Refractory Rejection Research Articles

Long-term experiences on cardiac retransplantation in adults

It remains disputed whether cardiac retransplantation should be performed. This study aimed to evaluate our long-term experiences on cardiac retransplantation in adults. Between March 1989 and December 2004, 2% (28/1290) of cardiac retransplantations were performed. The reasons for cardiac retransplantation were cardiac allograft vasculopathy (n=13; 47%), primary graft failure (n=11; 39%), and refractory acute rejection (n=4; 14%). The 30-day mortality risk was 29% (acute rejection: 50%; primary graft failure: 36%; cardiac allograft vasculopathy: 15%, p=0.324), compared to 8.5% for primary cardiac transplantation (p<0.001). The causes of early death were acute rejection (n=3; 37%), multiorgan failure (n=3; 37%), primary graft failure (n=1; 13%), and right ventricular failure (n=1; 13%). The late mortality rate was 96/1000 patient-years. The causes of late death were acute rejection (n=4; 50%), cardiac allograft vasculopathy (n=2; 25%), multiorgan failure (n=1; 13%), and infection (n=1; 13%). The 1-, 5-, 10-, and 15-year survival was respectively 78, 68, 54, and 38% (primary cardiac transplantation), and 46, 41, 32, and 32% (cardiac retransplantation) (p=0.003). The short-term survival for cardiac retransplantation due to cardiac allograft vasculopathy was likely better than primary graft failure and refractory acute rejection (p=0.09). The overall outcomes of cardiac retransplantation are significantly inferior to primary cardiac transplantation. Cardiac retransplantation should be only performed for selected patients.

Conversion of Immunosuppressive Monotherapy from Cyclosporin A to Tacrolimus Reverses Bone Loss in Rats

Tacrolimus is used for transplant patients with refractory graft rejection and those with intolerance to cyclosporin (CsA), without the disfiguring adverse effects frequently attributed to CsA therapy. Since we have shown that CsA-associated bone loss can also affect alveolar bone, the purpose of this study was to evaluate the effects of conversion of monotherapy from CsA to tacrolimus on alveolar bone loss in rats. Groups of rats were treated with either CsA (10 mg/kg/day, s.c.), tacrolimus (1 mg/kg/day, s.c.), or drug vehicle for 60 and 120 days, and an additional group received CsA for 60 days followed by conversion to tacrolimus for a further 60-day period. Bone-specific alkaline phosphatase (BALP), tartrate-resistent acid phosphatase (TRAP-5b), calcium (Ca(2+)), interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) concentrations were evaluated in the serum. Analyses of bone volume, bone surface, number of osteblasts, and osteoclasts were performed. Treatment with CsA for either 60 or 120 days was associated with bone resorption, represented by lower bone volume and increased number of osteoclasts; serum BALP, TRAP-5b, IL-1beta, IL-6, and TNF-alpha were also higher in these animals. After conversion from CsA to tacrolimus, all the altered serum markers returned to control values in addition to a significant increase of bone volume and a lower number of osteoclasts. This study shows that conversion from CsA to tacrolimus therapy leads to a reversal of the CsA-induced bone loss, which can probably be mediated by downregulation of IL-1beta, IL-6, and TNF-alpha production.

Living donor liver transplantation for acute liver failure in infants: The impact of unknown etiology

Infants with ALF occasionally have the most urgent need for a liver transplant. In urgent situations for liver transplantation, LDLT has been advocated. Between July 1995 and April 2004, medical records of 15 infants undergoing LDLT for ALF of unknown etiology were reviewed and their outcomes were compared with infants undergoing LDLT for other liver diseases. They received LLS (n = 9), MS (n = 3), and RMS (n = 3) grafts. Eight technical complications occurred, with a similar incidence for LDLT and the other liver diseases. On the other hand, the liver biopsies after LDLT showed a significantly higher incidence of ACR with centrilobular injuries. Ten patients died after primary LDLT because of refractory rejection (n = 6), rotavirus infection (n = 2), chronic rejection (n = 1), and surgical complications (n = 1). With a median follow-up of 7.0 months, five-yr graft and patient survival rates were 17.8% and 26.7%, respectively. In conclusion, the outcome of LDLT for ALF in infants, especially cases with unknown etiology, was unsatisfactory and refractory rejection often led to liver failure. From our observation the centrilobular changes were characteristics of ACR in infantile LDLT for cryptogenic ALF.

