnaire survey on immunosuppressants.

INTRODUCTION: To achieve a high graft survival rate, patient adherence to immunosuppressive therapy is critical. It is extremely difficult to establish the actual adherence status of transplant recipients; only a few surveys on the issue have been performed in Japan. METHODS: We conducted a questionnaire survey mainly on treatment adherence to calcineurin inhibitors among renal transplant recipients. RESULTS: The survey demonstrated some degree of nonadherence in a relatively high percentage of the patients. The adherence rate was significantly lower for the evening than the morning dose (McNemar test, P < .001). It significantly decreased with time following transplantation for both the morning and the evening doses (logistic regression analysis, P = .025 and <.001, respectively). CONCLUSIONS: Immunosuppressive treatment places a substantial burden on patients, some of whom cannot continue regular treatment at specified time points due to daily life restrictions after they have returned to work.

Severe Phlebitis Accompanying Vascular Rejection Type Acute T Cell-Mediated Rejection in Renal Transplantation.

PURPOSE: Renal transplant patients with vascular rejection type acute T cell-mediated rejection (ATCMR) grade II have a poor prognosis. Vascular lesions in those cases are thought to randomly occur, thus we searched for a novel pathological marker related to vascular rejection in kidney transplantation. METHODS: We determined pathological characteristics in 14 ATCMR grade II patients treated during an acute phase from 2004 to 2013. We then examined whether those findings appeared in transplant kidney biopsy specimens, except for cases of vascular rejection, in patients examined from 2010 to 2014. RESULTS: In 9 of the 14 ATCMR grade II patients, phlebitis was accompanied by inflammatory cells that formed polypoid projections in the venous lumen and partial disappearance of vascular endothelium. Further investigation showed those inflammatory cells to be T cells and macrophages. Histological findings revealed coexisting phlebitis in 2 of 13 patients with ATCMR grade I, 3 of 24 with borderline changes, and none with normal findings. Phlebitis occurred at a significantly greater rate than the other findings in cases of vascular rejection (P < .05). However, there was no significant difference in regard to graft survival between patients with and without phlebitis (P = .1829). CONCLUSION: Our results suggest severe phlebitis as a novel finding associated with the pathology of vascular rejection in patients with a renal allograft.

Altered expression of microRNA during fracture healing in diabetic rats.

OBJECTIVES: Diabetes mellitus (DM) is known to impair fracture healing. Increasing evidence suggests that some microRNA (miRNA) is involved in the pathophysiology of diabetes and its complications. We hypothesized that the functions of miRNA and changes to their patterns of expression may be implicated in the pathogenesis of impaired fracture healing in DM. METHODS: Closed transverse fractures were created in the femurs of 116 rats, with half assigned to the DM group and half assigned to the control group. Rats with DM were induced by a single intraperitoneal injection of streptozotocin. At post-fracture days five, seven, 11, 14, 21, and 28, miRNA was extracted from the newly generated tissue at the fracture site. Microarray analysis was performed with miRNA samples from each group on post-fracture days five and 11. For further analysis, real-time polymerase chain reaction (PCR) analysis was performed at each timepoint. RESULTS: Microarray analysis showed that there were 14 miRNAs at day five and 17 miRNAs at day 11, with a greater than twofold change in the DM group compared with the control group. Among these types of miRNA, five were selected based on a comparative and extended literature review. Real-time PCR analysis revealed that five types of miRNA (miR-140-3p, miR-140-5p, miR-181a-1-3p, miR-210-3p, and miR-222-3p) were differentially expressed with changing patterns of expression during fracture healing in diabetic rats compared with controls. CONCLUSIONS: Our findings provide information to further understand the pathology of impaired fracture healing in a diabetic rat model. These results may allow the potential development of molecular therapy using miRNA for the treatment of impaired fracture healing in patients with DM.Cite this article: S. Takahara, S. Y. Lee, T. Iwakura, K. Oe, T. Fukui, E. Okumachi, T. Waki, M. Arakura, Y. Sakai, K. Nishida, R. Kuroda, T. Niikura. Altered expression of microRNA during fracture healing in diabetic rats. Bone Joint Res 2018;7:139-147. DOI: 10.1302/2046-3758.72.BJR-2017-0082.R1.

Comparison of Sensitivity of Immunocomplex Capture Fluorescence Analysis for Detecting Donor-specific Anti-HLA Class II Antibodies in Kidney Transplant Patients.

