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A Systematic Review of the Use of Rituximab for Desensitization in Renal Transplantation

Macklin, Philip S.1; Morris, Peter J.1,2; Knight, Simon R.1,2,3

doi: 10.1097/TP.0000000000000362
Editorials and Perspectives: Special Feature
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Background Rituximab is a B lymphocyte–depleting agent used to treat lymphoma and autoimmune diseases. Recently, it has been used for desensitization therapy in ABO-incompatible and highly sensitized recipients undergoing renal transplantation.

Methods A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Four databases and three trial registries were searched for studies comparing rituximab with non-rituximab desensitization protocols. A lack of randomized evidence precluded meta-analysis, and thus a narrative review was conducted.

Results Forty-five records met the inclusion criteria, relating to 21 individual studies (two randomized controlled trials and 19 retrospective cohort studies). Ten studies investigated the use of rituximab in ABO-incompatible patients; most found no significant differences in patient and graft outcomes when compared most frequently to splenectomy-based protocols. Nine studies of limited quality focused on highly sensitized recipients (positive cross-match, donor-specific antibody, and elevated panel reactive antibody) and demonstrated some benefits in graft survival, acute and chronic rejection, and sensitization levels with rituximab. The remaining two studies combined ABO-incompatible and highly sensitized recipients and found no statistically significant increase in infectious complications with rituximab.

Conclusion Evidence of limited quality was identified to support the use of rituximab desensitization in highly sensitized recipients. Among ABO-incompatible recipients, rituximab was found to be equivalent to splenectomy, indicating that this invasive surgical procedure is not necessary. Further randomized controlled trials are required to better define the efficacy, long-term safety, and optimal dosing regimen of rituximab in this setting.

Supplemental digital content is available in the text.

1 Centre for Evidence in Transplantation (CET), Clinical Effectiveness Unit, The Royal College of Surgeons of England, London, United Kingdom.

2 Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.

3 Address correspondence to: Simon R. Knight, M.A., MChir, F.R.C.S., Centre for Evidence in Transplantation, Royal College of Surgeons of England, 35-43 Lincoln’s Inn Fields London, WC2A 3PE, United Kingdom.

The authors declare no funding or conflicts of interest.

E-mail: simon.knight@nds.ox.ac.uk

P.J.M. has chaired the Data and Safety Monitoring Committee for Renal Belatacept trials sponsored by Bristol-Myers Squibb during the past 10 years.

Received 4 April 2014. Revision requested 28 April 2014.

Accepted 16 June 2014.

International Prospective Register of Systematic Reviews registration number CRD42012002101

P.S.M. performed the database searches, screened search results for inclusion, quality assessed, and abstracted data from the included studies and cowrote the article. This work formed part of his thesis for the Edinburgh Surgical Sciences Qualification (ESSQ), an online Masters programme in surgical sciences at the University of Edinburgh (www.essq.rcsed.ac.uk). S.R.K. suggested the topic of the systematic review, screened search results for inclusion, quality assessed, and abstracted data from the included studies and cowrote the article. P.J.M. provided a third opinion in cases of discordance regarding study inclusion, reviewed the article, supervised P.S.M.’s thesis, and offered guidance throughout the project.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Transplantation is the optimal treatment for end-stage renal failure because of improved patient outcomes and cost efficiency (1–3). There is a shortage of donors and, to enlarge the organ pool, there has been an increase in ABO-incompatible transplants. In addition, levels of recipient sensitization are increasing (4). Sensitized recipients possess alloreactive antibodies, primarily against human leukocyte antigen (HLA). These antibodies develop after previous transplants, blood transfusions, and pregnancies; however, increases in detected sensitization levels may also reflect the advent of newer, more sensitive screening tests (4). These antibodies may be directed at a high proportion of the potential donor population (elevated panel reactive antibody [PRA]) or to a specific donor in the living donor setting (donor-specific antibodies [DSA]). High levels of sensitization mean that it is more difficult to identify a suitable donor, and sensitized patients often have to wait longer for a deceased donor transplant, if one is found at all.