Preceeding the rejection: In search for a comprehensive post-transplant immune monitoring platform

The survival of a transplanted organ is dependent on maintenance of continuous immunosuppression. However, even the strictest adherence to the recommended drug levels does not prevent the occurrence of numerous complications associated with immunosuppression. The efficacy of immunosuppression therapy protocols would be enhanced greatly by the availability of biotechnologies capable of identifying and predicting immunological events prior to the manifestation of clinical parameters indicating graft failure. The aim of the study was to evaluate the potential contribution of some modern tools for post-transplantation monitoring, and to propose a method for combining them into a comprehensive mechanism for this purpose. The technologies utilized in this study are among a group of ‘cutting edge’ diagnostic methods at the initial steps of evaluation for their potential contribution for post-transplantation immune monitoring. This study was a pioneering opportunity to combine and utilize these tools jointly. The method of research was based on monitoring 13 adult kidney transplant recipients. The Immuknow assay determined cellular immunity status by quantitative measurement of intracellular ATP level in CD4 + lymphocytes after PHA stimulation. Sera were analyzed for concentration of soluble CD30 reflecting primary allo-stimulation and for donor specific anti-HLA antibodies responsible for accelerated and refractory rejection. The results were correlated with clinical and pathological parameters and appraisal of predictive value was attempted. In Immuknow assay analysis ATP incremental changes indicative of rejection or infection were found in 75% and in 50% incidences, respectively. In stable patients, the ATP deviation from the preoperative baseline, indicative of stable engraftment, was much less pronounced than in other habitual clinical tests. CD30 concentrations were measured greatly above normal values prior to biopsy-proven rejection episodes, both before and after the transplant operation. Anti-HLA antibodies were elevated at a later stage, concurrently with clinical manifestation of graft failure and rejection. Anti-HLA antibody level remained negligible in patients going through a stable post-transplant clinical course. Overall, the utilization of the platform of combined biotechnologies could serve as a valuable tool for immune monitoring in organ transplantation, allowing for therapeutic intervention that can favorably affect the clinical outcome.

150] CADAVERIC WHOLE LIVER TRANSPLANTATION FOR NON-ACETAMINOPHEN FULMINANT HEPATIC FAILURE: A 20-YEAR EXPERIENCE

AIM: To investigate the long-term results of liver transplantation (LT) for non-acetaminophen fulminant hepatic failure (FHF). METHODS: Over a 20-year period, 29 FHF patients underwent cadaveric whole LT. Most frequent causes of FHF were hepatitis B virus and drug-related (not acetaminophen) liver failure. All surviving patients were regularly controlled at the out-patient clinic and none was lost to follow-up. Mean follow-up was 101 mo. RESULTS: One month, one-, fi ve- and ten-year patient survival was 79%, 72%, 68% and 68%, respectively. One month, one-, fi ve- and ten-year graft survival was 69%, 65%, 51% and 38%, respectively. Six patients needed early (< 2 mo) retransplantation, four for primary non-function, one for early acute refractory rejection because of ABO blood group incompatibility, and one for a malignant tumor found in the donor. Two patients with hepatitis B FHF developed cerebral lesions peri-transplantion: one developed irreversible and extensive brain damage leading to death, and one suffered from deep defi cits leading to continuous medical care in a specialized institution.

Proliferation signal inhibitors in cardiac transplantation

Standard immunosuppression after cardiac transplantation includes a calcineurin inhibitor in combination with mycophenolate mofetil or azathioprine and corticosteroids. These agents have led to excellent outcomes but have shortcomings in terms of efficacy and toxicity. A new class of immunosuppressants, proliferation signal inhibitors, may meet some of these shortcomings. The efficacy of the available proliferation signal inhibitors - sirolimus and its derivative everolimus - has been compared with azathioprine in three randomized clinical trials. Sirolimus or everolimus use was associated with lower rates of acute rejection and reduced development of chronic allograft vasculopathy. Sirolimus was not found to be superior to mycophenolate mofetil in a randomized trial. Proliferation signal inhibitors have been reported to be effective in refractory recurrent acute rejection. Nonrandomized studies have demonstrated that proliferation signal inhibitor-based immunosuppression enables recovery from renal dysfunction secondary to calcineurin inhibitor treatment. Proliferation signal inhibitor-based treatment is associated with a lower risk of malignancy than calcineurin inhibitor-based regimens. Proliferation signal inhibitors have significant adverse effects that may limit widespread use. Proliferation signal inhibitors are important new immunosuppressive agents that have added considerably to the armamentarium allowing further tailored immunosuppression to individualize patient care after heart transplantation.

