Acute Renal Transplant Rejection Research Articles

Peptide based adsorbers for therapeutic immunoadsorption.

Peptides as ligands for immunoadsorption exhibit several potential advantages over native proteins. Two newly developed adsorbers are based on peptides covalently coupled to sepharose CL-4B. Globaffin is capable of binding immunoglobulins independent from their antigen specificity and thus, applicable in transplant recipients and several antibody mediated autoimmune diseases. Among others, the most important disorders suitable for the treatment with Globaffin are rheumatoid arthritis, systemic lupus erythematosus, and acute renal transplant rejection. Coraffin is a specific adsorber using two linear peptide ligands mimicking epitopes of the beta1-adrenergic receptor, that bind corresponding autoantibodies from patients suffering from idiopathic dilated cardiomyopathy. Specific immunoadsorption has been shown to be beneficial for patients with dilated cardiomyopathy. Coraffin can be used as a new therapeutic option for these patients, who get only limited benefit from medical therapy. Both adsorbers may be combined with all approved apheresis control devices available.

Basiliximab: a review of its use as induction therapy in renal transplantation.

Basiliximab (Simulect), a chimeric (human/murine) monoclonal antibody, is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents. Basiliximab significantly reduced acute rejection compared with placebo in renal transplant recipients receiving dual- (cyclosporin microemulsion and corticosteroids) or triple-immunotherapy (azathioprine- or mycophenolate mofetil-based); graft and patient survival rates at 12 months were similar. Significantly more basiliximab than placebo recipients were free from the combined endpoint of death, graft loss or acute rejection 3 years, but not 5 years, after transplantation. The incidence of adverse events was similar in basiliximab and placebo recipients, with no increase in the incidence of infection, including cytomegalovirus (CMV) infection. Malignancies or post-transplant lymphoproliferative disorders after treatment with basiliximab were rare, with a similar incidence to that seen with placebo at 12 months or 5 years post-transplantation. Rare cases of hypersensitivity reactions to basiliximab have been reported. The efficacy of basiliximab was similar to that of equine antithymocyte globulin (ATG) and daclizumab, and similar to or greater than that of muromonab CD3. Basiliximab was as effective as rabbit antithymocyte globulin (RATG) in patients at relatively low risk of acute rejection, but less effective in high-risk patients. Numerically or significantly fewer patients receiving basiliximab experienced adverse events considered to be related to the study drug than ATG or RATG recipients. The incidence of infection, including CMV infection, was similar with basiliximab and ATG or RATG. Basiliximab plus baseline immunosuppression resulted in no significant differences in acute rejection rates compared with baseline immunosuppression with or without ATG or antilymphocyte globulin in retrospective analyses conducted for small numbers of paediatric patients. Limited data from paediatric renal transplant recipients suggest a similar tolerability profile to that in adults. Basiliximab appears to allow the withdrawal of corticosteroids or the use of corticosteroid-free or calcineurin inhibitor-sparing regimens in renal transplant recipients. Basiliximab did not increase the overall costs of therapy in pharmacoeconomic studies. Basiliximab reduces acute rejection without increasing the incidence of adverse events, including infection and malignancy, in renal transplant recipients when combined with standard dual- or triple-immunotherapy. The overall incidence of death, graft loss or acute rejection was significantly reduced at 3 years; there was no significant difference for this endpoint 5 years after transplantation. Malignancy was not increased at 5 years. The overall efficacy, tolerability, ease of administration and cost effectiveness of basiliximab make it an attractive option for the prophylaxis of acute renal transplant rejection.

The clinical significance of antibody to vascular endothelial cells after renal transplantation.