BACKGROUND: Immunocomplex capture fluorescence analysis (ICFA) detects donor-specific antihuman leukocyte antigen (HLA) antibodies (DSA), but the detection sensitivity of HLA class II antibodies using conventional ICFA is as low as 57%. The aim of the study was to improve the detection sensitivity of HLA class II antibodies by ICFA, and compare the ICFA results with the Luminex single-antigen bead test. METHODS: Six DSA-negative kidney transplant donors and recipient pairs and 10 HLA class II DSA-positive pairs were included in the study. The detection sensitivity of modified ICFA was compared with conventional ICFA, and the ICFA results were compared with the Luminex single-antigen bead test. RESULTS: The index value of modified ICFA was higher than that of conventional ICFA. The cutoff value of conventional ICFA was 30,686 (MFI), which was improved to 19,405 using modified ICFA. Regarding the HLA-DQ antibody, 5 samples found to be positive by Luminex single-antigen bead testing were all negative using modified ICFA. The reason for this discrepancy could be related to: (1) the difference in detection sensitivity; (2) the difference in HLA antigen surface expression between naive lymphocytes and synthetic beads; or (3) the structure of synthetic HLA DQ antigen on the Luminex single-antigen beads. CONCLUSION: The index value of the modified ICFA was higher than that of conventional ICFA, and the detection sensitivity of HLA class II antibodies was improved by modified ICFA. Further assessment is necessary to clarify the reasons for divergence between ICFA and Luminex single-antigen bead test results.

A clinicopathologic study of p27(kip1) expression in renal allograft biopsy.

BACKGROUND: P27 (Kip1) is an inhibitor of cyclin-dependent kinases/cyclin complex that keeps mature cells growth-arrested. In IgA nephropathy, a decreased p27kip1 expression in podocytes has been reported to be related to lesion formation of focal segmental glomerulosclerosis and renal dysfunction. We reviewed the p27kip1 expression in transplanted kidneys. METHODS: p27kip1 expression was examined immunohistochemically in 26 allograft biopsy specimens. RESULTS: p27kip1 expression was recognized in podocytes. Patients with more than 0.5 g proteinuria showed fewer p27kip1-positive cells than those with less than 0.5 g proteinuria. The decreased p27kip1 expression in podocytes was related to cg and ah of the Banff 97 classification. In the two cases in which p27kip1 expression was remarkably decreased, elevation of the serum creatinine level was recognized at the time of biopsy, resulting in kidney transplant loss. The histological findings were chronic/sclerosing allograft nephropathy grade II-(b) in both cases. CONCLUSION: In conclusion, decreased p27kip1 expression in podocytes suggested a significant role in proteinuria among renal transplant recipients.

Diffusion Tensor Imaging MRI With Spin-Echo Sequence and Long-Duration Measurement for Evaluation of Renal Fibrosis in a Rat Fibrosis Model.

BACKGROUND: Renal fibrosis (RF) is a well-known marker for chronic kidney disease (CKD) progression, including chronic renal injury after renal transplantation. However, invasive biopsy is an available examination for evaluation of RF. Diffusion MRI was once recognized as a promising option for RF. However, it is now controversial for RF evaluation in a unilateral ureteral obstruction (UUO) model. METHODS: To seek an optimal imaging method applicable for RF in UUO model kidneys, we attempted a series of MRI methods, including proton density-weighted imaging, T1-weighted imaging, T2-weighted imaging, T2*-weighted imaging, diffusion-weighted imaging, and diffusion tensor imaging (DTI). RESULTS: We identified DTI MRI by spin-echo sequence plus a special kidney attachment as the best option for evaluation of renal UUO fibrosis, compared with normal kidney on the opposite side. To confirm these results, we applied this technique to a rat UUO therapeutic model with the anti-fibrotic reagent Fasudil. Fractional anisotropy values calculated from DTI MRI showed statistically significant linear correlation with the RF area measured by use of Sirius red or Masson trichrome staining of the positive area [cortex (r = 0.6397, P = .0283) and outer stripe of the outer medulla (r = 0.7810, P = .0039)]. CONCLUSIONS: By use of the DTI MRI with spin-echo sequence, it may be possible to accurately evaluate RF in CKD.

Exogenous expression of Fas-ligand or CrmA prolongs the survival in rat liver transplantation.