Gene Polymorphisms of the Renin-Angiotensin-Aldosterone System and Angiotensin II Type 1-Receptor Activating Antibodies in Renal Rejection

Steroid refractory acute rejection (SRAR) is a major vital factor in renal transplantation recipients. The pathogenesis of SRAR may involve both immune and non-immune mechanisms. A decreased renal allograft function has also been associated with increased activity of renin-angiotensin-aldosterone system (RAS), which may be genetically determined. A total 206 renal transplant recipients, 116 males and 90 females, were included. The effects of gene polymorphisms of the four components of RAS including angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin type 1 receptor (AT1R), and aldosterone synthase (CYP11B2) were investigated in 19 cases of renal transplant patients with SRAR. The association between SRAR and the activating antibodies targeting the AT1R were also investigated. Genotyping was performed for the M235T-AGT, the I/D-ACE, the A1166C-AT1R, and the -344T/C-CYP11B2 gene polymorphisms using polymerase chain reaction. Our results showed that renal allograft recipients with SRAR had significantly higher occurrences of the DD genotype of ACE and CC genotype of AT1R than recipients without SRAR. The other genetic polymorphisms of the RAS were not associated with SRAR. Activating antibodies targeting the AT1R were detected in the sera from 14 SRAR victims with malignant hypertension and without anti-HLA antibodies. This study provides evidence that determination before transplantation of the polymorphism of the gene encoding components of RAS may help identify patients who are at risk for SRAR. The detection of the antibodies of AT1R may contribute to the prevention of SRAR.

Cadaveric liver transplantation for non-acetaminophen fulminant hepatic failure: A 20-year experience

To investigate the long-term results of liver transplantation (LT) for non-acetaminophen fulminant hepatic failure (FHF). Over a 20-year period, 29 FHF patients underwent cadaveric whole LT. Most frequent causes of FHF were hepatitis B virus and drug-related (not acetaminophen) liver failure. All surviving patients were regularly controlled at the out-patient clinic and none was lost to follow-up. Mean follow-up was 101 mo. One month, one-, five- and ten-year patient survival was 79%, 72%, 68% and 68%, respectively. One month, one-, five- and ten-year graft survival was 69%, 65%, 51% and 38%, respectively. Six patients needed early (< 2 mo) retransplantation, four for primary non-function, one for early acute refractory rejection because of ABO blood group incompatibility, and one for a malignant tumor found in the donor. Two patients with hepatitis B FHF developed cerebral lesions peri-transplantion: One developed irreversible and extensive brain damage leading to death, and one suffered from deep deficits leading to continuous medical care in a specialized institution. Long-term outcome of patients transplanted for non-acetaminophen FHF may be excellent. As the quality of life of these patients is also particularly good, LT for FHF is clearly justified, despite lower graft survival compared with LT for other liver diseases.

Association of Emergence of HLA Antibody and Acute Rejection in Intestinal Transplant Recipients: A Possible Evidence of Acute Humoral Sensitization

Development of HLA antibody has been associated with chronic allograft failure in kidney recipients. We tested HLA antibody in posttransplant sera of intestinal recipients: 126 sera from 28 pediatric recipients were tested for HLA antibody by flow PRA (f-PRA). Median age was 1.1 years (0.44–17). Graft types included isolated intestine ( n = 6), liver and intestine ( n = 3), modified multivisceral ( n = 3), and multivisceral grafts ( n = 16). Greater than 10% of either class I (CI) or class II (CII) f-PRA was considered positive, and >30% strongly positive. Five of 28 patients had positive f-PRA in multiple samples; the remaining 23 had either no positive or only one positive sample. Three patients had strongly positive f-PRA. Patients with multiple positive samples were recipients of two modified multivisceral and three multivisceral grafts. Only one of these patients had a positive PRA pretransplant. Cytotoxic cross-match at transplant was negative for all. The three with strongly positive f-PRA showed significant episodes of rejection around the time of positive samples. One of them who persistently had f-PRA value >80% (from day 13–113) died of refractory rejection. The other two had f-PRA of 76% and 53% during the early postoperative course with associated episodes of rejection. F-PRA value decreased with rejection therapy. Only one of the 23 patients (4%) with negative f-PRA had an episode of rejection around the time of sample collection. Development of HLA antibody after intestinal transplantation seems to have significant association with acute rejection episodes.

