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Anti-CD20 Blocker Rituximab in Kidney Transplantation

Sood, Puneet MD, MPH1; Hariharan, Sundaram MD1

doi: 10.1097/TP.0000000000001849
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Rituximab is a chimeric anti-CD20 monoclonal protein used in various clinical scenarios in kidney transplant recipients. However, its evidence-based use there remains limited due to lack of controlled studies, limited sample size, short follow-up and poorly defined endpoints. Rituximab is indicated for CD20+ posttransplant lymphoproliferative disorder. It may be beneficial for treating recurrent membranous nephropathy and recurrent allograft antineutrophilic cytoplasmic antibody vasculitis and possibly for recurrent focal segmental glomerulosclerosis. Rituximab, in combination with IVIg/plasmapheresis, appears to decrease antibody level and increase the odds of transplantation in sensitized recipients. The role of Rituximab in ABOi transplant remains unclear, as similar outcomes are achieved without its use. Rituximab is not efficacious in antibody-mediated rejection/chronic antibody-mediated rejection. Strict randomized control trials are necessary to elucidate its true role in these settings.

The authors analyze the use of the anti-CD20 monoclonal antibody, rituximab, in various aspects of kidney transplantation including desensitization, treatment of humoral rejection, treatment of disease recurrence and posttransplant lymphoproliferative disease. Despite nearly 20 years of introduction and use in the field, solid data are still anticipated.

1 Division of Renal and Electrolytes and Division of Transplant Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA.

Received 20 March 2017. Revision received 1 June 2017.

Accepted 3 June 2017.

The authors declare no funding or conflicts of interest.

P.S. involved in primary concept and organizing flow of the first draft, literature search, writing up first draft, editing of the paper and writing the final draft. S.H. involved in primary concept and organizing flow of the first draft, literature search, editing of the initial and subsequent drafts and editorial overview.

Correspondence: Sundaram Hariharan, MD, Division of Renal and Electrolytes and Division of Transplant Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, 3459 Fifth Avenue, 7S Pittsburgh, PA 15213. (hariharans@upmc.edu).

Rituximab is a chimeric murine monoclonal antibody created by fusing the light and heavy chain variable domains of 2B8, a murine monoclonal anti-CD20 antibody, and human k-light chain and Y1 heavy chain constant regions.1 Rituximab binds specifically to CD20, an antigen expressed by most human B lymphocytes and in 1997 was the first FDA approved antibody for cancer treatment, primarily the B cell lymphomas.2 Since then, with better understanding of mechanisms of action of Rituximab, its use has been extended to broader range of malignancies, hematological nonhematological diseases, singly or in combination with other agents. The focus of this report is to review the clinical utility of Rituximab in the field of kidney transplantation based on data from various clinical studies. We will address the use of Rituximab for the following:

  • (A) Desensitization protocols for highly sensitized recipients before or concurrent with kidney transplantation, and in ABO incompatible kidney transplantation
  • (B) Treatment of Acute and Chronic Antibody-Mediated Rejection
  • (C) Treatment of Recurrent and de novo Glomerular Diseases after kidney transplant, and
  • (D) Treatment of Posttransplant Lymphoproliferative Disorder (PTLD).
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MECHANISM OF ACTION

Rituximab is composed of 2 heavy chains of 451 amino acids and 2 light chains of 213 amino acids with a molecular weight of 145 kDa. Rituximab has a binding affinity for the CD20 antigen like the parent murine antibody, 2B8.1 CD20 is a hydrophobic trans membrane protein antigen expressed on most B cells but is not found on stem cells, pro B cells or normal plasma cells, though plasma blasts and stimulated plasma cells may express CD20.3Figure 1 shows CD 20 expression in cells in bone marrow, blood and lymphoid organs with susceptibility to anti-CD20 including factors influencing its susceptibility specifically the lipid raft composition of these cells, the FCγRIIIA polymorphisms and their FCγRIIB expression. The mechanisms of action of Rituximab that cause beneficial effect in seemingly unrelated clinical settings are not completely understood. However, direct signaling, complement-dependent cellular toxicity (CDCC) and antibody-dependent cellular toxicity (ADCC) all seem to play a role individually or in complex interactions which may be at play in different clinical scenarios.4

FIGURE 1

FIGURE 1

  • (i) Direct signaling pathway. Specifically direct signaling involves cell cycle arrest and apoptosis in the absence of immune effector mechanisms and involves cross linking of CD20 molecules by Rituximab/anti-Rituximab binding antibody that causes downstream inhibition of p38 mitogen-activated protein kinase, NF-κB, extracellular signal-regulated kinas e 1/2 (ERK 1/2) and AKT antiapoptotic survival pathways.5
  • (ii) CDCC. In the second pathway, complement is activated during treatment with Rituximab and can result in cell death of Rituximab coated cells.6
  • (iii) ADCC. The ADCC from Rituximab is mediated through NK cells through the interaction of CD16 on NK cells and the Fc portion of Rituximab coated on malignant cells. Activated NK cells can also produce IFN-Y that can have direct antitumor effects on the malignant cells, or the NK cells could be activating other immune effector cells which contribute to ADCC.7

