Review

Nature Clinical Practice Nephrology (2006) 2, 221-230
doi:10.1038/ncpneph0133  
Received 22 August 2005 | Accepted 13 January 2006

Drug Insight: rituximab in renal disease and transplantation

Alan D Salama* and Charles D Pusey  About the authors

Correspondence *Department of Renal Medicine, Division of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK

Email salama@imperial.ac.uk

Summary

Rituximab, a monoclonal antibody directed against the CD20 molecule found on pre-B cells and mature B cells (but not on plasma cells), was introduced in the late 1990s for the treatment of non-Hodgkin's lymphoma. Recently, this antibody has been used to treat autoimmune diseases, especially those associated with a prominent humoral component and with potentially pathogenic autoantibodies. Small cohort studies have indicated that rituximab could have an important role in the management of these disorders. Rituximab has also been utilized in the transplant setting, to diminish levels of alloreactive antibodies in highly sensitized patients, to manage ABO-incompatible transplants, and to treat rejection associated with B cells and antibodies. The exact mechanism by which rituximab exerts its effects in autoimmunity and transplantation remains unclear, as specific autoantibody or alloantibody levels often seem not to diminish in parallel with clinical improvement. A role for rituximab in depleting B cells and compromising their antigen-presenting function seems likely; rituximab might also inhibit T-cell activation. A synergistic effect has been noted in vitro following administration of corticosteroids to B-cell lines, with accentuation of B-cell cytotoxicity; this observation might be relevant to certain studies, as some regimens have utilized both agents simultaneously. This article reviews the current use of rituximab in renal disease and transplantation, and includes discussion of the drug's potential role in novel therapeutic protocols.

Review criteria

We searched PubMed, for articles published in English, using the following terms: "rituximab" and "renal disease", "autoimmune disease", "glomerulonephritis", "vasculitis", "renal transplantation" and "kidney transplantation".

Keywords:

autoimmune disease, kidney transplant, MabThera®, rituximab

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Introduction

Rituximab is an engineered chimeric monoclonal antibody that contains murine heavy and light chain variable regions directed against CD20 plus a human IgG1 constant region. The CD20 antigen, a transmembrane protein, is found on immature and mature B cells, as well as on malignant B cells; this antigen is found in more than 85% of non-Hodgkin's lymphoma. CD20 mediates B-cell proliferation and differentiation (Figure 1). The CD20 antigen is not internalized upon antibody binding, and is not shed or found in soluble forms. Following treatment with rituximab, B cells are prevented from proliferating (Figure 2), and undergo apoptosis and lysis through COMPLEMENT-dependent and complement-independent mechanisms. These mechanisms include complement-dependent cytotoxicity, antibody-dependent cell cytotoxicity, and activation of tyrosine kinases as a direct effect of the antibody binding to its CD20 ligand. The exact contribution that each of these mechanisms makes in vivo remains unclear. Evidence that the degree of B-cell depletion correlates with levels of serum rituximab and the Fcgr3a genotype indicates that antibody-dependent cell cytotoxicity is crucial;1 however, prolonging the 'off rate' of the monoclonal antibody seems to increase complement-dependent cytotoxicity and therapeutic efficacy, indicating that complement-dependent mechanisms are also important.2 B-cell depletion generally persists for 6–9 months in over 80% of patients,3 although the degree of depletion is highly variable.1

Figure 1 B-cell development and antigen expression.
Figure 1 : B-cell development and antigen expression Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Surface expression of immunoglobulin chains and B-cell antigens during B-cell development and maturation is shown. CD20 is predominantly expressed on immature and mature B cells (bold). sIgG, surface IgG; sIgM, surface IgM.

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Figure 2 B-cell functions are inhibited following cell depletion by rituximab.
Figure 2 : B-cell functions are inhibited following cell depletion by rituximab Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Following activation, B cells produce cytokines, modify immunoglobulin production, process antigen for presentation to T cells, and proliferate and differentiate into plasma cells. Rituximab perturbs these processes.