The emerging role of rituximab in organ transplantation

Long-term acceptance of solid organ allografts remains a challenge. While many acute rejection episodes can be treated, new mechanisms of allograft damage are now being defined especially in kidney transplantation. Unexpected clusters of CD20(+) cells have been discovered in renal biopsies performed for clinical rejection. C4d deposition is now routinely seen in refractory rejection. Despite the rapid introduction of new immunosuppressive agents in transplantation, the search for an efficacious anti-B-cell agent remains. With novel mechanisms of allograft damage now being defined, it is important to consider how an anti-B-cell agent might fit into an immunosuppressive regimen. Rituximab is a high-affinity CD20 specific antibody that depletes the B-cell compartment by inducing cellular apoptosis. Thus, it is a rational choice for therapy in transplantation to abrogate B-cell mediated events. In this review, we will discuss the mechanisms of action of rituximab, and its use in for a variety of indications in solid organ transplantation. There are emerging case reports that show that rituximab may be an effective agent to treat antibody-mediated rejection, and post-transplant lymphoproliferative disorder. Rituximab has been frequently cited as an important adjunct therapy in desensitization protocols for highly sensitized transplant recipients as well as recipients of ABO incompatible transplants. Rituximab demonstrates promise in this regard and warrants additional consideration in prospective clinical trials.

Treatment of humoral rejection in kidney transplantation

Abstract Acute antibody-mediated rejection (acute humoral rejection [AHR]) of organ allografts presents most of the time as severe dysfunction with a high risk of allograft loss. Peritubular capillary complement C4d deposition is diagnostic of AHR in kidney allografts and is associated with circulating donor-specific anti-HLA alloantibodies. Removal of alloantibodies with suppression of antibody production and rejection reversal is now possible. Therapeutic strategies that include combinations of plasmapheresis (or immunoadsorption), mycophenolate mofetil, tacrolimus, and/or intravenous immunoglobulins have been used to successfully treat AHR. The optimal protocol to treat humoral rejection remains to be defined. Anti-CD20 monoclonal antibody therapy (rituximab) aiming at depleting B cells and suppressing antibody production has been used as a rescue therapy in some episodes of refractory humoral rejection. Plasmapheresis and/or intravenous polyclonal immunoglobulin, as well as rituximab, have also been used to successfully desensitize selected high-immunologic risk patients who were in anticipation of crossmatch-positive (or ABO-incompatible) kidney transplantation. Recent data suggest that chronic kidney allograft rejection might also be monitored by complement C4d in biopsies. The efficacy and safety of immunosuppressive drugs such as tacrolimus, mycophenolate mofetil (or enteric-coated mycophenolic acid), sirolimus, or everolimus in controlling antidonor humoral responses in patients with chronic allograft dysfunction remains to be studied prospectively. The combination of tacrolimus and mycophenolate mofetil appears to effectively suppress antidonor antibody production. In the near future, the possible role of specific anti–B-cell approaches with drugs, such as rituximab, or possibly of new anti–T-cell activation approaches using selective agents such as belatacept should be assessed to refine the management of chronic allograft dysfunction.

OKT3 Therapy in Addition to Tacrolimus Is Associated with Improved Long-Term Function in Patients with Steroid Refractory Renal Allograft Rejection