In kidney transplantation per se, Rituximab administration may lead to rapid elimination of B cells which are effective antigen presenting cells, thus be responsible for the containment of T-cell response.8,9 B cells also perform several other diverse functions besides antigen presentation such as antibody secretion, cytokine production, and lymphoid architecture organization.10 The presence of B-cell lymphoid aggregates which contribute to local immune response in acute or chronically rejecting grafts supports this notion.11-13 The role of B cell secreted cytokines TNF-α and IL-10 is also described in renal allograft injury.14 B cells also secrete effector cytokines and costimulatory molecules that promote activated T-cell transition to cytotoxic T cells, influence their cytokine production and memory development.15,16 Rituximab, thus, has the potential to interrupt the allo-reactive immune response at multiple levels.

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PHARMACOKINETICS AND PHARMACODYNAMICS OF RITUXIMAB

Rituximab is usually administered by the intravenous (iv) route because of low oral bioavailability. The SC administration for Rituximab (bioavailability ~ 60%) was not found to be noninferior to iv administration in terms of pharmacokinetics and safety.17 The dose used in transplant setting varies based on indication for its use. The first approved dose of Rituximab was 375 mg/m2 given weekly for 4 weeks which was derived from cancer literature. Since then, the dosing regimen has evolved from weekly for single agent to monthly when combined with chemotherapy, to additional induction cycles,6-12 increased frequency of administration, and maintenance therapy with the same dose given every 2 or 3 months.18 There have been few investigations in transplant correlating dose and effect for Rituximab. However, there are reports that suggest that smaller does may be efficacious in certain clinical scenarios. The volume of distribution of Rituximab is 9.6 L, suggesting extra vascular distribution in tissues, except central nervous system (CNS) where it is limited by blood brain barrier.19 Rituximab disposition is characterized by a 2-exponential decay, with a long elimination half-life of about 3 weeks.19 Rituximab shows target (CD20)-mediated disposition where antibody-antigen binding influences the rate and extent of antibody distribution and elimination. The total clearance is the sum of specific target-mediated internalization, which is not linear and saturable, and nonspecific clearance, which is linear and mediated by proteolysis by liver Kupfer cells/macrophages and nonspecific FcγR-dependent endocytosis.18 After iv administration, Rituximab binds to the CD20 antigen present on the surface of normal or neoplastic B cells in the peripheral blood, bone marrow and lymph nodes.20 This leads to clearance of these cells from their respective reservoirs by various mechanisms. A single dose of Rituximab causes complete long term elimination of B cells in peripheral blood and kidney tissue in a majority of patients, however, lesser reduction of B cells in lymph nodes.21

In patients undergoing plasmapheresis (PP) sessions with Rituximab administration, the AUC for Rituximab is reduced by up to 26% when PP is performed less than 3 days after infusion and must be taken into account.22 Rituximab can be detected in the serum for many months after the dose of drug23 and this has implications for crossmatch and tissue-typing analyses. Since rituximab is cytotoxic in the presence of complement, sera that contain Rituximab would produce a positive B cell cytotoxic-positive crossmatch. The human portion of the IgG1 would provide a target for the antihuman Ig fluorochromes used in flow cytometric crossmatches again resulting in a false positive B cell crossmatch. Flow and cytotoxic crossmatches and PRA determinations, however, can be successfully done after either elimination of the cell surface CD20 by pronase treatment of the cells or removal of the circulating rituximab by immunomagnetic bead absorption.24

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Therapeutic Uses of Rituximab in Kidney Transplantation

The use of Rituximab in kidney transplantation discussed in this article remains off label. Table 1 summarizes important studies of Rituximab use in desensitization, ABOi transplantation and treatment of antibody-mediated rejection (AMR).