Vascular endothelial cells (ECs) are considered to be a primary target for injury in allograft rejection. However, the relationship between serum antibody activity to ECs and rejection episodes has not been examined extensively in renal transplantation. Twenty-two renal transplant recipients were included in this study. Serum antibody activity to vascular endothelial cells (AECA) was measured using a cellular enzyme-linked immunosorbent assay (ELISA) in which human umbilical vein endothelial cells (HUVEC) and human glomerular endothelial cells (HGEC) were preincubated with TNF-alpha used as target cells. Serum samples were obtained just before transplantation and once a week during the immediate 1-3-month post-transplantation period. There was a significant correlation between the presence of AECA against HGEC and rejection episodes (P < 0.05). Patients with multi-episodes of rejection showed significantly higher frequencies of AECA than patients with mono-episodic rejection (P < 0.0005). It should be noted that patients suffering from multi-episodes of rejection revealed higher AECA titres before transplantation. These findings imply that the HGEC-ELISA could be used as a prospective, informative test to identify patients with a higher risk of acute rejection in renal transplantation.

EFFECT OF BASILIXIMAB ON ACUTE REJECTION IN PEDIATRIC RENAL TRANSPLANTATION: RESULTS FROM TWO CENTERS

Acute rejection is a major determinant of chronic allograft dysfunction and graft survival. This study evaluated the effect of basiliximab (Simulect®), a 156‐kDa chimeric monoclonal antibody (human and murine) directed against the alpha chain of the interleukin (IL)‐2 receptor of human lymphocytes, on acute rejection in pediatric renal transplantation. Data were collected from two pediatric renal transplantation centers. Forty transplantations (22 males and 18 females; mean age 14.8±3.6 years) were performed between 1996 and 2001. Twelve of the grafts came from cadaveric donors and 28 from living‐related donors. Twenty‐four of the patients were on hemodialysis, 15 were on peritoneal dialysis, and one case was a pre‐emptive transplantation. All patients were placed on triple‐drug immunosuppression [prednisolone + (azathioprine or mycophenolate mofetil) +(cyclosporine or tacrolimus)]. Basiliximab was also administered in 17 cases. The respective rates of biopsy‐proven acute rejection in the basiliximab group and the standard‐regimen group were 0% vs. 17.4% (P&gt;0.05) at 1 month post‐transplantation; 0% vs. 26.1% (P&lt;0.05) at 3 months; and 0% vs. 26.1% (P&lt;0.05) at 6 months. Thirty and 16 patients had completed 1‐ and 3‐year follow ups, respectively, at the time of writing; the 1‐ and 3‐year graft survival rates were 96% (29/30) and 81% (13/16), respectively.Basiliximab significantly reduced the rates of acute rejection at 3‐ and 6 months post‐pediatric renal transplantation. It was well tolerated by all patients, and caused no significant adverse effects. The effect of basiliximab on long‐term graft survival and chronic allograft dysfunction deserves further investigation.

Daclizumab has a definite role in preventing acute rejection in renal transplants and may be beneficial in other solid organ transplants

Daclizumab has a definite role in preventing acute rejection in renal transplants and may be beneficial in other solid organ transplants

Simple determination of mycophenolic acid in human serum by column-switching high-performance liquid chromatography

A column-switching high-performance liquid chromatographic analysis was established to monitor the serum concentration of mycophenolic acid, the active metabolite from mycophenolate mofetil administered for the prophylaxis of acute organ rejection in renal transplantation. The system consisted of two pumps for solvent delivery, a column-switching valve, a precolumn, and a reversed-phase analytical column. The present method enabled us to determine MPA by injecting serum samples directly into HPLC without any pretreatment. The mobile phases with different amounts of organic solvent were delivered to the precolumn and analytical column by separate lines, and samples were applied to the precolumn. The column switching valves were switched automatically following the processes for the elimination of protein and the drug analysis. The peak heights of MPA were linearly related to the concentrations ( r=0.999) in the range of 0.1–20 μg/ml, and the limit of quantification was 0.1 μg/ml ( S/ N ratio=3). This method was accurate and reproducible on the basis of the results of recovery (94.0–98.0%) and small coefficient of variations of intra and inter-assay (less than 8.3%).

