- Email: [email protected]
Rituximab in Highly Sensitized Kidney Transplant Recipients
Rituximab in Highly Sensitized Kidney Transplant Recipients A.S. Munoz, A.A. Rioveros, C.B. Cabanayan-Casasola, R.A. Danguilan, and E.T. Ona ABSTRACT Objectives. Rituximab, an anti-CD20 monoclonal antibody therapy, depletes B cells and suppresses antibody production. This study sought to describe the efficacy and safety of rituximab among seven highly sensitized kidney transplant patients. Methodology. A highly sensitized patient was defined as panel-reactive antibody (PRA) ⬎30%, more than three pregnancies, or history of positive tissue crossmatch. Demographics, immunological risk profile, and immunosuppression were collected on all highly sensitized patients transplanted from March to July 2007 and given rituximab. We noted graft function as well as clinical events posttransplantation. Results. The seven patients included in the study showed a mean age of 39 years (range ⫽ 17– 60) and a mean follow-up of 3 months (range ⫽ 1.5–5). Their average PRA was 62% with mean HLA mismatches of three. Five patients (71%) were retransplantations; one had a history of a positive crossmatch, and two had multiple pregnancies. Two had donor-specific antibody, but negative tissue crossmatches. All had living donors. Six patients received a single dose of rituximab (375 mg/m2) 1 day prior to transplantation and one received two doses after 19 sessions of plasmapheresis. All were given tacrolimus, mycophenolate, and steroids combined with induction therapy using 30 mg alemtuzumab in 33%; two doses of 20 mg basiliximab in 33%; and seven doses of 1 mg/kg/dose of daclizumab in 14%. Mean shown creatinine levels were 1.1 and 1.2 mg/dL at 1 and 6 months posttransplantation. Two recipients experienced acute humoral rejections within 1 month after transplantation. Both were given steroid pulsing, one of whom was steroidresistant necessitating alemtuzumab therapy and plasmapheresis. Graft function of both improved with creatinine values of 1.3 mg/dL on discharge. No episodes of infection were noted. Conclusions. Rituximab can be safely administered and may be effective to improve outcomes among highly sensitized kidney transplant patients.
H
IGHLY SENSITIZED PATIENTS pose many challenges for the transplant community. Individuals with elevated panel-reactive antibodies (PRA) levels suffer from increased rejection rates despite aggressive induction protocols and complex maintenance immunosuppression regimens. It is estimated that 25% of patients awaiting renal transplantation display significant amounts of preexisting anti-HLA antibodies.1 The percent (PRA) results from previous transplantations, pregnancies, and blood transfusions. They are identified by testing the reactivity of recipient sera against a panel of well-defined HLA antigens. Strategies applied to reduce HLA antibodies among potential transplant recipients show only partial success: intravenous immunoglobulin (IVIG) and/or plasmapheresis. With-
out some form of intervention, the typical patient with preformed HLA antibodies waits at least 3 years before receiving a transplant.1 Rituximab is a monoclonal antibody directed against the CD20 molecule on pre-B and mature B cells, but not on plasma cells. In the transplant setting, it is used to diminish levels of alloreactive antibodies in highly sensitized patients, From the Departments of Adult Nephrology (A.S.M., A.A.R., C.B.C.-C., R.A.D.) and Organ Transplantation (E.T.O.), National Kidney and Transplant Institute, Quezon City, Philippines. Address reprint requests to A. Rioveros, Department of Adult Nephrology, National Kidney and Transplant Institute, Quezon City, Philippines. E-mail: [email protected]
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.07.046
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2218
Transplantation Proceedings, 40, 2218 –2221 (2008)
RITUXIMAB IN HIGHLY SENSITIVE RECIPIENTS
2219
Table 1. Demographic Data Patient
Age (y)
Sex
Renal Disease
Donor Type
1 2 3 4 5 6 7
17 60 34 55 35 44 29
Male Female Male Female Male Female Male
CGN HPN CGN FMF CGN CGN CGN
LNRD Son Brother LNRD LNRD Son LNRD
posttransplant. We noted episodes of acute rejection and adverse clinical events. In addition to rituximab, patients were given an interleukin-2 receptor blocker (basiliximab or daclizumab) or an anti-CD52 monoclonal antibody (alemtuzumab) for induction and immunosuppression with a calcineurin inhibitor (cyclosporine or tacrolimus), mycophenolate (mofetil or sodium), and prednisone, depending on the choice of the attending nephrologist.