TABLE 1

TABLE 1

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A. RITUXIMAB USE IN SENSITIZED AND ABOI KIDNEY TRANSPLANTS

(i) Desensitization Before Transplantation for Highly Sensitized Recipients

Patients who are sensitized to HLA antigens wait longer for transplantation or find difficulties in identifying a suitable living donor. Rituximab has been used in various settings to either decrease the level of PRA/c-PRA to facilitate deceased donor transplantation or to decrease the degree of cross reactivity between the donor and recipient in living donor transplants to allow transplantation. Vo et al25 reported one of the first uses of Rituximab given at a dose of 1 g on days 7 and 22 along with high-dose IVIg (2 g/kg of body weight on days 0 and 30) in 20 highly sensitized patients awaiting a kidney transplantation. They reported a reduction in mean time to transplant from 144 ± 89 months to 5 ± 6 months in 16 of 20 patients transplanted, with a 1-year graft and patient survival of 94% and 100%, respectively. The mean PRA decreased from 77 ± 19% to 44 ± 30% after the second dose of IVIg. The same group further published their experience of 207 highly sensitized patients (DSA positive or PRA ≥ 80%) desensitized with Rituximab (single dose 1 g iv on day 15) and IVIg (2 g/kg on days 0 and 30) that led to transplant in 146 patients (71%). At 48 months, patient and graft survival was 95% and 87.5%, respectively. In this study, 22% of patients had AMR and 5.5% lost their allografts to AMR episodes.26 On the other hand, Marfo prospectively desensitized 11 patients with cPRA > 50% who were waitlisted for more than 5 years, using IVIg 2 g/kg on days 0 and 30 and single-dose Rituximab 375 mg/m2 on day 15. At a mean of 334 ± 82 days, only 2 of 11 patients were transplanted as compared to 14 nonsensitized patients transplanted over the same period at that center. The desensitization therapy did not lead to significant reduction in cPRA, the number of unacceptable antigens or their mean florescent intensity (MFI) values.27 Kozlowski and Andreoni46 used a similar regimen of Rituximab and high-dose IVIg for desensitization of 5 patients with c-PRA >85% and noted only transient depletion in antibody that was not enough to facilitate transplantation. Recently, Rituximab 375 mg/m2 was used with 2 doses of IVIg (2 g/kg) and 4 doses of Bortezomib (1.3 mg/m2 per dose) for desensitization in 19 highly sensitized patients in a prospective clinical trial and compared with 17 patients in the control group. They reported increased transplant rate of 42% versus 23% and concluded that the new strategy increases the probability of deceased donor kidney transplantation (hazard ratio [HR], 46.9; 95% confidence interval [CI], 4.5-634.2; P = 0.004).28

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(ii) Desensitization at the Time of Transplantation for Highly Sensitized Recipients

In this setting, Rituximab has been used for positive cytotoxic/flow cytometric crossmatch, positive DSA but negative crossmatch and in high PRA/high immunological risk patients. Umanath et al47 compared 15 CDC crossmatch-positive recipients receiving Rituximab and high-dose IVIg with 12 patients receiving only IVIg and found a significant increase in rejection free survival, but no difference in graft function at 1 and 12 months. In a retrospective study by Ishida et al,29 74 crossmatch-negative but DSA-positive recipients received fixed-dose Rituximab 200 mg iv ×1, 3 sessions of PP and standard-dose Basiliximab and were compared with similar group which got Basiliximab alone (n = 39). The study concluded that addition of Rituximab and PP resulted in significant reduction in AMR at 6 months (15% vs 39% at 6 months) and prevented formation of de novo DSA. Graft loss from chronic AMR (CAMR) was 17.9% versus 6.8% (P = 0.01) in Rituximab/PP group. At 5 years, the graft survival in Rituximab group was 98% versus 84% in Basiliximab group alone. Amrouche et al30 compared 43 DSA-positive deceased donor patients undergoing posttransplant desensitization with rituximab, PP and IVIg to 53 patients receiving IVIg alone. At 1 year, the incidence of AMR was similar (23% and 24%) but there was a significant reduction in DSA positivity (56% vs 77%, P = 0.04) and CAMR (28% vs 50%) in Rituximab/PP/IVIg-treated patients.

Jackson et al31 used single-dose Rituximab at 375 mg/m2 as part of induction therapy in 25 of 50 highly sensitized transplant patients. In addition to Rituximab induction, the desensitization therapy included multiple sessions of single-volume plasma exchanges, additional induction with thymoglobulin or Basiliximab and initiation of standard-dose CNI and MMF before transplant. They concluded that Rituximab induction in HLA-incompatible recipients reduced the incidence and magnitude of HLA antibody rebound, but did not affect DSA elimination, AMR, or 5-year allograft survival when compared with recipients desensitized without Rituximab. Macklin conducted a systematic review on use of Rituximab for desensitization in renal transplantation and concluded that that there is limited evidence to support the use of Rituximab as a desensitizing agent for transplantation.48 In a meta-analysis conducted by Zhao et al32 involving 589 highly sensitized patients, Rituximab induction (n = 312) pretransplant had significantly fewer AMR after kidney transplantation (odds ratio [OR], 0.52; 95% CI 0.28, 0.98, P = 0.04) and higher 1-year graft survival rates (OR 3.02, 95 % CI 1.14, 8.02, P = 0.03). No differences were noted in other efficacy and safety parameters in the groups. Van den Hoogen et al33 conducted a randomized, double blind, placebo controlled study of 280 patients who were randomized to a single-dose Rituximab (375 mg/m2) or placebo during transplant surgery. All received standard triple immunosuppression (IS). The biopsy proven acute rejection rate at 6 months was similar in 2 groups (23/138, 16.7% and 30/142, 21%, P = 0.25).