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Rituximab has been used in over half a million patients with hematological malignancies, as both first-line treatment and maintenance therapy. In this setting, rituximab has been found to be a very safe drug. Most adverse events are first-infusion effects such as fevers and chills4 and are generally of mild severity. Moreover, these adverse effects occur less frequently during subsequent infusions. More-serious adverse effects are uncommon and relate, in part, to the tumor load of non-Hodgkin's lymphoma and to the combination therapy used to treat hematological disease, and might therefore not be directly translatable to the context of other diseases. A recent trial of rituximab in rheumatoid arthritis indicates, however, that the spectrum of adverse events in this setting is similar to that associated with hematological malignancies, but that the frequency of occurrence might be lower.5 This difference could be partially due to differences in B-cell load or concurrent therapies used in the autoimmune protocols. Commonly reported adverse events and their frequencies in studies of autoimmune (and hematological) diseases are summarized in Table 1. Antichimeric antibodies develop in some cases,6, 7 but their therapeutic significance is uncertain and their true incidence unknown, as many authors have not specifically looked for them. The dosing protocol in the initial studies was four weekly doses of 375 mg/m2. Since then a number of adaptations have been made (Box 1), including prolongation of treatment and fixed-dose regimens (in the context of autoimmunity and transplantation).

Table 1 Reported adverse effects attributed to rituximab therapy in autoimmune and hematological diseaseb–e.
Table 1 - Reported adverse effects attributed to rituximab therapy in autoimmune and hematological diseaseb|[ndash]|e
Full tableFigures & Tables indexDownload PowerPoint slide (230K)

Box 1 Rituximab protocols for treatment of renal disease.

 

Standard

Four weekly infusions (375 mg/m2) for non-Hodgkin's lymphoma, cryoglobulinemia (in association with hepatitis C virus infection), systemic lupus erythematosus, idiopathic membranous nephropathy and pure red cell aplasia

 

Prolonged

Eight weekly infusions (375 mg/m2) for non-Hodgkin's lymphoma and cryoglobulinemia

 

Extended

Standard dosing regimen plus two or three monthly infusions (375 mg/m2) for nephrotic syndrome and idiopathic membranous nephropathy

 

Modified short

Two 2-weekly infusions (1 g per infusion) for anti-neutrophil cytoplasmic autoantibody-associated vasculitis and systemic lupus erythematosus

 

Single dose

One infusion (50–375 mg/m2) for transplant rejection, reduction of preformed alloantibodies or anti-blood-group antibodies

Because pathological antibody production is characteristic of a number of systemic diseases that affect the kidneys and is a problem in renal transplantation, rituximab has been used to treat a number of these disorders, although the exact mechanisms by which it exerts its effect remain unclear (Box 2). Specifically, this antibody has been used to treat membranous nephropathy, cryoglobulinemic glomerulonephritis, systemic lupus erythematosus (SLE) and ANTINEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-associated vasculitis, especially cases that were resistant to conventional therapy. In the setting of transplantation, rituximab has been used in refractory-B-cell-associated or antibody-associated rejection, as a means of modulating allo or blood group antibodies prior to or at the time of transplantation, and to treat POST-TRANSPLANTATION LYMPHOPROLIFERATIVE DISORDERS. Most published reports on this subject are small cohort studies, and negative results might be underreported. Randomized controlled trials are warranted for several of the indications discussed below, to confirm or refute the benefits reported to date.

Box 2 Immune effects of B-cell depletion by rituximab.

  • Evidence that rituximab affects production of antibodies and regulation of immunoglobulin maturation by B cells includes reduced levels of IgM (variable), rheumatoid factor and autoantibodies (variable)
     
  • Evidence that rituximab affects cytokine production by B cells includes reports of cytokine-release syndromes in patients with hematological disease, which potentially accounts for some infusion-related adverse effects. No evidence for alteration in B cell cytokine profiles is available
     
  • Evidence that rituximab affects T-cell activation by B cells includes reduced T-cell expression of HLA-DR, CD154 and CD69
     
  • Evidence that rituximab affects lymphocyte homeostasis mediated by B cells includes normalization of lymphocyte subsets in active systemic lupus erythematosus
     
  • There are few data to support an effect of rituximab on antigen presentation by B cells

Note: few data regarding the mechanisms of action of rituximab in autoimmune disease are available.