RESULTS
CGN, chronic glomerulonephritis; HPN, hypertensive nephrosclerosis; FMF, familial Mediterranean fever; LNRD, living nonrelated donor.
to manage ABO-incompatible transplants, and to treat rejection episodes associated with donor-specific antibodies. The exact mechanisms by which rituximab exerts its effects in autoimmunity and transplantation remain unclear, as specific autoantibody or alloantibody levels often do not diminish in parallel with clinical improvement.2 A role for rituximab to deplete B cells, compromising their antigen-presenting function, seems likely, as does the inhibition of T-cell activation. This report describes a case series of highly sensitized patients who received rituximab as part of induction therapy. We examined the efficacy of rituximab to prevent acute humoral rejection in the early posttransplant period among highly sensitized kidney transplant patients as well as its safety. METHODS This study included highly sensitized patients who received rituximab as part of an induction protocol prior to transplantation from living donors, from March to July 2007. Subjects were at least 18 years old and were on maintenance hemodialysis. A highly sensitized patient was defined as one with PRA ⬎30%, more than three pregnancies or an history of a positive T-cell crossmatch. Subjects were given one or two doses of rituximab (375 mg/m2) 1 day prior to transplant. The data set included demographics, immunological risk profile, % PRA for class 1 and class II HLA antigens (enzyme-linked immunosorbent assay [ELISA OneLambda Antigen Tray), donor-specific antibody (DSA; ELISA technique), and type of immunosuppression. T-cell crossmatch was negative in all patients prior to transplantation. Graft function was assessed monthly by estimated glomerular filtration rate (GFR; Cockroft-Gault formula) up to 3 months
The seven patients included in the study showed a mean age of 39 years (range ⫽ 17– 60) and a mean follow-up of 3 months (range ⫽ 1.5–5) posttransplantation (Table 1). The primary renal disease was chronic glomerulonephritis in 57%. The immunological risk profile is shown in Table 2. The average PRA was 35.7% for class I and 52% for class II, and the average number of HLA mismatches was three. Five of seven patients (71%) were retransplants and two had multiple pregnancies. One patient had a history of recurrent positive T-cell crossmatches with his donor, but after 17 sessions of combined plasmapheresis and intravenous IVIG (100 mg/kg), the T-cell crossmatch became negative and he was transplanted. Two patients showed donorspecific antibody to their current donor. Both DSA were class II (DR4 and 15(2), but since they had a negative T-cell crossmatch, they were transplanted. Six patients received a single dose of rituximab (375 mg/m2) 1 day prior to transplantation. One patient received two doses, 2 weeks apart, with the second dose given a day prior to transplant (Table 3). Induction consisted of alemtuzumab or interleukin-2 receptor blockers. Maintenance immunosuppression in all patients consisted of tacrolimus, with a target trough of 7 to 10 ng/mL, mycophenolate with a mean dose of 1.5 g/d, and steroids (1 mg/kg/d). Except for 2 (29%) cases, all patients showed immediate graft function. Their serum creatinine remained at 1.8 to 2 mg/dL a week after transplant with decreasing urine output. Ultrasound-guided graft biopsy revealed acute humoral rejection with positive C4d at 1 week and 1 month posttransplantation. Both patients had DSA prior to transplant though T-cell crossmatch was negative. They were given methylprednisolone for 3 days. One subject was steroidsensitive as the creatinine decreased from 1.8 to 1.4 prior to discharge. The other person was steroid-resistant and re-
Table 2. Immunological Risk Most Recent PRA Patient
Number of HLA Mismatches
Number of Previous Transplants
Number of Pregnancies
I (%)
II (%)
Pretransplant Donor-Specific Antibody
History of Positive Crossmatch with the Present Donor
1 2 3 4 5 6 7
3 1 4 5 6 0 4
2 1 2 2 3 1 2
0 9 0 1 0 3 0
82 7 4 56 9 57 74
100 0 50 13 100 0 100
No No Yes No No No Yes
No No No No No No Yes
PRA, panel-reactive antibodies.