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Limitations

Many studies are retrospective, often with no formal comparison group. The dosing and schedule of Rituximab is not standardized and nor is its combination use with IVIg and PP. The induction therapy as well as maintenance immunosuppressive regimens also vary from center to center. The outcomes measures used are not uniform and thus cannot be compared across various series. In addition, the reduction in antibody levels is incomplete, often transient, with a significant rebound and in certain cases, the reduction could be explained by effective IVIg or PP alone. The use of Rituximab does not result in acceptable crossmatch results in all patients and an individualized approach is still required. The rates of AMR remain high and DSAs persist despite treatment. In addition, these desensitization studies report predominantly short-term incidences of AMR and graft outcomes. Rituximab has no effect on CD-27 positive memory B cells and CD-138 positive plasma cells in spleen and that explains a lack of consistence efficacy in these settings.49

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Key Points of Rituximab Use in Desensitization

There is mixed evidence to support that Rituximab with IVIg and PP can decrease antibody level, increase the odds of transplantation in sensitized individuals and lower the incidence of early posttransplant AMR but the numerous limitations of these studies preclude a strong recommendation for rituximab use in these settings.

Also, the new kidney allocation system implemented in December 2014, increased transplantation rates in highly sensitized patients (c-PRA 99% and 100%) by allotting them extra points and providing first access at the regional and national level.50 Though there is no published data on use of desensitization for this cohort in the new allocation era, this practice has likely reduced because of the disadvantage it will give to the desensitized recipient by reducing the c-PRA and taking away the priority allocation points. However, a subgroup of highly sensitized patients (c-PRA >99.95) who have not benefitted as much from the new allocation system, could be considered for desensitization and this area is currently under active investigation.

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(iii) Rituximab for ABO Incompatible Transplantation

ABOi kidney transplants were introduced in Japan in 1989. Until year 2002, preoperative desensitization with combination PP, IVIg and splenectomy formed the backbone of ABOi transplant success. In 2002, Rituximab was introduced in lieu of splenectomy to achieve medical splenectomy in ABOi kidney transplants. In 1 of the first reports, Tyden G reported successfully transplanting 4 patients in 2003 and then in 2005, 11 patients, across the ABO barrier using a 10-day pretransplant conditioning regimen of single-dose Rituximab 375 mg/m2 on day −10 along with antigen specific immunoadsorption on days −6, −5, −4 and −1 followed by a single dose of IVIg 0.5 g/kg after the last session. Standard-dose CNI/MMF was started at the same time. There were no side effects from the regimen, no hyper acute rejections, and all transplants had a normal graft function after transplant.51,52 In 2004, Sonnenday used a preconditioning regimen of PP to achieve a titer <16, low-dose CMV hyperimmuneglobulin (CMVIg) 100 mg/kg after each PP session and a single-dose Rituximab 375 mg/m2 on last day of PP, to successfully transplant 6 patients across ABO barrier without the use of splenectomy. At 12 months, the serum creatinine was 1.3 ± 0.1 mg/dl, no episodes of AMR and the ABO titers remained low.34 In 2005, Gloor reported on 34 ABOi transplants, 23 with perioperative splenectomy and 11 with preoperative Rituximab conditioning but no splenectomy. The patient and graft survival and ABO titers at 3 and 12 months were similar in the 2 groups. The AMR rates were 30% in splenectomized versus 18% in Rituximab group.35 There was also a case series of 4 patients who did not respond to conventional treatment with plasma exchange alone and a combination of splenectomy and Rituximab along with PP was successfully used.53 Fuchinoue et al36 reported 5-year experience with ABOi transplantation comparing outcomes in 3 groups: group A (n = 280) underwent ABOc transplantation, group B (n = 63) received ABOi transplant with splenectomy and group C (n = 50) received ABOi transplant utilizing Rituximab only. All groups received standard maintenance IS. In this study, 1- 3- and 5-year graft survival was 100% in group 3 and were superior to ABOc group as well. The renal function and rates of rejections at these points were not different in the 3 groups (P = 0.65 and 0.09, respectively). Kong et al37 used a preconditioning regimen of Rituximab and PP along with standard maintenance IS and on demand PP posttransplant based on ABO titers. Over a follow up of 21 months, 3 patients developed an AMR. The 2-year patient and graft survival was 99% and 97.5%, respectively and no graft loss was from AMR. Rituximab has also been used in combination with antigen specific immunoadsorption in 20 adult and pediatric ABOi transplants which gave comparable 3-year graft outcomes when compared to 48 ABOc transplants.54 However, the necessity of Rituximab in ABOi transplant is unclear as more recent reports have described excellent outcomes without the use of splenectomy or Rituximab. Flint reported successful ABOi transplants in 37 patients with just PP and standard IS and no Rituximab/splenectomy. Patient and graft survival was 100% at a median of 26 months which was similar to ABOc comparison group.38 Montgomery reported outcomes of 28 ABOi transplants that received only PP/IVIg for desensitization and had similar initial titers as the comparison historic group desensitized with Rituximab or splenectomy. At 21 months, they reported similar AMR rates between the groups.39 Opelz reported 804 ABOi transplants from Collaborative Transplant Study receiving Rituximab with 96 patients who didn’t. There was a nonsignificantly lower death censored graft survival in nonRituximab group (P = 0.081) and no difference in death from infection (P = 0.42).40