Even when a suitable organ is identified, ABO-incompatible and highly sensitized patients are at high immunologic risk with increased propensity to acute rejection and poor short-term and long-term outcomes (5, 6). Without pretransplant desensitization, 90% of highly sensitized patients experience rejection within 3 months (7, 8). Transplantation in such patients had, until recently, been considered contraindicated. Improved immunosuppression now permits these patients to be eligible for transplantation. Desensitization, based on the use of plasmapheresis and intravenous immunoglobulin (IVIg) to remove DSA and splenectomy to prevent rebound of antibody levels, has been shown to produce good short-term results in ABO-incompatible transplants (9). However, such patients are still at increased risk of rejection and interest exists in ways of improving these regimens. One area of focus is the use of B lymphocyte–depleting medications to avoid the need for splenectomy.

Rituximab is a monoclonal antibody active against CD20, a protein found on the cell membrane of B lymphocytes before their terminal differentiation into plasma cells and which is responsible for regulating cell cycling (10). Rituximab eliminates B lymphocytes, depleting circulating levels for 6 to 12 months (11), and thus abrogates antibody-mediated immune responses. As B lymphocytes also function as antigen-presenting cells, rituximab may also indirectly depress T-lymphocyte activity (12). Rituximab has traditionally been used to treat lymphoma (13) and autoimmune diseases (14, 15). More recently, it has been used as an immunomodulatory agent in renal transplantation in the settings of desensitization and antibody-mediated rejection (AMR).

Despite early encouraging results relating to the use of rituximab as desensitization therapy (16), its exact role in this setting has yet to be established. This systematic review aims to clarify the issue by critically evaluating the existing evidence for the use of rituximab as part of desensitization protocols in ABO-incompatible and highly sensitized recipients.

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RESULTS

Study Selection and Characteristics

Forty-five records met inclusion criteria (17 full articles (17–33) and 28 abstracts (34–61)), relating to 21 distinct studies (Tables 1–5). One record was identified by reviewing reference lists of other records (30). Searching trial registries identified nine ongoing or unpublished studies that were potentially relevant. After contacting their lead investigators and the pharmaceutical companies that manufacture rituximab, no further data for inclusion were identified. The flow of trials through the review process is depicted in Figure 1.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

TABLE 3

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Table 4

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TABLE 5

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FIGURE 1

FIGURE 1

Two randomized controlled trials (RCTs) were identified; the remaining 19 studies were retrospective cohort studies. Twelve were reported as full papers, and nine were reported in abstract form only. The Downs and Black Quality Index scores for the full publications ranged between 10/32 and 25/32 SDC 1,http://links.lww.com/TP/B38). Scoring was stronger in the domains of reporting (whether the article contains sufficient information to permit unbiased assessment of its findings) and external validity (the extent to which the study findings can be generalized to the population from which the study subjects were derived). Weaker scoring was achieved for internal validity (whether the study addresses bias in the selection of study subjects and in the measurement of outcomes) and power (all studies scored 0 for lack of sample size calculation).

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ABO-Incompatible Recipients

Ten retrospective cohort studies were identified, most commonly comparing a rituximab-based protocol to splenectomy-based protocol (Table 1).

One study (44) found significant benefits with the use of rituximab, comparing 42 recipients desensitized with rituximab and basiliximab to 19 patients who underwent splenectomy. There was a nonsignificant reduction in antibody titres among the rituximab group (P=0.05), leading to a significant decrease in overall acute rejection (19.0% vs. 68.4%; P=0.01). Additionally, there was a trend to improved graft survival among patients receiving rituximab (97.6% vs. 68.4%; P=0.05). There was no difference in patient survival at 3 years, graft function, or infectious complications. There was less peptic ulcer disease and posttransplant diabetes mellitus among rituximab patients because of the low-dose steroid protocol used in this group.

Waigankar et al. (25) also reported improved patient (85.7% vs. 78.9%) and graft survival (unadjusted, 85.7% vs. 68.4%; death-censored, 100.0% vs. 89.4%) among seven patients receiving rituximab, plasmapheresis, and IVIg compared to 19 patients who underwent splenectomy with plasmapheresis and IVIg. However, this study received a low Downs and Black score (10/32), contained inaccurate data requiring clarification from the authors, and did not provide a statistical comparison between groups.

Hyodo et al. (34) compared 29 patients desensitized with rituximab and mycophenolate mofetil (MMF) with 31 patients who underwent splenectomy with MMF and 62 patients who underwent splenectomy with azathioprine. Although all protocols suppressed anti-ABO antibody titres, there was a statistically significant decrease among those receiving rituximab compared to the other groups. Graft survival at 5 years was equivalent between the rituximab and splenectomy plus MMF groups. Patients in the azathioprine group showed a significantly poorer graft survival (P=0.014).