Background/Aims: The aim of this study was to evaluate long-term allograft salvage rates of patients with steroid refractory allograft rejection after kidney transplantation and to identify factors indicating a successful outcome. Patients and Methods: Fifty patients with continuing rejection after high-dose steroids were included in the study. Baseline immunosuppression was switched from cyclosporine to tacrolimus in all patients. Twenty patients additionally received OKT3 as antirejection therapy. Patients having received a cadaveric renal transplant in 1995, excluding patients with steroid resistant rejection, were chosen as a control cohort. Results: Patient survival rates were 96% (n = 48) and 90% (n = 45) and allograft survival rates were 66% (n = 33) and 62% (n = 31) after 5 and 7 years following steroid refractory renal allograft rejection. Graft survival within the control cohort was 73% after 5 years and 69% after 7 years. Creatinine clearance increased from 20 ± 15 ml/min/1.73 m² at the start of tacrolimus therapy to 37 ± 29 ml/min/1.73 m² and to 32 ± 26 ml/min/1.73 m² after 5 and 7 years. OKT3 treatment predicted successful rescue therapy (p = 0.005 and p = 0.04 after 5 and 7 years). Conclusion: Our data indicate a reasonable graft survival in steroid refractory renal allograft rejection using tacrolimus. OKT3 treatment in addition to tacrolimus therapy may be beneficial for long-term allograft survival.

Successful Reversal of Acute Vascular Rejection and Cyclosporine-Associated Nephrotoxicity in Renal Allograft With Combined Sirolimus and Mycophenolate Mofetil as Immunotherapy

Cyclosporine (CsA) has substantially improved patient and graft survival rates in solid organ transplantation. In clinical studies, sirolimus has been shown to be as effective as CsA to maintain survival of renal and cardiac allografts without causing nephrotoxicity. Herein we describe a patient with biopsy-proven CsA-associated nephrotoxicity and refractory renal allograft rejection who was converted from steroids, CsA, and azathioprine to steroids, sirolimus (RAPA), and low-dose mycophenolate mofetil (MMF). The follow-up period was 60 months. We observed substantial improvement, even normalization in renal function. Our patient did not give consent to repeat biopsy after conversion. We also observed a beneficial effect of CsA withdrawal on blood pressure control. The spectrum of adverse events induced by sirolimus seemed to be mild relative to the potency of the immunosuppressive effect. The excellent response to combined RAPA and MMF in this patient was probably due to “concerted actions” of these agents on both B- and T-cell functions. The combination enhanced therapeutic efficacy while minimizing the toxicity of individual drugs used in the regimen. These findings suggest that sirolimus, when used as a base therapy in combination with low-dose MMF in a renal allograft recipient, may be an alternative to CsA-based therapy, providing potent immunosuppression of a renal allograft. Sirolimus administration facilitated steroids dose reduction.

Late-onset invasive aspergillosis in organ transplant recipients in the current era

We assessed predictive factors and characteristics of patients with late-onset invasive aspergillosis in the current era of novel immunosuppressive agents. Forty transplant recipients with invasive aspergillosis were included in this prospective, observational study initiated in 2003 at our institutions. In 50% (20/40) of these patients, the infections were late-occurring. Receipt of sirolimus in conjunction with tacrolimus for refractory rejection or cardiac allograft vasculopathy (P=0.047) was significantly associated with late-onset infection. The use of depleting or non-depleting T or B-cell antibodies, either as induction or as antirejection therapy did not correlate with time to onset of invasive aspergillosis. Mortality at 90 days was 20% (4/20) for the patients with early-onset infection and 45% (9/20) for those with late-onset infection (P=0.17). Thus, nearly one-half of the Aspergillus infections in transplant recipients in the current era are late-occurring. These data have implications relevant for prophylactic strategies and guiding clinical management of transplant recipients presenting with pulmonary infiltrates.

Clinical outcome of heart recipients with cyclosporine refractory cardiac rejection receiving tacrolimus with or without mycophenolate mofetil

Introduction: Tacrolimus (TAC) is a calcineurin inhibitor that is used for cyclosporine A refractory cardiac allograft rejection. Efficacy and safety data of a combined TAC/mycophenolate mofetil (MMF) therapy in comparison to a TAC/cortisone therapy in heart recipients with refractory cardiac rejection are lacking.

Effects of Photopheresis on Mononuclear Cells from Healthy Individuals.