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Key Points of Rituximab Use in ABOi Transplants

Overall, the outcomes of ABOi kidney transplants have been acceptable and comparable to the ABOc transplants in terms of patient and graft survival, AMR rates or infectious complications. However, 2 major studies could achieve similar outcomes without the use of Rituximab. The long-term outcomes of this regimen will need to be looked at carefully. With increasing number of kidney transplants performed through national donor exchange programs, ABOi transplants and desensitization continue to decline. Desensitization procedure still holds promise in ABOi donor exchange programs where the recipient is broadly sensitized and can benefit from a hybrid modality utilizing desensitization after identifying a more immunologically favorable donor from the exchange pool.55,56

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(B) RITUXIMAB USE IN ACUTE AND CHRONIC AMR

(i) Treatment of Acute AMR

The incidence of AMR ranges from 5.6% to 23% in unselected populations to 30% to 60% in patients undergoing preconditioning for ABO or HLA-incompatible transplants.57,58 The modalities used to prevent and treat AMR vary across centers but includes some combination of PP/IVIg/Rituximab/Bortezomib. Hychko conducted a meta-analysis of studies of Rituximab use in AMR, which included 249 patients and reported a pooled ratio of response to Rituximab defined by at least partial improvement in graft function (OR 3.16, 95% CI: 1.75-5.70). However, this meta-analysis was limited by paucity of randomized control trial (RCTs) and prospective studies, nonuniform definition of response and heterogeneity in the standard treatment.41 Sautenet et al42 looked at a composite of graft loss or no improvement in renal function at month 12 in a phase III, double blind randomized trial of 38 patients with biopsy-proven AMR who received Rituximab 375 mg/m2 or placebo at day 5 along with PP/IVIg/corticosteroids in either group. The primary end point frequency was 52% and 57% in Rituximab and placebo group, respectively (P = 0.74). There was no difference in proteinuria at 12 months, Banff scores at 1 and 6 months or MFI scores. Although the study concluded no benefit, it was underpowered to detect many important differences and reported only a short-term follow up. Other studies have reported Rituximab use in refractory AMR.59,60

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(ii) Treatment of CAMR

Bachelet et al43 studied outcome of TG in CAMR treated with IVIg/Rituximab in 21 patients and compared with untreated control group of 10 patients. The graft survival and DSA kinetics were similar at 24 months but the adverse effects were more in the Rituximab/IVIg-treated group. They concluded that Rituximab does not alter the natural history of TG. Chung et al44 compared 25 Rituximab treated patients with CAMR with 29 historical controls. They reported stabilization of renal function at 6 months (P < 0.05) and an overall higher graft survival even in patients with high degree of proteinuria when compared to nonRituximab treated group.44 Hong treated 6 cases of CAMR with a single dose of Rituximab and 4 doses of IVIg. They reported stabilization of renal function and proteinuria in 3 of 6 patients who also had early-stage CAMR and concluded that Rituximab therapy has limited role in advanced stage CAMR.61 Waiser et al45 reported comparison of single cycle Bortezomib use in AMR (n = 10) and historical controls treated with single-dose Rituximab 500 mg iv (n = 9) and reported improved graft survival at 18 months in Bortezomib group but did not report long term outcomes. In this study, both groups received PPX6 sessions, IVIg 30 g and pulse steroids.

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Limitations

These studies are nonrandomized, single center retrospective reports with arbitrarily chosen outcomes and timelines and historical controls. The groups are not similar in terms of maintenance IS, stage of chronicity, grade of rejection, renal function or proteinuria at treatment.