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MUNOZ, RIOVEROS, CABANAYAN-CASASOLA ET AL
Table 3. Treatment and Clinical Outcome of Patients Given Rituximab Pretransplant
Patient
Desensitization
Induction
Acute Humoral Rejection
1 2 3 4 5 6 7
None None None None None None PP ⫹ IVIG
Alemtuzumab Alemtuzumab Basiliximab Basiliximab Daclizumab Alemtuzumab Basiliximab
No No Yes No No No Yes
Serum Creatinine (at 3 mo)
cGFR (mL/min)
0.9 1.0 1.4 0.9 1.1 1.1 1.3
102 94 65 92 74 86 68
PP, plasmapheresis; IVIG, intravenous immunoglobulin; cGFR, calculated glomerular filtration rate.
ceived one session of plasmapheresis followed by a single dose of (30 mg) alemtuzumab. A repeat DSA postplasmapheresis was not done. Graft function of both patients improved, with a serum creatinine of 1.3 mg/dL on hospital discharge. Figure 1 shows the mean serum creatinine of 1.1, 1.1, and 1.2 mg/dL at 1, 2, and 3 months posttransplantation, respectively with the mean calculated GFR was 80 mL/min, 81 mL/min, and 82 mL/min, respectively. There were no reports of adverse reactions during or after rituximab infusion. There were no episodes of acute cellular rejection or infections during the study period. DISCUSSION
Rituximab, a chimeric anti-CD20 antibody, is approved for the treatment of lymphoma, due to efficient elimination of B cells.4 CD20 is expressed early in B-cell ontogeny, but expression is absent on plasma cells. It eliminates B cells by three potential mechanisms: antibody-dependent cellmediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis. A study of patients with end-stage renal failure reveales that rituximab could be given safely at lower doses than those recommended for cancer treatment.3 Acute humoral rejection occurs in highly sensitized patients who develop de novo allospecific antibodies, or those with preexisting anti-HLA. Currently, several protocols facilitate successful transplantation of sensitized renal allograft recipients; however, no single method has shown
Fig 1. Calculated glomerular filtration rate at 1, 2, and 3 months posttransplantation.
superiority.5 Plasmapheresis and immunoabsorption protocols have been used to decrease HLA antibodies in the pretransplant period, which has allowed transplantation to occur in some but not all patients. Their use has decreased the incidence of hyperacute rejection;1 however, nearly 90% of highly sensitized patients still develop rejection in the first 3 months following transplantation.3 Even with a negative crossmatch, the rejection rates were 80% (IVIG), 37% (plasmapheresis), and 29% (plasmapheresis/monitoring), respectively (P ⬍ .05 IVIG vs plasmapheresis). Combination strategies including plasmapheresis, IVIG, and now rituximab have become an important adjunct to desensitization protocols. Used as a means to reduce the titer of preformed anti-HLA alloantibodies prior to kidney transplantation, two studies showed that rituximab alters the specificity of, and reduces PRA titers in most if not all patients. Patients whose titers did not change showed negative donor-specific crossmatches, thereby allowing the transplantation to proceed. Because of the lack of controlled trials, though, the role of rituximab in kidney transplantation remains unclear. This study demonstrated that rituximab may have a role to prevent acute humoral rejection (AHR) among highly sensitized patients in the early posttransplant period. Their immunological risk was high, although the patients were T-cell crossmatch-negative prior to transplant. Together with rituximab, addition of monoclonal antibodies directed against the alpha chain of CD25 (daclizumab and basiliximab) or the profound lymphocyte-depleting agent alemtuzumab (anti-CD52) were used to further decrease the incidence of AHR in our study. Studies have shown, though, that AHR remains high partly because plasma cells, which do not express the CD52 epitope in detectable concentrations, are not depleted by alemtuzumab.6 Although combination therapies may prove more effective, the challenge of inhibiting plasma cells remains. Rituximab, together with other induction therapies resulted in an AHR rate of 29% in our study, compared to 90% reported by Reisater et al.7 The majority of patients showed unremarkable posttransplant courses, maintaining normal graft function up to 3 months. In our study, the use of rituximab and alemtuzumab may have prevented AHR in
RITUXIMAB IN HIGHLY SENSITIVE RECIPIENTS
two patients going on their third and second transplantations, who received mismatched kidneys. Patients become sensitized after exposure to nonself HLA during pregnancy, blood transfusion, and organ transplantation. Approximately 15% of men were sensitized by transfusions before their first grafts, and about 40% of women, by pregnancies and transfusions.9 Patients with a high peak level of antibody tended to have reduced graft survival. Thus, pregnancy by itself exerted a deleterious effect on graft outcomes, which is why we considered two patients to be highly sensitized despite having low levels of PRA. Therapeutic strategies that include combinations of tacrolimus and mycophenolate mofetil (MMF) have been used recently, however, the optimal protocol remains unclear. This combination has been found to limit antidonor B-cell responses in recipients with AHR and was associated with a rapid, sustained