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Autoimmunity

Idiopathic membranous nephropathy

The subepithelial deposition of IgG on the glomerular basement membrane, in response to unknown antigens, is the hallmark of idiopathic membranous nephropathy (IMN). This known mechanism, together with the identification of CD20+ cells in renal biopsies from patients with IMN,8 constitutes the rationale for using rituximab for this indication.

Remuzzi et al.9 reported on eight patients with persistent IMN and nephrotic syndrome, in whom four weekly infusions of 375 mg/m2 rituximab were administered. Mean urinary protein levels were significantly reduced after 4 weeks. These levels were maintained for 5 months, but remained within the nephrotic range for five patients (mean proteinuria reduced from 8.6 to 3.8 g/day). Only two patients achieved full remission (less than or equal to1 g/day of urinary protein) by 5 months, whereas B cells were depleted in all for the duration of the study. During 12 months' follow-up of these patients,10 no additional remissions were attained, but two further patients achieved proteinuria levels of less than 3.5 g/day. Proteinuria was reduced at 4 weeks in all but two patients; lower levels were maintained and improved at 12 months. Therapy was well tolerated, and there was no significant change in renal function over the course of the year. B cells remained suppressed below the normal range for 12 months. No changes in total IgG levels were observed; however, no IgG subclass analysis was performed.

Rossi et al.11 used rituximab to successfully treat another case of IMN and nephrotic syndrome (with proteinuria of 14 g/day) complicated by autoimmune hemolytic anemia. In this instance, a more prolonged course of treatment was administered: four weekly pulses followed by five monthly pulses (all 375 mg/m2). The patient also received a tapering dose of methylprednisolone. Interestingly, after only one dose of rituximab a benefit was observed as judged by an increase in hemoglobin and a decrease in proteinuria. By 6 months proteinuria was just 0.3 g/day, and was maintained at low levels for 1 year of follow-up.

Focal segmental glomerulosclerosis

Although there is evidence that idiopathic focal segmental glomerulosclerosis is dependent on circulating factors, few immune deposits are observed on renal biopsy, and the pathogenesis remains unclear. Benz and colleagues12 reported on a pediatric patient with steroid-dependent nephrotic syndrome secondary to focal segmental glomerulosclerosis, previously treated unsuccessfully with cyclophosphamide, ciclosporin A and tacrolimus. The patient developed immune thrombocytopenic purpura whilst on therapy. His platelet count was maintained with weekly intravenous immunoglobulin. The patient was then treated with rituximab. Having suffered over 35 relapses in a 15-year interval, he was maintained in remission (of both immune thrombocytopenic purpura and nephrotic syndrome) following treatment with standard-dose rituximab for 13 months of follow-up.12

Mixed essential cryoglobulinemia

Type II mixed essential CRYOGLOBULINEMIA (MEC) is often associated with hepatitis C virus (HCV) infection, and leads to a membranoproliferative glomerulonephritis usually accompanied by systemic vasculitis. This disorder is characterized by immune complexes containing a monoclonal IgM (rheumatoid factor) and polyclonal IgG. As CD20 is expressed on IgM-bearing pre-B cells, removal of these cells underlies the rationale for the use of rituximab in this condition. Additionally, rituximab had been used in the context of lymphoma with associated cryoglobulinemia.

Lamprecht and co-workers reported on one HCV-positive patient with cryoglobulinemic vasculitis in association with non-Hodgkin's lymphoma who had failed to respond to interferon-alpha and cyclophosphamide, but responded to an extended course of rituximab.13 Subsequently, the patient's HCV was eradicated with a combination of pegylated interferon and ribavirin. Roccatello et al.14 reported on six patients with HCV-associated MEC (renal involvement in five) who were treated with a prolonged regimen of rituximab (four weekly pulses followed by two monthly pulses) and no other immunosuppressive agents. Four of the six patients had already failed to respond to conventional immunosuppressive agents. Overall there was no change in viral load, but symptoms improved markedly, complement levels recovered, and IgM levels were reduced. In addition, bone marrow abnormalities normalized. Proteinuria declined in all cases, and renal function improved in all but one patient, at 12–18 months of follow-up. No adverse effects were reported.