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Key points About Rituximab in Acute and Chronic AMR

There is no consensus on role of Rituximab in the treatment of acute and chronic AMR and larger multicenter RCTs are required.

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(III) RITUXIMAB USE IN RECURRENT GN

(i) Recurrent Membranous Nephropathy

Recurrence of idiopathic membranous nephropathy (MN) posttransplant is observed with an incidence of 7% to 51% and progression related to degree and duration of proteinuria.62 Idiopathic MN can present early after transplant as de novo disease or late as recurrence of primary MN. Previously, cyclophosphamide, steroids and cyclosporine were the main stay of therapy for MN.63 Gallon and Chhabra64 first described a case of successful treatment of recurrent MN with 4 weekly doses of Rituximab 375 mg/m2 with resultant stable renal function and negligible proteinuria at 3 years. El-Zoghby et al65 reported recurrence of MN in 42% patients using a historical cohort and a current cohort diagnosed with protocol biopsies. Eight of 14 recurrences were treated with 2 doses of Rituximab 1000 mg iv each given 2 weeks apart and 6 of 8 had partial or complete response at 24 months and resolution of electron dense immune deposits on posttreatment biopsies. Sprangers et al66 described a recurrence rate of MN posttransplant of 44% in 34 idiopathic MN patients at a median of 13.6 months. They treated 4 out 15 cases of recurrent MN with Rituximab and reported stabilization/improvement of proteinuria in all 4 cases. The dosing of Rituximab in this study was at the discretion of the treating physicians but included either 4 weekly doses of 375 mg/m2 or 2 doses of 1000 mg iv given 2 weeks apart. Debiec et al67 described a recurrence of MN 13 days posttransplant which was PLA2R positive and treatment with Rituximab (4 doses of 375 mg/m2 every 2 weeks) resolved proteinuria by 6 months and stabilized serum creatinine at 6 months. Spinner et al68 reported treating glomerulonephritis posttransplant with a dose of Rituximab 200 mg per patient. They treated 20 patients (cases) with glomerulonephritis posttransplant with rituximab and 13 patients with recurrent GN with no Rituximab (controls). In this report, significantly more patients achieved complete response (urine protein/Cr <0.3) in recurrent MN patients treated with Rituximab (P = 0.029). Several others have published case reports of the beneficial effects of Rituximab in this setting.69 Due to heterogeneity of patient populations, their disease characteristics and the retrospective nature of these reports, no firm conclusions can be made about which patients will benefit from Rituximab more than others. More recently, Kattah et al70 reported posttransplant recurrence rate of 83% (n = 12) and 58% (n = 12), respectively in PLA2R (phospholipase A2 receptor antibody) positive and negative patients. The persistence or reappearance of PLA2R ab was associated with increasing proteinuria and resistant disease while resolution of PLA2R resulted in improvement in proteinuria. Other studies have reported various pretransplant PLA2R ab cut offs to predict recurrent MN.71,72 However, there are currently no credible data on preferential or preemptive use of Rituximab for PLA2R ab based increased risk of recurrence of MN. Research in this area is actively needed now.

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(ii) Recurrent Focal Segmental Glomerulosclerosis

Recurrence of primary idiopathic focal segmental glomerulosclerosis (FSGS) occurs in 30% to 50% of transplanted patients.73,74 Plasma exchange has been the main stay of therapy for FSGS. There are case reports of partial or complete remission of FSGS with Rituximab when given alone or in combination with PP.75-78 Lionaki et al79 studied early recurrence of idiopathic FSGS posttransplant in 12 patients and used Rituximab plus PP in 4 of those patients resulting in partial remission. Audard et al80 reported 4 cases where Rituximab alone or with PP was successfully used in prophylaxis of FSGS recurrence in second transplants after loss of first graft to FSGS recurrence. A compilation of reports of 39 cases of FSGS recurrence treated with Rituximab reported partial or complete remission in FSGS recurrence in 64% patients. In this study, lesser Rituximab infusions, lower age at transplant and normal serum albumin at FSGS recurrence were associated with higher frequency of response.81 This observation has been described earlier in similar settings. Therefore, to avoid opportunistic infections with higher/repeated doses, Rituximab should be titrated to required B cell depletion.82 Cravedi et al83 had reported a single dose achieved complete depletion of B cells for the entire study duration of 12 months and was equally effective as 4 weekly doses of Rituximab for same level of B cell depletion and idiopathic MN remission in native kidney disease. There was also a case report where Rituximab failed to improve proteinuria in recurrent FSGS patient.84 A recent European multicenter-pooled data showed complete and partial remission in 9 of 19 (47%) and 3 of 19 (16%) cases, respectively of recurrent FSGS with rituximab therapy achieving overall response rate of 63%.85 Mechanistically, Rituximab binds to a human podocyte protein SMPDL-3b that is involved in actin remodeling and stabilizes it. This molecule on podocytes is down regulated in vitro upon exposure to sera from FSGS patients, which is countered by Rituximab.86,87 Thus, the response to Rituximab may be related to its anti-CD20 activity or its ability to block the circulating factor in the serum. There are mixed reports of use of Rituximab to prevent recurrence of FSGS in high risk patients (young patients, rapid progression to ESRD and previous recurrence).87,88 Currently, there is more data supporting Rituximab use in documented recurrence than its use in prevention of FSGS recurrence in high-risk patients.