Serum antibody activity to glomerular endothelial cells is a prospective indicator of renal allograft rejection

Background. Vascular endothelial ells (ECs) are considered to be a primary target for injury in allograft rejection. However, the relationship between serum antibody activity to ECs and rejection episodes has not been extensively examined in renal transplantation. Methods. Twenty-two renal transplant recipients were included in this study. Serum levels of anti-endothelial cell antibody (AECA) were measured using a cellular enzyme-linked immunosorbent assay (ELISA) in which human umbilical vein endothelial cells (HUVEC), human glomerular endothelial cells (HGEC), and human dermal microvascular endothelial cells (MvE) were used as target cells. Serum samples were obtained just before transplantation and once a week during the immediate 1- to 3-month posttransplantation period. Results. There was a significant correlation between the the presence of AECA against HGEC and rejection episodes (P < 0.05). Patients with multiple episodes of rejection showed significantly higher frequencies of AECA than patients with a single episode of rejection (P < 0.001). It should be noted that patients suffering from multiple episodes of rejection had higher AECA titers than those without a rejection episode before transplantation. Conclusions. These findings imply that the HGEC-ELISA could be used as a prospective, informative test to identify patients at a high risk of acute rejection in renal transplantation.

Local synthesis of complement component C3 regulates acute renal transplant rejection.

Accumulating evidence suggests that innate immunity interacts with the adaptive immune system to identify potentially harmful antigens and eliminate them from the host. A central facet of innate immunity is complement, which for some time has been recognized as a contributor to inflammation in transplant rejection but without detailed analysis of its role in what is principally a T cell mediated process. Moreover, epithelial and vascular tissues at local sites of inflammation secrete complement components; however, the role of such local synthesis remains unclear. Here we show that the absence of locally synthesized complement component C3 is capable of modulating the rejection of renal allografts in vivo and regulating T-cell responses in vivo and in vitro. The results indicate that improved success in kidney transplantation could come from therapeutic manipulation of innate immunity in concert with T cell directed immunosuppression.

Review: metabolism of immunosuppressant drugs.

Pharmacokinetic concepts provide a basis for individualization of drug therapy to optimize outcomes of the critical-dose drugs cyclosporine (CsA), tacrolimus (TRL), sirolimus (SRL), and mycophenolate mofetil (MMF). The therapeutic range of a drug-defined as the concentrations at which the desired pharmacologic effect is produced without adverse effects in most patients-is difficult to achieve given the significant inter-and intrapatient variability of the effects of a given concentration of therapeutic agents. Because of the highly variable rates of absorption of immunosuppressive agents and clinical responses to given concentrations in transplant recipients, individualization of drug regimens by using therapeutic drug monitoring (TDM) is essential to optimize pharmacotherapy Assessing proclivity for acute rejection episodes in transplant recipients currently is attempted by estimating drug exposure using the area under the time-concentration curve (AUC) for MMF and the average concentration (Cav, the quotient of the AUC and the dosing interval) for CsA. These studies have revealed that low oral bioavailability was a more important predictor of rejection than was a rapid clearance rate. In addition, the degree of intra-individual variability of AUC values correlated with the development of chronic rejection in renal transplant recipients. Similarly, TDM of MMF requires AUC determinations. Low mycophenolic acid (MPA) exposure, as estimated by the AUC, demonstrates a significant association with an increased risk of an acute renal transplant rejection episode. The AUC0-2 estimate of MPA shows good agreement with the 12-hr AUC estimate from samples obtained during the entire dosing interval. In contrast, trough levels are utilized during treatment with TRL or SRL, potent new immunosuppressive agents that display a pleiotropic array of side effects. Standard body measures, including weight and body mass index, poorly predict the concentration of SRL in whole blood. Large inter- and intra-individual differences displayed in patients also could not be predicted by demographic features or by laboratory parameters. When SRL is given with other immunosuppressive agents such as CsA, which shares with SRL mutual microsomal metabolism by the cytochrome P450 3A system, pharmacokinetic interactions occur, especially when the agents are administered concomitantly. Because of the critical-dose nature of most of the recent generation of immunosuppressive agents, therapeutic drug monitoring is becoming increasingly important in the selection of doses and treatment regimens.