decrease in anti-HLA class I and II antibody production and, consequently, DSA production in renal allograft recipients. This effect was more pronounced in patients given MMF immediately after transplantation compared to its late introduction. The presence of DSA in the sera of renal allograft recipients is associated with poorer graft function. Thus, the combination of tacrolimus and mycophenolate should probably be part of standard immunosuppression in high immunological risk patients. Rituximab was safely administered to all the patients in this study. Moreover, no infections occurred up to the 3-month follow-up period. This observation was comparable to the mild toxicity profile of rituximab among end-stage renal disease patients as reported by Garrette et al.8 In conclusion, the use of rituximab as part of desensitization or induction strategies in highly sensitized patients prior to kidney transplantation seems to be a promising
2221
strategy to decrease the incidence of AHR. It was well tolerated and not associated with any infections. Prospective randomized clinical trials are needed to determine their role to prevent AHR. The ideal dosing strategies for rituximab, the possible synergistic combinations with other agents, and its role in chronic humoral rejection still need to be addressed. REFERENCES 1. Vieira CA, Agarwal A, Book BK, et al: Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation. 1. Safety, pharmacodynamics, and pharmacokinetics. Transplantation 77:542, 2004 2. Becker Y, Becker B, Knechtle S, et al: Refractory acute kidney transplant rejection with CD20 graft infiltrates and successful therapy with rituximab. Clin Transplant 19:137, 2005 3. Sonnenday CJ, et al: Plasmapheresis, CMV hyperimmune globulin, and anti-CD20 allow ABO-incompatible renal transplantation without splenectomy. Am J Transplant 4:1315, 2004 4. Sawada T, Fuchinoue S, Teraoka S: Successful A1-to-O ABO incompatible kidney transplantation after a preconditioning regimen consisting of anti-CD20 monoclonal antibody infusions, splenectomy, and double-filtration plasmapheresis. Transplantation 74:1207, 2002 5. Stegall MD, Gloor J, Winters JL, et al: A comparison of plasmapheresis versus high-dose IVIG desensitization in renal allograft recipients with high levels of donor specific alloantibody. Am J Transplant 6:1510, 2006 6. Hill P, Gagliardini E, Ruggenenti P, et al: Severe early acute humoral rejection resulting in allograft loss in a renal transplant recipient with Campath-1H induction therapy: case report. Nephrol Dial Transplant 20:1741, 2005 7. Reisater A, Leivestad T, Albrechtson D, et al: Pretransplant plasma exchange or immunoadsorption facilitates renal transplantation in immunized patients. Transplantation 60:242, 1995 8. Garrett HE Jr, Duvall-Seaman D, Helsley B, et al: Treatment of vascular rejection with rituximab in cardiac transplantation. J Heart Lung Transplant 24:1337, 2005 9. Iwaki Y, Terasaki PI: Sensitization effect. Clin Transpl 257, 1986
H
IGHLY SENSITIZED PATIENTS pose many challenges for the transplant community. Individuals with elevated panel-reactive antibodies (PRA) levels suffer from increased rejection rates despite aggressive induction protocols and complex maintenance immunosuppression regimens. It is estimated that 25% of patients awaiting renal transplantation display significant amounts of preexisting anti-HLA antibodies.1 The percent (PRA) results from previous transplantations, pregnancies, and blood transfusions. They are identified by testing the reactivity of recipient sera against a panel of well-defined HLA antigens. Strategies applied to reduce HLA antibodies among potential transplant recipients show only partial success: intravenous immunoglobulin (IVIG) and/or plasmapheresis. With-
out some form of intervention, the typical patient with preformed HLA antibodies waits at least 3 years before receiving a transplant.1 Rituximab is a monoclonal antibody directed against the CD20 molecule on pre-B and mature B cells, but not on plasma cells. In the transplant setting, it is used to diminish levels of alloreactive antibodies in highly sensitized patients, From the Departments of Adult Nephrology (A.S.M., A.A.R., C.B.C.-C., R.A.D.) and Organ Transplantation (E.T.O.), National Kidney and Transplant Institute, Quezon City, Philippines. Address reprint requests to A. Rioveros, Department of Adult Nephrology, National Kidney and Transplant Institute, Quezon City, Philippines. E-mail: [email protected]
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.07.046
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2218
Transplantation Proceedings, 40, 2218 –2221 (2008)
RITUXIMAB IN HIGHLY SENSITIVE RECIPIENTS
2219
Table 1. Demographic Data Patient
Age (y)
Sex
Renal Disease
Donor Type
1 2 3 4 5 6 7
17 60 34 55 35 44 29
Male Female Male Female Male Female Male
CGN HPN CGN FMF CGN CGN CGN
LNRD Son Brother LNRD LNRD Son LNRD
posttransplant. We noted episodes of acute rejection and adverse clinical events. In addition to rituximab, patients were given an interleukin-2 receptor blocker (basiliximab or daclizumab) or an anti-CD52 monoclonal antibody (alemtuzumab) for induction and immunosuppression with a calcineurin inhibitor (cyclosporine or tacrolimus), mycophenolate (mofetil or sodium), and prednisone, depending on the choice of the attending nephrologist.