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(iii) Recurrent Antineutrophilic Cytoplasmic Antibody Vasculitis

There is increasing evidence of role of Rituximab in antineutrophilic cytoplasmic antibody (ANCA) vasculitis involving the native kidneys.89 However, its role in posttransplant recurrence is not well studied. The recurrence rate of ANCA vasculitis posttransplant in the current immunosuppressive era is 9%.90 Murakami et al91 reported successful treatment of 4 of 5 patients with biopsy proven recurrent ANCA vasculitis (necrotizing, crescentic GN, median recurrence at 26 months) with Rituximab and steroids, with clinical remission at 3.5 months and pathological remission in 2 of 3 cases. Similarly, Geetha et al92 reported successful remission of 2 cases of recurrent ANCA vasculitis with 4 weekly doses of Rituximab with stabilization of renal function, resolution of proteinuria and biopsy lesions and disappearance of circulating ANCA.

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(iv) Recurrent IgA Nephropathy and Recurrent Membranoproliferative Glomerulonephritis

A report of Rituximab use in 3 biopsy proven cases of recurrent immunoglobulin A nephropathy (IgAN) posttransplant with crescents and endocapillary proliferation on light microscopy showed stabilization of proteinuria and renal function.93 A phase 4 RCT for Rituximab in recurrent IgA nephropathy is currently recruiting.94 There are case reports of successful treatment of recurrent crescentic idiopathic MPGN resistant to IVIg/PP, with 2 doses of Rituximab with resolution of proteinuria at 4 months.95,96

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(v) Recurrent Lupus Nephritis

There is currently no data for use of Rituximab in recurrent lupus nephritis.

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Limitations

Studies on Rituximab in recurrent GN are retrospective, single center, nonrandomized, without comparator arms, have small sample size, with limited follows up and no clear endpoints. There is a possibility of reporting bias as series with nonresponders is not likely to be published. Also, the characteristics determining response have not been effectively gleaned from them. Immune-modulator and antiproteinuria agents like steroids, RAAS inhibitors and statins have been used in a nonrandomized manner, which makes it difficult to attribute beneficial effects to Rituximab alone.

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Key Points About Rituximab in Recurrent GN

The utility of Rituximab in recurrent MN appears promising with pending results from multi-center trial in native kidney disease with MN. Rituximab may be beneficial for recurrent FSGS through nonspecific activity in stabilizing glomerular cytoskeleton. Based on native kidney disease data, Rituximab appears to be beneficial in patients with recurrence of allograft vasculitis. However, there is no evidence to support Rituximab in patients with recurrent MPGN, IgAN or lupus recurrence posttransplant.

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(IV) RITUXIMAB USE IN PTLD

PTLD is a spectrum of lymphoproliferative disorders ranging from benign to neoplastic B cell (and occasionally T cell) processes. The incidence of PTLD in kidney transplant recipients is reported to be 1.58 cases/1000 patient years in adults and 4.4% to 6.9% in pediatric population.97,98 Infection of B cells with EBV leads to transformation of B cells leading to activation and continuous proliferation, which is not adequately controlled by T cells in immunocompromised patients.