Radiotherapy within the scope of allogeneic kidney transplantation: an indication for local irradiation?

In the past decades the indications for local graft irradiation (LGI) in acute renal transplant rejection have been limited and considered unfavorably. Despite major advantages in maintenance immunosuppression and management of acute allograft rejection a minority of patients remains with drug resistant transplant rejection. This subgroup of patients may benefit from LGI. Between 1979 and 1990, eight patients with biopsy-proven acute renal allograft rejection and failure of all other immunosuppressive measures (corticosteroids, ATG, ALG or OKT3) were treated with LGI. Retrospective analysis was conducted for this control group. Radiotherapy was performed with Co-60 up to a median total dose of 6.0 Gy (single doses: 1.5-2.0 Gy). Six of eight patients were dialysis dependent prior to irradiation. In addition a literature review was performed including most important textbooks, electronic databases (Medline, Embase, Science Citations Index), and the internet. Two of eight patients experienced a clinical reversal of rejection and an improvement of renal function: serum creatinine decreased significantly. One patient remained free of dialysis with a functioning graft, the other had a recurrent rejection 2 months later and became dialysis dependent. The literature review showed, that adjuvant LGI has no advantage over conventional immunosuppression. However, in case of a drug refractory allograft rejection LGI restores long-term stable organ function in 13-60% of cases. The value of LGI of organ transplants, like renal allografts, is still not clearly defined. As a rescue measure in drug refractory allograft rejection special patients may clinically benefit, when a transplant nephrectomy can be avoided. Further prospective clinical trials are needed for a better assessment of LGI in organ transplantation.

Chemokine receptor polymorphism and risk of acute rejection in human renal transplantation.

Chemokines regulate the trafficking of leukocytes in immunity and inflammation and have been implicated in mouse models in acute cardiac and renal allograft rejection; however, their significance to human transplantation is not yet defined. The association of human chemokine receptor genetic variants, CCR5-Delta32, CCR5-59029-A/G, CCR2-V64I, CX3CR1-V249I, and CX3CR1-T280M, with outcome in 163 renal transplant recipients was examined here. Significant reductions were found in risk of acute renal transplant rejection in recipients who possessed the CCR2-64I allele (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.12 to 0.78; P = 0.014) or who were homozygous for the 59029-A allele (OR, 0.37; 95% CI, 0.16 to 0.85; P = 0.016). There were no significant differences in the incidence of rejection among patients stratified as with or without CCR5-Delta32 or by the CX3CR1-V249I or CX3CR1-T280M genotypes. Adjustment for known risk factors for transplant rejection confirmed the univariate findings for possession of the CCR2-64I allele (OR, 0.20; P = 0.032) and homozygosity for the 59029-A allele (OR, 0.26; P = 0.027). It was concluded that the risk of acute rejection in renal transplantation is associated with genetic variation in the chemokine receptors CCR2 and CCR5.

Evolution of immunosuppression and continued importance of acute rejection in renal transplantation