Zaja et al.15 described their experience of 15 patients with type II MEC (12 with HCV) treated with standard protocol rituximab. At follow-up of between 9 and 31 months, there was significant improvement of symptoms (arthralgias, fevers, skin manifestations) and laboratory parameters (increasing C4, and decreasing IgM and rheumatoid factor). Two patients experienced possible adverse effects; one had a retinal artery thrombosis, and the other panniculitis (possibly related to the underlying cryoglobulinemia). Only two patients in this series had nephritis; the urinary sediment of one of these patients normalized, but the second did not complete the course because of the retinal artery thrombosis. Rituximab treatment permitted steroid usage to be significantly reduced in all but one patient.

A successful outcome has also been reported for a patient with HCV- MEC and membranoproliferative glomerulonephritis with dialysis-dependent renal failure that was resistant to conventional therapy.16 Following prolonged rituximab therapy (eight doses of 375 mg/m2) the patient recovered independent renal function. Cryoglobulin levels were reduced, although these subsequently returned to baseline within 17 months of therapy initiation. Finally, a single case of an initial increase in cryoglobulin level (1 day after the first rituximab dose) has been documented, prior to a significant improvement in symptoms.17 The mechanism involved remains uncertain.

Systemic lupus erythematosus

As SLE is the prototypic immune complex disorder, and involves a wide range of autoantibodies, it is not surprising that rituximab has been repeatedly utilized in this setting. An open label study of 10 patients with proliferative nephritis (four WHO class III, six class IV) treated with standard protocol rituximab and oral steroids was reported by Sfikakis and colleagues.18 Seven of the 10 patients had already experienced episodes of nephritis requiring steroids plus cyclophosphamide or mycophenolate mofetil. Four patients achieved complete remission (normalization of serum creatinine and serum albumin, inactive urinary sediment and proteinuria <0.5 g/day) at 1 year. One attained temporary complete remission, and three partial remission (>50% improvement in all renal parameters). Notably, one patient developed pneumococcal meningitis, and one received only two doses of rituximab because of a hypersensitivity reaction (but still went on to achieve complete remission). Clinical improvement appeared to correlate with reduced expression of markers of T-cell activation, such as CD69 and HLA-DR, as well as of the costimulatory molecule CD154. Interestingly, following B-cell depletion, the number of T cells expanded, although no significant increase in the CD4CD25 regulatory population was detected. Only IgM levels decreased significantly; levels of anti-double-stranded DNA antibodies declined in all patients, as did antinuclear antibodies in eight out of ten patients (see Box 2).

Other series of patients with SLE treated with rituximab have been reported, containing only a proportion of patients with lupus-related renal disease.7, 19, 20, 21, 22 Overall, the majority of patients with SLE in whom B-cell depletion was achieved derived some clinical and biochemical benefit. Importantly, B-cell depletion failed more often in African-American patients.7

The specific effect of rituximab on renal lupus pathology has been addressed in few studies. van Vollenhoven et al.20 detected a reduction in lupus activity in two patients treated with cyclophosphamide and rituximab in whom conventional cyclophosphamide therapy alone had not improved nephritis. Both patients were re-biopsied a year following therapy. One patient, with WHO nephritis class IIIB and an activity score of 6 pre-rituximab, had a class IB lesion 1 year later. The second patient, with class IVc nephritis and an activity score of 5, had a membranous pattern (Vc) 1 year later with an activity score of 3. Similarly, in a series of 18 patients (7 with nephritis) reported by Looney and colleagues, treated with varying doses of rituximab—but not with concurrent cyclophosphamide or pulsed steroid therapy—the proliferative nephritis of one patient was markedly resolved 1 year following treatment. The other patients attained stable renal function, but no comment was made by the authors regarding proteinuria/hematuria.7