RESULTS
CGN, chronic glomerulonephritis; HPN, hypertensive nephrosclerosis; FMF, familial Mediterranean fever; LNRD, living nonrelated donor.
to manage ABO-incompatible transplants, and to treat rejection episodes associated with donor-specific antibodies. The exact mechanisms by which rituximab exerts its effects in autoimmunity and transplantation remain unclear, as specific autoantibody or alloantibody levels often do not diminish in parallel with clinical improvement.2 A role for rituximab to deplete B cells, compromising their antigen-presenting function, seems likely, as does the inhibition of T-cell activation. This report describes a case series of highly sensitized patients who received rituximab as part of induction therapy. We examined the efficacy of rituximab to prevent acute humoral rejection in the early posttransplant period among highly sensitized kidney transplant patients as well as its safety. METHODS This study included highly sensitized patients who received rituximab as part of an induction protocol prior to transplantation from living donors, from March to July 2007. Subjects were at least 18 years old and were on maintenance hemodialysis. A highly sensitized patient was defined as one with PRA ⬎30%, more than three pregnancies or an history of a positive T-cell crossmatch. Subjects were given one or two doses of rituximab (375 mg/m2) 1 day prior to transplant. The data set included demographics, immunological risk profile, % PRA for class 1 and class II HLA antigens (enzyme-linked immunosorbent assay [ELISA OneLambda Antigen Tray), donor-specific antibody (DSA; ELISA technique), and type of immunosuppression. T-cell crossmatch was negative in all patients prior to transplantation. Graft function was assessed monthly by estimated glomerular filtration rate (GFR; Cockroft-Gault formula) up to 3 months
The seven patients included in the study showed a mean age of 39 years (range ⫽ 17– 60) and a mean follow-up of 3 months (range ⫽ 1.5–5) posttransplantation (Table 1). The primary renal disease was chronic glomerulonephritis in 57%. The immunological risk profile is shown in Table 2. The average PRA was 35.7% for class I and 52% for class II, and the average number of HLA mismatches was three. Five of seven patients (71%) were retransplants and two had multiple pregnancies. One patient had a history of recurrent positive T-cell crossmatches with his donor, but after 17 sessions of combined plasmapheresis and intravenous IVIG (100 mg/kg), the T-cell crossmatch became negative and he was transplanted. Two patients showed donorspecific antibody to their current donor. Both DSA were class II (DR4 and 15(2), but since they had a negative T-cell crossmatch, they were transplanted. Six patients received a single dose of rituximab (375 mg/m2) 1 day prior to transplantation. One patient received two doses, 2 weeks apart, with the second dose given a day prior to transplant (Table 3). Induction consisted of alemtuzumab or interleukin-2 receptor blockers. Maintenance immunosuppression in all patients consisted of tacrolimus, with a target trough of 7 to 10 ng/mL, mycophenolate with a mean dose of 1.5 g/d, and steroids (1 mg/kg/d). Except for 2 (29%) cases, all patients showed immediate graft function. Their serum creatinine remained at 1.8 to 2 mg/dL a week after transplant with decreasing urine output. Ultrasound-guided graft biopsy revealed acute humoral rejection with positive C4d at 1 week and 1 month posttransplantation. Both patients had DSA prior to transplant though T-cell crossmatch was negative. They were given methylprednisolone for 3 days. One subject was steroidsensitive as the creatinine decreased from 1.8 to 1.4 prior to discharge. The other person was steroid-resistant and re-
Table 2. Immunological Risk Most Recent PRA Patient
Number of HLA Mismatches
Number of Previous Transplants
Number of Pregnancies
I (%)
II (%)
Pretransplant Donor-Specific Antibody
History of Positive Crossmatch with the Present Donor
1 2 3 4 5 6 7
3 1 4 5 6 0 4
2 1 2 2 3 1 2
0 9 0 1 0 3 0
82 7 4 56 9 57 74
100 0 50 13 100 0 100
No No Yes No No No Yes
No No No No No No Yes
PRA, panel-reactive antibodies.