As steady improvement in short-term kidney graft survival and long-term outcomes prolongs the lives of transplant patients, responsibility for their care is shifting away from transplant specialists and into the hands of community nephrologists. Therefore, community nephrologists need to have a deeper understanding of immunosuppressive therapies than ever before. Pharmacologic immunosuppression has been continuously evolving over the past two decades. Azathioprine was introduced in the early 1960s. Introduction of cyclosporine (CsA) in 1983 revolutionized short-term outcomes after renal transplantation. The first monoclonal antibody immunosuppressant, OKT3, was introduced in 1986. The 1990s saw the introduction of a number of important new agents, including mycophenolate mofetil (MMF), tacrolimus, and a microemulsion CsA, as well as two new monoclonal antibodies. Combinations of these new agents, along with improving clinical care, have produced 1-year patient survival approaching 100% and graft survival exceeding 90%. The newest class of agents, the first of which is sirolimus, is called target of rapamycin (TOR) inhibitors and is used with CsA for maintenance therapy. Immunosuppressive drug therapy after kidney transplantation continues to evolve. There is a variety of pharmacologic combinations from which to choose, based on immunologic risk and side effect profiles. As new regimens are developed, ongoing communications between the transplant center and community nephrologists will be required to implement therapeutic changes and optimize patient care successfully.

Tacrolimus rescue therapy for children with acute renal transplant rejection.

Seventeen children with renal transplants (11 living-related, age 2-18 years) were converted from cyclosporine to tacrolimus because of acute rejection that failed to respond to high-dose corticosteroids. Resistance to corticosteroids was confirmed by renal biopsy in 14 patients, and assumed in 3 patients because of failure of serum creatinine to improve to baseline values. Four patients were also treated with OKT3, and 15 children had been receiving mycophenolate maintenance therapy prior to conversion to tacrolimus. Rejection occurred at 2-174 weeks post transplant (mean 52 weeks). Actuarial 1- and 2-year graft survival was 87% and 78%. Three children progressed to end-stage renal disease after 4, 12, and 13 months of tacrolimus. The remaining 14 children have functioning allografts after 20-168 weeks of treatment (mean 80 weeks). All 14 children exhibit stable or improved renal function: serum creatinine 1.1+/-0.7 mg/dl versus 2.0+/-0.9 mg/dl prior to tacrolimus. In conclusion, tacrolimus was effective therapy for both early and late acute rejection in children who failed to respond to high-dose corticosteroids. No significant short-term adverse effects were encountered.

Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation.

A retrospective analysis was performed on adult renal transplant recipients to evaluate the relationship between tacrolimus trough concentrations and the development of rejection in the first month after transplant. A total of 349 concentrations from 29 patients, measured by enzyme-linked immunosorbent assay (ELISA), were recorded. Based on an increased serum creatinine, 12 patients were considered to have organ rejection. Rejection was confirmed by biopsy in five of these. The median trough concentration of tacrolimus over the first month of therapy, or until the time of first rejection was compared in rejecters vs non-rejecters. Median trough concentrations of tacrolimus were found to be lower in biopsy-proven rejecters vs non-rejecters (P=0.03) and all rejecters vs non-rejecters (P=0.04). The average median concentration (+/-SD) in the biopsy-proven rejecter group was 5.09+/-1.16 ng/ml, compared to 9.20+/-3.52 ng/ml in the non-rejecter group. After exclusion of an outlier, the average median concentration in all rejecters was 5.57+/-1.47 ng/ml, compared with 9.20+/-3.52 ng/ml in non-rejecters. A rejection rate of 55% was found for patients with a median trough concentration between 0 and 10 ng/ml. This compared with no observed rejection in patients with a median concentration between 10 and 15 ng/ml. A significant relationship exists between organ rejection and median tacrolimus trough concentrations in the first month post-transplant, with patients displaying low concentrations more likely to reject. In order to minimize rejection in the first month after renal transplantation, trough concentrations greater than 10 ng/ml must be achieved.

Rapid steroid withdrawal versus standard steroid therapy in patients treated with basiliximab, cyclosporine, and mycophenolate mofetil for the prevention of acute rejection in renal transplantation

Rapid steroid withdrawal versus standard steroid therapy in patients treated with basiliximab, cyclosporine, and mycophenolate mofetil for the prevention of acute rejection in renal transplantation

Daclizumab: a review of its use in the management of organ transplantation.