The first-line therapy for PTLD is reduction in IS.99-101 The strategies used for reduction in IS are based on allograft type, IS at diagnosis and severity of PTLD but the common theme for kidney allografts has been cessation of MMF or Azathioprine at the time of diagnosis with reduction in Tacrolimus dose to target trough level of 2 to 3 ng/mL if diagnosed in first year posttransplant and 3 to 5 ng/mL if diagnosed beyond 12 months.100,101 However, therapies against B cells, chemotherapeutic agents, adoptive T-cell therapy and surgical resection have all been used in cases where reduction in IS alone is not sufficient. Successful use of anti–B-cell therapy for PTLD was first described in early 1990.102 Based on several reports, Rituximab is now the standard treatment for all CD20+ PTLD, both monomorphic and polymorphic diffuse large B-cell subtypes.103-107 For CD20-negative monomorphic PTLD or primary CNS lymphoma, most clinicians agree to treat them similar to their immunocompetent counterparts, and Rituximab has limited role in their management.108 Sequential immune-chemotherapy for PTLD was first reported by Zimmerman et al.109,110 In PTLD-1 Trial, the largest to date, prospective, multicenter, phase 2 trial on treatment of PTLD, treatment naïve CD20 + ve PTLD patients who failed to respond to initial reduction in IS, received Rituximab weekly doses ×4 followed 3 weeks later with 4 cycles of Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Prednisone (CHOP) every 3 weeks. The primary end points were response rates and duration. 53 of 59 patients had a complete or partial response (90%, 95% CI, 79-96), of which 40 (68%, 95% CI, 55-78) were complete responses. The medial overall survival was 6.6 years. The authors concluded support for sequential use of immune-chemotherapy for treatment of CD20+ PTLD who progressed despite initial Rituximab therapy.111 In a subsequent comprehensive analysis of the PTLD-1 trial, patients in complete remission after Rituximab treatment and those with partial remission with low International Prognostic Index (IPI) score less than 3 were found to be low risk for progression of PTLD while those with no response to Rituximab or partial remission with IPI score greater than 3 were high risk for progression. The trial identified this subgroup to benefit the most from sequential immune-chemotherapy (Rituximab plus chemotherapy).112Table 2 summarizes Rituximab use in the setting of PTLD.

TABLE 2

TABLE 2

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Key Points About Rituximab in PTLD

The use of Rituximab in PTLD, though based on data from small cohorts, has been accepted by oncology and transplant community. The strategies used for reduction in IS along with concurrent use of Rituximab were like initial reduction in IS done at the time of diagnosis of PTLD.

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Adverse Events of Rituximab

Rituximab is well tolerated overall. The infusion reactions in the form of urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death have been described. The onset of these reactions is typically between 30 and 120 minutes. All recipients should be pretreated with acetaminophen and antihistamines. Infectious complications associated with Rituximab include prolonged neutropenia, CMV reactivation, activation of tuberculosis, reactivation of hepatitis B leading to fulminant hepatic failure and progressive multifocal leukoencephalopathy from JC virus infection.113 Grim et al114 reported rates of infectious complication, mostly bacterial, at 48% versus 11% for Rituximab treated ABOi group at 6 months. Khwaji et al115 described the infectious complications in 170 Rituximab treated ABOi and 191 nonRituximab ABOc comparison group. At 18 months, there were equal rates of bacterial (34% vs 39%), viral (22% vs 25%), fungal (5.9% vs 5.2%) and serious infections (22.9% vs 25.5%). BK viremia was nonsignificantly more common in Rituximab group (10.6% vs 5.8%). A retrospective review of 77 patients with and 902 patients without Rituximab use reported similar rates of bacterial, lower rates of viral and a higher rate of fungal infection with Rituximab. In this cohort, 7/9 (11.6%) deaths were infection related compared to 1.5% in nonRituximab group (P = 0.0007).116 Overall, the infectious risk of Rituximab alone is difficult to discern posttransplant as used in combination with induction, maintenance IS or where overall IS is intensified along with Rituximab administration.

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FUTURE DIRECTIONS

The role of Rituximab as suggested by uncontrolled studies needs to be confirmed with RCTs. For diseases with rare occurrence like posttransplant GN, transplant centers must form consortiums, use uniform interventions, and outcomes to increase the power and confidence in the results. Studies are needed to investigate its role in combination with antiplasma cell therapies which when given alone have limitations due to rapid differentiation of memory B cells in to plasma cells to repopulate the depleted niches. There is a concern that nonselective pan depletion of B cells could also remove Breggs and potentially worsen the alloimmune response. Mechanistic studies of origin and role of various B-cell subsets in transplant are needed to develop directed novel therapies against the injury causing subsets of B cells and to optimize the use of existing therapies like Rituximab in combination with those therapies. Newer anti-CD20 agents approved by FDA for hematological malignancies are humanized or fully human molecules to reduce immunogenicity. They differ in their recognition of a different epitope of CD20 compared with Rituximab, resulting in more avid binding, or have higher affinity interaction with FcγR resulting in stronger efficacy in Rituximab-sensitive or -resistant cells.117 These newer agents have not been systematically studied in transplantation likely because of largely unproven effects of prototype Rituximab in transplant clinical settings.

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CONCLUSIONS

The evidence-based use of Rituximab in kidney transplantation remains limited. Strict RCTs are necessary, which can be accomplished through combined efforts of, and partnership between academic transplant centers, industry partners, and government agencies.

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ACKNOWLEDGMENTS

The authors would like to thank Dr. Aravind Cherukuri, MD, PhD, at the University of Pittsburgh, for contributing Figure 1 in this article.

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