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MUNOZ, RIOVEROS, CABANAYAN-CASASOLA ET AL
Table 3. Treatment and Clinical Outcome of Patients Given Rituximab Pretransplant
Patient
Desensitization
Induction
Acute Humoral Rejection
1 2 3 4 5 6 7
None None None None None None PP ⫹ IVIG
Alemtuzumab Alemtuzumab Basiliximab Basiliximab Daclizumab Alemtuzumab Basiliximab
No No Yes No No No Yes
Serum Creatinine (at 3 mo)
cGFR (mL/min)
0.9 1.0 1.4 0.9 1.1 1.1 1.3
102 94 65 92 74 86 68
PP, plasmapheresis; IVIG, intravenous immunoglobulin; cGFR, calculated glomerular filtration rate.
ceived one session of plasmapheresis followed by a single dose of (30 mg) alemtuzumab. A repeat DSA postplasmapheresis was not done. Graft function of both patients improved, with a serum creatinine of 1.3 mg/dL on hospital discharge. Figure 1 shows the mean serum creatinine of 1.1, 1.1, and 1.2 mg/dL at 1, 2, and 3 months posttransplantation, respectively with the mean calculated GFR was 80 mL/min, 81 mL/min, and 82 mL/min, respectively. There were no reports of adverse reactions during or after rituximab infusion. There were no episodes of acute cellular rejection or infections during the study period. DISCUSSION
Rituximab, a chimeric anti-CD20 antibody, is approved for the treatment of lymphoma, due to efficient elimination of B cells.4 CD20 is expressed early in B-cell ontogeny, but expression is absent on plasma cells. It eliminates B cells by three potential mechanisms: antibody-dependent cellmediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis. A study of patients with end-stage renal failure reveales that rituximab could be given safely at lower doses than those recommended for cancer treatment.3 Acute humoral rejection occurs in highly sensitized patients who develop de novo allospecific antibodies, or those with preexisting anti-HLA. Currently, several protocols facilitate successful transplantation of sensitized renal allograft recipients; however, no single method has shown
Fig 1. Calculated glomerular filtration rate at 1, 2, and 3 months posttransplantation.
superiority.5 Plasmapheresis and immunoabsorption protocols have been used to decrease HLA antibodies in the pretransplant period, which has allowed transplantation to occur in some but not all patients. Their use has decreased the incidence of hyperacute rejection;1 however, nearly 90% of highly sensitized patients still develop rejection in the first 3 months following transplantation.3 Even with a negative crossmatch, the rejection rates were 80% (IVIG), 37% (plasmapheresis), and 29% (plasmapheresis/monitoring), respectively (P ⬍ .05 IVIG vs plasmapheresis). Combination strategies including plasmapheresis, IVIG, and now rituximab have become an important adjunct to desensitization protocols. Used as a means to reduce the titer of preformed anti-HLA alloantibodies prior to kidney transplantation, two studies showed that rituximab alters the specificity of, and reduces PRA titers in most if not all patients. Patients whose titers did not change showed negative donor-specific crossmatches, thereby allowing the transplantation to proceed. Because of the lack of controlled trials, though, the role of rituximab in kidney transplantation remains unclear. This study demonstrated that rituximab may have a role to prevent acute humoral rejection (AHR) among highly sensitized patients in the early posttransplant period. Their immunological risk was high, although the patients were T-cell crossmatch-negative prior to transplant. Together with rituximab, addition of monoclonal antibodies directed against the alpha chain of CD25 (daclizumab and basiliximab) or the profound lymphocyte-depleting agent alemtuzumab (anti-CD52) were used to further decrease the incidence of AHR in our study. Studies have shown, though, that AHR remains high partly because plasma cells, which do not express the CD52 epitope in detectable concentrations, are not depleted by alemtuzumab.6 Although combination therapies may prove more effective, the challenge of inhibiting plasma cells remains. Rituximab, together with other induction therapies resulted in an AHR rate of 29% in our study, compared to 90% reported by Reisater et al.7 The majority of patients showed unremarkable posttransplant courses, maintaining normal graft function up to 3 months. In our study, the use of rituximab and alemtuzumab may have prevented AHR in