The humanised monoclonal antibody daclizumab is an immunosuppressive agent that reduces acute rejection in solid organ transplantation. It is specific for the alpha subunit (Tac/CD25) of the interleukin (IL)-2 receptor on activated T cells and achieves immunosuppression by competitive antagonism of IL-2-induced T cell proliferation. When added to standard triple immunosuppression regimens, daclizumab significantly reduces the rate of acute rejection at 1 year in renal transplantation by 36% and there are indications that it may be effective in other solid organ transplantations. Three-year outcomes of two phase III clinical trials in renal transplantation indicate similar values for graft and patient survival between daclizumab and placebo when given in addition to triple immunosuppression; however, these pivotal trials were not designed with sufficient power to demonstrate any statistical significance. The addition of daclizumab induction shows potential in allowing calcineurin inhibitor- and corticosteroid-sparing regimens without increasing the rate of acute graft rejection or adverse effects in renal and liver transplantation. Preliminary reports indicate that daclizumab may also be a useful agent in delayed graft function and graft versus host disease (GVHD). Further investigation of its efficacy in these groups and in children is needed. Data from clinical trials show daclizumab to be well tolerated in solid organ transplantation. It does not increase the incidence of infection, including cytomegalovirus infection, when compared with placebo or no induction groups. Preliminary comparative data with muromonab CD3 indicate that daclizumab may be associated with a lower rate of infectious complications and similar or better efficacy. In conclusion, daclizumab has been proven to reduce acute rejection in renal transplant recipients when given in addition to traditional baseline immunosuppression. It has shown potential to reduce acute rejection in other solid organ transplants; however, well designed, randomised studies are required to confirm this. Clinical experience from trials to date indicate that daclizumab has a tolerability profile similar to placebo with no significant effect on the incidence of infection. The relative efficacy and tolerability of daclizumab compared with other induction agents has yet to be defined. Available data suggest that daclizumab may allow the use of calcineurin inhibitor-sparing and corticosteroid-sparing regimens and may have potential in the treatment of GVHD.

Granulysin expression is a marker for acute rejection and steroid resistance in human renal transplantation

Differentiating etiologies of transplant dysfunction without biopsy and optimizing therapy for acute rejection by predicting steroid resistance will reduce patient morbidity. Granulysin is a cytolytic molecule released by CTL and NK cells and coexpressed with effectors of acute allograft rejection, like perforin and granzymes. Granulysin mRNA and protein expression were studied in peripheral blood lymphocytes (PBL; n = 61 total, n = 10 with intercurrent infections) and biopsy tissue from adult and children renal transplant recipients ( n = 97) by competitive quantitative-reverse transcriptase-PCR (QC-RT-PCR) and immunohistochemistry. Differences in cell phenotypes were studied in steroid sensitive and resistant acute rejection biopsies. Granulysin was studied in phytohemagglutinin (PHA) stimulated cell lines (donor PBL and CD45RO + T cells) by FACS, Western blotting, and RT-PCR after pretreating with cyclosporine A (CSA), azathioprine, mycophenolic acid, and steroids. Granulysin mRNA was significantly increased in patient PBL and transplant biopsies during acute rejection ( p < 0.0001) and infection ( p < 0.001). Rejecting biopsies alone ( n = 53) had mononuclear cell granulysin staining. Steroid resistant biopsies ( n = 25) had denser granulysin staining (>2 cells/high power field) and CD45RO + lymphocytes, when compared with steroid sensitive ( n = 28) rejecting tissue. Granulysin levels were unchanged after azathioprine and mycophenolic acid treatment, decreased after treating activated PBL with steroids and cyclosporine A (CSA), and paradoxically, increased ( p < 0.05) after treating CD45RO + CTL with CSA. Elevated PBL granulysin is a peripheral marker for acute rejection and infection and dense granulysin staining a tissue marker for steroid resistance. Memory CTL abound in steroid resistant grafts and may have a markedly different response to CSA immunotherapy, suggesting a possible mechanism for steroid resistance.