Background: Extracorporeal photopheresis (ECP) has been proposed as an alternative therapy for immune-mediated disease including graft-versus-host-disease (GVHD) and transplant rejection (Photopheresis for the treatment of refractory renal graft rejection, Transplantation 2005; 79(1):123–5, Kumlien G et al). The mechanisms of photopheresis are still poorly understood but induction of tolerogenic dendritic cells and regulatory T cells as well as a shift of cytokine profile from Th1 to Th2 have been observed in patients treated with ECP. We wanted to investigate some basic effects of ECP on mononuclear cells from healthy individuals unaffected by pathogenic mechanisms and immunosuppressive drugs.Method: Mononuclear cells (MNCs) were collected from six healthy volunteer apheresis donors using CobeSpectra apheresis machine (Gambro BCT, Lakewood, CO, USA) and peripheral blood was drawn immediately before apheresis. Apheresis products were thoroughly mixed and divided into three equal parts. One part was left untreated, one part was irradiated with UVA 365 nm, 2J/cm2 (BioGenic, Vilber Lourmat, Marne-la-Vallée, France) and one part was treated with psoralen (8-methoxypsoralen 200 ng/ml) plus UVA-irradiation (PUVA). Peripheral MNCs and aliquots of apheresis MNCs were analysed simultaneously regarding incorporation of 3H Thymidine after stimulation with mitogens (PHA, ConA, SpA) and production of cytokines correlated with GVHD pathogenesis (IL-2, IL-6, IL-12, TNFα, IFNγ) after stimulation with antigens (BG, PHA, LPS) using commercial ELISA-kits (Quantikine, R&D Systems, Minneapolis, MN, USA). Statitical analysis was performed using a nonparametric method (one-sided ANOVA).Results: Mitogenic capacity was reduced to baselevel after PUVA-treatment but not affected by the apheresis procedure or UVA-irradiation alone. Table 1. Statistically significant decrease of cytokine production was seen only after PUVA-treatment but production of IL-2 and IL-6 was reduced after both apheresis and UVA-irradiation alone. Small amounts of IL-2, IL-6, TNFα and IFNγ were produced even after PUVA-treatment.Conclusion: Significant reduction of mitogenic capacity only after PUVA-treatment was the expected finding. Apheresis can theoretically effect cells through mechanic damage (centrifugation) and/or interaction with apheresis harness and UVA is known to have immunomodulatory effects which can explain the reduction of cytokine production. Cytokines detected after PUVA-treatment may be explained by release from apoptotic cells or by production in cells that escape apoptosis.Lymphocyte proliferation assayConAPHASpAperipheral vs apheresis MNCsnsnsnsperipheral vs UVA-irradiated MNCsnsnsnsapheresis vs UVA-irradiated MNCsnsnsnsperipheral vs PUVA-treated MNCsp<0.05p<0.05p<0.05apheresis vs PUVA-treated MNCsp<0.05p<0.05p<0.05UVA -irradiated vs PUVA-treated MNCsp<0.05p<0.05p<0.05MNCs = mononuclear cells

Therapy With Plasmapheresis and Intravenous Immunoglobulin for Acute Humoral Rejection in Kidney Transplantation

Background Acute humoral rejection (AHR) is characterized by acute graft dysfunction associated with de novo production of donor-specific alloantibodies (DSA) and C4d deposition in peritubular capillaries of the renal allograft. It has been reported the combination of plasmapheresis (PP) and intravenous gamma globulin (IVIG) as effective rescue therapy for established AHR. Methods Between 1999 and 2004, seven kidney allografts recipients suffered from AHR diagnosed by severe rejection and C4d staining in peritubular capillaries. All patients had a negative cross-match before renal transplantation. Results All patients were treated with daily sessions of PP and in four cases IVIG was added after the last PP session. Tacrolimus and mycophenolate mofetil were employed as maintenance immunosuppressive regimen. In one case, rituximab was added to PP and IVIG owing to refractory humoral rejection. At 1 year, patient survival was 100%, allograft survival was 70%, and the mean serum creatinine was 201 μmol/L. Conclusions AHR is a severe form of rejection associated with a poor prognosis, but its early diagnosis and treatment with PP and IVIG allows reversal of AHR reaching a 70% graft survival at 1 year.