Modulation of donor organs by transfection of a gene encoding immmunosuppresive molecules has been recognized as a less toxic approach to prevent allograft rejection. Fas-ligand (FasL) plays a critical role in activation-induced cell death of activated cytotoxic lymphocytes. This may provide a potential for induction of "immune privileged sites" to escape the host immune surveillance system. Cytokine response modifier A (CrmA), a gene product of cowpox virus, blocks caspase as well as perforin/granzyme-mediated apoptotic pathways. Therefore, it may suppress intragraft apoptosis. The aim of the present study was to investigate whether transfection of FasL or CrmA genes prolonged the survival of rat liver allografts. Using the high responder rat combination of DA (RT-1(a)) donor to LEW (RT-1(1)) recipient, we performed orthotopic liver transplantation with subsequent delivery of adenoviral vectors containing FasL, CrmA, or LacZ, at a dose of 1 x 10(9) pfu via a recipient tail vein using a Cre-mediated gene expression system. Recipient survival was assessed as well as immunohistochemical examination of the grafts for anti-CD2, TUNEL, and H&E staining. Statistical analysis was performed with the Mann-Whitney U test. The therapeutic groups showed significantly prolonged recipient survival compared with the LacZ-treated control group. Histologic analysis revealed reduced hepatocyte apoptosis in the CrmA-treated group and increased apoptosis of infiltrating mononuclear cells in the FasL-treated group. These data suggested that FasL and CrmA may be potent genes to prolong rat liver allograft survival.

Induction Immunosuppressive Therapy With Everolimus and Low-Dose Tacrolimus Extended-Release Preserves Good Renal Function at 1 Year After Kidney Transplantation.

BACKGROUND: Utilization of everolimus (EVR) has been increasing in recent years for patients undergoing renal transplantation to reduce calcineurin inhibitor (CNI) levels. However, an optimum regimen has yet to be established. METHODS: We retrospectively examined 12 renal transplant recipients who underwent an induction immunosuppressive protocol; the protocol comprises 5 agents, including EVR plus low-dose tacrolimus extended-release (TAC-ER) treatment. We compared those findings from those of 14 patients who underwent a conventional protocol without EVR. Clinical outcome and pathologic changes were assessed by using protocol graft biopsy findings obtained at 3 months and 1 year after transplantation. RESULTS: The estimated glomerular filtration rate was significantly higher for the EVR group at both 3 months and 1 year compared with the conventional group (P < .01 and P = .03, respectively). TAC-ER trough levels were also significantly lower at 3 months and 1 year (both, P < .01). Histologic findings of the 3-month protocol biopsy samples in the EVR group revealed 4 cases of borderline change and 2 of acute cellular-mediated rejection. The findings from the 1-year biopsy samples revealed 10 cases with normal findings with no evidence of CNI toxicity. Patients in the EVR group developed subclinical borderline change and acute cellular-mediated rejection after 3 months at a significantly higher rate than the conventional group (P = .02). CONCLUSIONS: Use of the present therapeutic strategy successfully maintained the trough of each drug at a lower level, and it also kept renal function stable up to 1 year after transplantation.

Post-Transplant Anemia Has Strong Influences on Renal and Patient Outcomes in Living Kidney Transplant Patients.

BACKGROUND: Post-transplant anemia (PTA) is a risk factor for mortality and graft loss in kidney transplant patients. METHODS: In all, 172 patients were included in this study. PTA was defined as hemoglobin <13.0 g/dL in men and 12.0 g/dL in women. The primary outcome of interest was the renal outcome, defined as a 50% increase in serum levels of creatinine, a return to chronic dialysis, and subsequent kidney transplantation (KTx). The secondary outcome was a composite of the primary outcome and death. RESULTS: At baseline, 75 patients (43.6%) had PTA. During follow-up of a median of 7.3 years, 52 patients (30.2%) had 2-fold higher creatinine levels than at baseline, 24 patients (14.0%) had to return to chronic dialysis or subsequent KTx, and 11 patients (6.4%) died; 8 (4.7%) of the deceased patients had functioning allografts. Univariate regression analyses showed that a lower hemoglobin level and positive proteinuria were significantly associated with both outcomes. After adjusting for important clinical variables, a lower hemoglobin level remained a strong predictor for both outcomes. Restricted cubic splines showed an almost linear inverse association with a hemoglobin level ≥12 g/dL. The risk of the outcomes increased with decreasing tertiles of the baseline hemoglobin level for both men and women, but the associations in women were much weaker than those in men, suggesting a different prognostic value of the hemoglobin level between men and women. CONCLUSIONS: PTA strongly influenced the renal and patient outcomes in living kidney transplant patients.