Rituximab has also been used successfully in pediatric patients with SLE,23, 24 including seven patients refractory to standard therapy with cyclophosphamide and steroids (six with nephritis)23 and a single case in which a protracted dosing schedule was used (six monthly doses followed by maintenance doses every 3 months). In this latter case, extra-renal disease responded well, but nephritis was incompletely controlled.24

Primary systemic vasculitis

Primary systemic vasculitis affecting small vessels is generally associated with ANCA. Evidence is accumulating to support the pathogenicity of ANCA, and hence the rationale for the use of rituximab. Successful treatment of patients with refractory ANCA-associated vasculitis for whom conventional therapy has failed or was contraindicated has been reported by a number of groups.25, 26, 27, 28, 29 Most of these patients had relapsing or 'grumbling' disease that did not respond to agents such as cyclophosphamide, mycophenolate, azathioprine or methotrexate, or experienced immunosuppressant-related adverse effects that precluded ongoing use. Five of the 11 patients studied by Keogh et al.26 had renal disease. Most disease features responded to treatment; the persistent lung nodules of one patient were an exception. Overall, remission was achieved in all cases following rituximab therapy and high-dose steroids, and was maintained for between 1 and 2 years (in some cases maintenance required additional courses of rituximab). Eight of 11 patients became ANCA-negative. The B cells of three patients re-emerged but they remained ANCA-negative, and patients were in remission at latest follow-up. Determining the exact nature of the relationship between B cells, ANCA and relapse was complicated by prophylactic treatment of patients with rituximab upon re-emergence of ANCA.

In the trial of 12 patients reported in abstract form by Smith and co-workers,27 patients were treated with standard protocol rituximab (later changed to two fixed doses of 1 g 2 weeks apart) plus a single dose of cyclophosphamide. During 14 months of follow-up, 10 patients achieved remission, but four relapsed when their B cells returned (at between 6 and 8 months). In most series, clinical responses correlate with B-cell depletion, and relapses occur when B cells and ANCA re-emerge; however, clinical responses are not exclusive to ANCA-positive patients and are not always associated with attainment of ANCA-negative status. Of nine patients (two with anti-MYELOPEROXIDASE antibodies and seven with anti-PROTEINASE 3 antibodies) resistant to conventional therapy, treated with two or four weekly infusions of 500 mg rituximab in addition to steroids and mycophenolate mofetil, azathioprine or cyclophosphamide, Eriksson et al.30 reported eight complete responses and one partial response at 6 months. Two minor relapses occurred and seven patients remained ANCA positive.

More recently, Keogh and co-workers31 reported on an open label trial of 10 patients with refractory Wegener's granulomatosis treated with steroids and rituximab only. Seven had renal involvement (biopsy proven in three), three had lung nodules and one had retro-orbital pseudotumor. All achieved remission within 3 months. Return of ANCA or B cells prompted preemptive therapy with rituximab. Patients remained in remission while B cells were depleted. One patient relapsed at 9 months, the point at which he was due to undergo preemptive therapy.

The organ-specific response to rituximab therapy seems to be variable. Kallenbach et al.28 reported on a patient with Wegener's granulomatosis who failed to respond to conventional agents. Rituximab lowered this patient's anti-proteinase 3 levels and induced remission of disease—including pulmonary lesions—for 11 months of follow-up. Similarly, a patient of Ferraro et al.29 with severe refractory Wegener's granulomatosis (mainly affecting the ears, nose and throat) achieved remission with rituximab alone, associated with reduced ANCA and B cells.

Others have reported less significant responsiveness of granulomatous lesions to rituximab therapy.32, 33 In the study by Aries et al.,32 eight patients with severe refractory Wegener's granulomatosis were treated. Despite peripheral B-cell depletion, no change in ANCA profile was noted. Only two patients went into remission, and three progressed. Interestingly, pulsed or high-dose steroids were not used. Omdal et al.33 reported on three patients, treated with various rituximab regimens, in whom sinus and retro-orbital granulomas did not regress despite B-cell depletion, diminution of ANCA, and remission of other disease features. Our own series of five patients with refractory disease, including severe progressive ocular disease, treated with rituximab (AD Salama, unpublished data) corroborates the findings that such treatment reduces disease activity in the majority of cases, decreasing the need for other immunosuppressive agents, but that the size of retro-orbital masses generally remains unchanged.