RITUXIMAB IN HIGHLY SENSITIVE RECIPIENTS
two patients going on their third and second transplantations, who received mismatched kidneys. Patients become sensitized after exposure to nonself HLA during pregnancy, blood transfusion, and organ transplantation. Approximately 15% of men were sensitized by transfusions before their first grafts, and about 40% of women, by pregnancies and transfusions.9 Patients with a high peak level of antibody tended to have reduced graft survival. Thus, pregnancy by itself exerted a deleterious effect on graft outcomes, which is why we considered two patients to be highly sensitized despite having low levels of PRA. Therapeutic strategies that include combinations of tacrolimus and mycophenolate mofetil (MMF) have been used recently, however, the optimal protocol remains unclear. This combination has been found to limit antidonor B-cell responses in recipients with AHR and was associated with a rapid, sustained decrease in anti-HLA class I and II antibody production and, consequently, DSA production in renal allograft recipients. This effect was more pronounced in patients given MMF immediately after transplantation compared to its late introduction. The presence of DSA in the sera of renal allograft recipients is associated with poorer graft function. Thus, the combination of tacrolimus and mycophenolate should probably be part of standard immunosuppression in high immunological risk patients. Rituximab was safely administered to all the patients in this study. Moreover, no infections occurred up to the 3-month follow-up period. This observation was comparable to the mild toxicity profile of rituximab among end-stage renal disease patients as reported by Garrette et al.8 In conclusion, the use of rituximab as part of desensitization or induction strategies in highly sensitized patients prior to kidney transplantation seems to be a promising
2221
strategy to decrease the incidence of AHR. It was well tolerated and not associated with any infections. Prospective randomized clinical trials are needed to determine their role to prevent AHR. The ideal dosing strategies for rituximab, the possible synergistic combinations with other agents, and its role in chronic humoral rejection still need to be addressed. REFERENCES 1. Vieira CA, Agarwal A, Book BK, et al: Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation. 1. Safety, pharmacodynamics, and pharmacokinetics. Transplantation 77:542, 2004 2. Becker Y, Becker B, Knechtle S, et al: Refractory acute kidney transplant rejection with CD20 graft infiltrates and successful therapy with rituximab. Clin Transplant 19:137, 2005 3. Sonnenday CJ, et al: Plasmapheresis, CMV hyperimmune globulin, and anti-CD20 allow ABO-incompatible renal transplantation without splenectomy. Am J Transplant 4:1315, 2004 4. Sawada T, Fuchinoue S, Teraoka S: Successful A1-to-O ABO incompatible kidney transplantation after a preconditioning regimen consisting of anti-CD20 monoclonal antibody infusions, splenectomy, and double-filtration plasmapheresis. Transplantation 74:1207, 2002 5. Stegall MD, Gloor J, Winters JL, et al: A comparison of plasmapheresis versus high-dose IVIG desensitization in renal allograft recipients with high levels of donor specific alloantibody. Am J Transplant 6:1510, 2006 6. Hill P, Gagliardini E, Ruggenenti P, et al: Severe early acute humoral rejection resulting in allograft loss in a renal transplant recipient with Campath-1H induction therapy: case report. Nephrol Dial Transplant 20:1741, 2005 7. Reisater A, Leivestad T, Albrechtson D, et al: Pretransplant plasma exchange or immunoadsorption facilitates renal transplantation in immunized patients. Transplantation 60:242, 1995 8. Garrett HE Jr, Duvall-Seaman D, Helsley B, et al: Treatment of vascular rejection with rituximab in cardiac transplantation. J Heart Lung Transplant 24:1337, 2005 9. Iwaki Y, Terasaki PI: Sensitization effect. Clin Transpl 257, 1986