Delayed-Onset Neutropenia in a Patient Receiving Rituximab as Treatment for Refractory Kidney Transplantation

The use of rituximab against early refractory rejection in kidney transplantation or its preoperative administration for cross-match positive or ABO-incompatible transplants (1, 2, 3) has increased in the recent years, but caution is required regarding the occurrence of severe delayed-onset neutropenia. We describe a case of late-onset neutropenia secondary to rituximab administration. A 47-year-old woman with chronic nephritis (renal biopsy, mesangial proliferative glomerulonephritis) and a body weight of 45 kg started hemodialysis in August 2004. Blood tests for autoimmunity were negative for SLE. Then, a living-donor kidney was transplanted from her ABO-compatible sister on September 3, 2004. The preoperative cross-match and anti-HLA antibody were both negative, and FK, prednisolone, MMF, and basiliximab were used concomitantly. Early humoral rejection accompanied by decreased urine volume, edema and elevated creatinine was observed 48 hr later. Plasmapheresis was conducted in response 9 times on consecutive days, but because her condition was refractory and the risk of graft loss was imminent, rituximab at 150 mg/m2 was administered and resulted in a dramatic recovery. At her final visit on January 13, 2005, as an outpatient, her blood biochemical tests were normal with leukocyte count of 4260/μl, neutrophil count of 2340/μl, and platelet count of 27.6×104/ml, but 5 days later she was admitted into the hospital with sudden fever and diarrhea. The visceral function examination on admission was within the normal range, with leukocyte count of 1190/μl, agranulocytosis and visual determination was not possible. hypogammaglobulinemia, platelet count of 19.5×104/ml, and all viral and bacterial tests were negative. Bone mar-row biopsy revealed a condition of maturation arrest without hemophagocytosis, and the megakaryocytic series and erythrocytic series were within the normal range. With peripheral CD19 and CD20 both at 0%, the patient was placed in a clean room for supportive treatment, with consequent recovery from this neutropenia 7 days later. Six months after rituximab administration, CD19 and CD20 were both 0%, and in an examination after 8 months the values were still low with CD19 at 0.1% and CD20 at 0.5%. MMF administration was discontinued since the onset of neutropenia up till now to avoid over-immunosuppression. MMF immediately before onset was 0.5 g, and DLSTs on concomitant drugs were all negative. Since the transplant patients are not cancer patients, the absolute number of B-cells, which are the target of CD20, is much less than in the B-cell lymphoma patients, although the applied dose of rituximab for medical transplantation is 375 mg/m2 administered one to 4 times as with B-cell lymphoma. The occasional reports of severe delayed-onset neutropenia in the lymphoma patients who receive rituximab therapy (4–6) are also a cause for concern. The dose level of Rituximab to renal transplant patients was decided from the results of a phase I study on ML (7), pharmacokinetics of patients waiting for renal transplant (8). We urge the prompt establishment of methods for rituximab administration, and we also strongly warn that severe delayed-onset of neutropenia can occur even at small doses. Naoki Mitsuhata Ryuji Fujita Seiichi Ito Department of Urology Kure Kyosai Hospital Hiroshima, Japan Makoto Mannami Kojima Keimei Department of Urology Uwajima Tokushukai Hospital Uwajima, Japan

Refractory Acute Renal Allograft Rejection Successfully Treated With Photopheresis

Introduction Acute rejection episodes still occur in spite of modern immunosuppressive protocols. We present seven patients with biopsy-proven acute rejections after kidney transplantation refractory to repeated pulses of high-dose steroids and antithymocyte globulin (ATG) or OKT-3, but responsive to photopheresis therapy. Methods Photopheresis is a nontoxic immunomodulatory, apheresis-based treatment with no general immunosuppressive action. Rather, it suppresses specific pathogenic T-cell clones. During photopheresis mononuclear leukocytes are collected from the patient using centrifugation technique, treated with a photosensitizing agent, irradiated, and subsequently retransfused. Results All patients tolerated the treatment well, with no notable side effects. At the 12-month follow-up the median creatinine had decreased to 161 μmol/L compared to 282 μmol/L at the start of photopheresis and at the last follow-up 12 to 43 months after transplantation all patients still had functioning grafts. In five of the seven cases there had been a significant improvement in renal function, whereas in two of the patients the renal function remained stable but without a decrease in creatinine. Conclusions It is our experience that the prognosis for renal allografts with acute rejection unresponsive to conventional antirejection treatment (ie, repeated pulses of methylprednisolone and ATG or OKT-3) is very poor. Therefore, we conclude that the photopheresis treatment contributed to the favorable outcome in this small group of patients. We are presently designing a prospective randomized study to further evaluate the effect of photopheresis after renal transplantation.

Immunosuppression in Pediatric Liver and Intestinal Transplantation: A Closer Look at the Arsenal

Immunosuppression in Pediatric Liver and Intestinal Transplantation: A Closer Look at the Arsenal