In order to identify those who will derive the most benefit from rituximab therapy, it is necessary to define the factors that predict response to treatment (in the presence and absence of ANCA diminution) and correlate these factors with patient phenotype (predominantly granulomatous or vasculitic lesions), duration, extent and severity of disease, and differences in concurrent therapies. This analysis needs to be carried out in the context of a formal clinical trial.

Pure red cell aplasia with anti-erythropoietin antibodies

Pure red cell aplasia can develop as a result of therapy with certain recombinant forms of erythropoietin (EPO), probably because of production of antibodies that cross-react with native EPO. Mandreoli et al.34 described an 80-year-old man with chronic renal failure, treated with subcutaneous EPO-alpha, in whom neutralizing anti-EPO antibodies developed after 8 months of therapy, in association with profound anemia. The patient was transfusion-dependent, with evidence of impaired erthyropoiesis. Treatment with four doses of rituximab was followed by an increase in his EPO levels and a decline in anti-EPO antibody titer. The patient was re-challenged with recombinant EPO (intravenously). His hemoglobin levels increased significantly, and were maintained at this higher level for 1 year of follow-up.

Thrombotic microangiopathies

One patient with end-stage renal failure secondary to familial HEMOLYTIC UREMIC SYNDROME (HUS) was treated with rituximab when HUS recurred in her renal transplant and was not controlled by plasmapheresis.35 Four episodes of HUS were successfully treated with rituximab, although the graft was eventually lost because of persistent hemorrhage. Another form of thrombotic microangiopathy, THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP), is associated with deficiency of the metalloproteinase ADAMTS13, generally as a result of autoantibodies directed against it. Numerous cases of resistant TTP, in which rituximab (with or without cyclophosphamide) was efficacious, have been published.36, 37, 38, 39, 40 A larger single cohort of 11 patients with recurrent or refractory TTP (most with renal involvement) who were treated with standard protocol rituximab has recently been published. All 11 patients achieved remission and had significant increases in ADAMTS13 plasma activity.41

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Renal transplantation

Acute humoral rejection can occur in patients who develop de novo allospecific antibodies, or in those in whom pre-existing anti-HLA or anti-ABO blood group antibodies are reactive towards donor antigens (in which case hyperacute rejection might occur). Currently, in order to eliminate these antibodies, plasmapheresis or immunoadsorption followed by intravenous immunoglobulin therapy are the mainstays of management. In ABO-incompatible recipients, splenectomy has frequently been employed. Rituximab has been used to treat refractory humoral rejection, and in attempts to eliminate anti-HLA or anti-ABO blood group antibodies. Furthermore, this agent is ideal for post-transplantation lymphoproliferative disease, and has been used in this context in both adult and pediatric patients.42, 43 Recent evidence indicates that addition of rituximab might be more efficacious and associated with fewer adverse effects than standard current therapy for post-transplantation lymphoproliferative disease. One added complication in this context is that rituximab can interfere with the cross match (flow-based or complement-cytotoxicity-based assays). Modifications of the assays might therefore be required following therapy.44

Cellular and humoral rejection

The presence of CD20+ B cells in transplant biopsy infiltrates is associated with poorer outcome and less steroid responsiveness.45 Thus, there is a rationale for the use of rituximab in acute rejection episodes characterized by heavy CD20+ infiltrates. Such a case of acute renal allograft rejection unresponsive to steroids or antithymocyte globulin, but successfully treated with rituximab, has recently been reported.46 Rejection episodes in which alloantibodies have a predominant role have also been successfully treated with rituximab. Becker et al.47 reported on the use of rituximab in humoral rejection resistant to conventional treatment with pulsed steroids, plasmapheresis, intravenous immunoglobulins and anti-lymphocyte globulin. Twenty-seven patients were treated, and graft function improved significantly in 24 (mean serum creatinine 495 micromol/l pretreatment to 84 micromol/l post-treatment [5.60 and 0.95 mg/dl, respectively]). Similar results have been described for a series of four cases of antibody-mediated rejection resistant to conventional therapy.48