Hepatocyte growth factor: a sensitive indicator for the acute rejection of renal transplants

Hepatocyte growth factor: a sensitive indicator for the acute rejection of renal transplants

The Duffy antigen receptor for chemokines is up-regulated during acute renal transplant rejection and crescentic glomerulonephritis

Recruitment of leukocytes during immune responses requires the coordinate expression of adhesion molecules in concert with chemokines and their receptors. The Duffy antigen receptor for chemokines (DARC) binds multiple chemokines and is expressed on postcapillary venules in the normal kidney. The chemokine receptor CCR5, which shares the ligand regulated upon activation, normal T-cell expressed and secreted (RANTES) with DARC, is expressed by infiltrating T cells in the renal interstitium. As DARC might be involved in the attraction of CCR5-positive cells, we studied the distribution of DARC and CCR5 in two forms of cell-mediated renal injury: renal allograft rejection and crescentic glomerulonephritis (cGN). A total of 87 renal specimens, including 12 pretransplant biopsies, 47 transplant biopsies (Banff 1, N = 10; Banff 2, N = 19; and various other lesions N = 18), and 28 biopsies from patients with cGN, was analyzed. Immunohistochemistry for CCR5 and DARC was performed on serial sections of formalin-fixed and paraffin-embedded tissue. Compared with pretransplant biopsies, the mean number of DARC-positive interstitial venules was significantly increased during both transplant rejection and cGN. This was accompanied by an infiltration of CCR5-positive leukocytes. During transplant rejection, the number and distribution of CCR5-positive cells correlated with DARC-positive venules. Infiltrating CCR5-positive leukocytes were found mainly in the interstitium, often clustering around Bowman's capsules in biopsies from cGN. The number of glomerular CCR5 positive cells is low, but they are common in a subset of crescents. We hypothesize that the increased number of DARC-positive venules in areas of interstitial injury and the colocalization with CCR5-positive infiltrating leukocytes may indicate a role for endothelial DARC expression during leukocyte adhesion and interstitial infiltration.

Acute humoral rejection of kidney allografts in patients with a positive flow cytometry crossmatch (FCXM).

The patients with a positive flow cytometry crossmatch (FCXM) are categorized as a high-risk group causing hyperacute or accelerated acute rejection after kidney transplantation. According to the successful results of ABO-incompatible renal transplantation, we have performed the living related transplant operations in the recipients with positive FCXM for donor T cells, but having a negative complement-dependent lymphocytotoxic reaction test. We have followed the clinical course of 4 FCXM-positive patients, and 2 of them have developed acute humoral rejection. We report the strategies for FCXM-positive living kidney transplantations and the characteristics of pathological findings of acute humoral rejection in FCXM-positive renal transplants. We have had few episodes of acute humoral rejection in ABO-incompatible kidney transplantations under immunosuppressive regimens, including cyclophosphamide, but 2 patients of 4 with FCXM-positive kidney transplantations developed acute humoral rejections. The differences in immunosuppressive regimen between ABO-incompatible and FCXM-positive kidney transplantations concern anti-lymphocyte globulin (ALG) and splenectomy. We have not performed splenectomy and ALG administration in FCXM-positive kidney transplantations. Severe acute rejection episodes have been experienced on post-operative days 7 and 9 in 2 of 4 FCXM-positive recipients. The early acute rejection episodes were clinically and pathologically diagnosed as typical humoral rejections. We have examined an immunofluorescent study to prove the diagnosis of humoral rejection in FCXM-positive kidney transplantations; both immunoglobulin M and C3 were positive for the whole course of humoral rejection. The 2 patients with acute humoral rejection recovered after treatment with double filtration plasmapheresis or plasma exchange to remove their anti-donor antibodies. The gold standard of success in FCXM-positive kidney transplantations is to suppress the production and reduce the level of anti-donor antibodies after transplant operations.