Reduction in preformed alloantibody titers

In ABO-incompatible grafts, Tyden and co-workers49 showed that a protocol including single dose ritixumab allowed successful kidney transplantation of all 11 patients, without splenectomy. These results were reproduced by Sonnenday et al.50 in six ABO-incompatible recipients. Sawada et al.51, 52 successfully utilized rituximab, splenectomy and plasmapheresis in four patients resistant to plasmapheresis alone. A recent retrospective analysis of ABO-incompatible renal grafts indicated that pre-transplant splenectomy and plasmapheresis result in similar outcomes to preconditioning with rituximab followed by more-intensive post-transplant plasmapheresis.53 Humoral rejection seemed to correlate more closely with pre-transplant antibody titer than with the antibody-depleting protocol used. These data emphasize the need for formal trials.

Used as a means of reducing the titer of preformed anti-HLA alloantibodies prior to kidney transplantation, Sidner et al.54 showed that single dose rituximab reduced panel-reactive antibodies in all nine patients studied. Vieira and colleagues6 demonstrated that, of nine patients, rituximab altered the specificity and titer of panel-reactive antibodies in six. In one patient in whom the titer did not change, a donor-specific cross match became negative, thereby allowing the transplant to proceed. Although only a single dose of rituximab was used, two patients developed antichimeric antibodies. Rituximab, in addition to an intensive regimen including splenectomy and plasmapheresis, was administered to patients with a positive pre-transplant living donor cross match, and resulted in successful transplantation in all 14, with 11 maintaining their grafts for over 1 year.55

Post-transplantation lymphoproliferative disorder

Rituximab has been successfully used to treat lymphoproliferative disorder following solid organ transplantation. In a recent trial, 46 patients with this disorder (of whom 18 were renal transplant recipients) were treated with rituximab; immunosuppression was also reduced. The response rate at 80 days was 44% and more than half the patients achieved complete remission. Survival at 1 year was 67%. Importantly, in about 20% of patients, transplant rejection (acute and chronic) was precipitated by the immunosuppression reduction strategy.56 Similar response and overall survival rates were reported for two other smaller cohorts with shorter follow-up.57, 58 Further investigation of a rituximab-based strategy for treatment of post-transplantation lymphoproliferative disorder is warranted.

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Conclusions

Rituximab has been used in a variety of renal diseases and in renal transplantation, with anecdotal success. Randomized controlled trials are clearly required before we can accept this drug as a standard treatment. With the development of other therapeutic anti-B-cell antibodies, the responsibility for such trials will be with the renal community, in collaboration with the pharmaceutical companies. Numerous questions regarding ideal dosing strategies, possible synergistic combinations with other agents and the effect of repeated dosing in relapsing diseases need to be answered. Recent development of a transgenic mouse expressing human CD20 might help us to better understand the pathophysiological role of CD20+ cells and the effect of their depletion on rodent models of human disease.59 The long-term effects of rituximab in autoimmune diseases need to be established, and it remains to be seen whether antibodies to the chimeric molecule will prove to be a significant problem if repeated doses are used. Newer anti-B-cell agents are being developed with altered pharmacodynamics, which may prove to be even more potent in vivo.2 Hence, it seems likely that biological agents directed at B cells will form part of our immunotherapeutic armamentarium in the future treatment of renal disease.

Key points

  • Immune responses mediated by B cells (which produce antibodies and cytokines and present antigen to T cells) are important in autoimmune renal disease and transplantation

  • B-cell depletion can alter the course of autoimmune and alloimmune responses

  • Monoclonal antibodies to B-cell antigens can effectively deplete circulating B cells, diminishing their effector functions

  • Rituximab, a monoclonal antibody directed against CD20, has been successfully used in hematological B-cell disorders

  • Rituximab has been used in a number of autoimmune conditions and in transplantation with some success

  • Randomized trials are required to compare the short-term and long-term efficacy of B-cell deletional strategies with conventional immuno-suppressants in the treatment of renal disease

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References

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