Harada retrospectively compared 46 patients receiving rituximab to 24 undergoing splenectomy (42). Five-year patient and graft survival and incidence of acute antibody-mediated rejection (AAMR) and acute T-cell–mediated rejection were comparable between groups. However, the incidence of cytomegalovirus (CMV) infection was lower in the rituximab cohort (5% vs. 50%).

The most extensive experience comes from Tokyo Women’s Medical University (17–21, 36–41), where 57 recipients desensitized with rituximab and plasmapheresis were compared to 45 patients who underwent splenectomy with plasmapheresis (17). Unfortunately, this study compared results across the rituximab, splenectomy, and ABO-compatible cohorts and did not contain a statistical two-group comparison between rituximab and splenectomy. However, patient survival, graft survival, rejection-free survival, and median serum creatinine (SCr) seem to be comparable across the three groups. There was a higher incidence of leukopenia with rituximab (24.6% vs. 2.2%) but all affected patients responded to treatment, and there was no increase in infectious complications. The group previously reported a significant reduction in CMV infection with rituximab compared with splenectomy (26.0% vs. 44.4%; P=0.0428) (18).

As part of a larger study, Ashimine et al. (22) reported their experiences of 30 ABOi recipients receiving rituximab and 51 ABOi recipients who underwent splenectomy, but no statistical comparison was provided. The splenectomy group had a longer follow-up (57.3±20.4 vs. 34.3±7.6 months), at which point there was one death in the rituximab cohort (96.7% survival) and five deaths in the splenectomy cohort (90.2% survival). Three-year uncensored graft survival was 96.7% in the rituximab group and 90.2% in the splenectomy group. Incidence of acute rejection (3.3% vs. 11.8%), glomerular filtration rate (44.7±12.0 vs. 46.0±13.7 mL/min/m2), development of de novo HLA antibodies (14.3 % vs. 13.2%), and incidence of CMV infection (40.0% vs. 49.0%) and severe infection (3.3% vs. 7.8%) seem to be broadly comparable between the groups given that the splenectomy patients had been subject to longer follow-up.

Montgomery detailed the experience of 60 consecutive ABO-incompatible transplants at Johns Hopkins (23). Fifteen received rituximab, three underwent splenectomy plus rituximab, and 14 patients underwent splenectomy alone. All of these patients also underwent plasmapheresis and received IVIg. The remaining 28 patients underwent plasmapheresis with IVIg alone. At publication, median SCr was 106.1, 79.6, 106.1, and 114.9 µmol/L, respectively. Because removal of B-cell depleting therapies from their protocol did not increase rates of AMR, they have adopted a regimen of pretransplant and posttransplant plasmapheresis and IVIg coupled with daclizumab induction and quadruple immunosuppression for maintenance and report equivalent 5-year graft survival to registry data for ABO-compatible patients.

Three remaining studies reported no differences between rituximab and the comparison protocols (24, 35, 43).

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Highly Sensitized Recipients

Nine studies (two RCTs and seven retrospective cohort studies) reported the use of rituximab in highly sensitized transplant recipients. Two studies investigated rituximab in patients with a positive T-cell complement-dependent cytotoxicity (CDC) cross-match, two included patients with DSAs detected on single-antigen analysis, four included patients with high PRA levels and one combined patients with a positive cross-match, circulating DSA, elevated PRA, and previous allograft loss because of acute rejection.

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Rituximab in Patients With a Positive CDC Cross-Match

Two retrospective cohort studies combined rituximab with IVIg in patients with a positive CDC cross-match (Table 2). Stegall et al. (26) compared three sequential desensitization strategies in 61 patients—rituximab, low-dose IVIg, and plasmapheresis (32 patients, of which the first 19 also underwent splenectomy); high-dose IVIg alone (13 patients); and rituximab, low-dose IVIg, plasmapheresis, and pretransplant antithymocyte globulin (ATG, 16 patients). Significantly more patients receiving rituximab achieved a negative cross-match (84.4%, 38.5%, and 87.5%; P<0.05), and there were also significantly fewer AMR episodes among rituximab patients (36.7%, 80.0%, and 28.6%; P<0.05), although graft function was equivalent between groups. Because the two rituximab arms also included plasmapheresis, it is difficult to discern how much of the benefit resulted from the addition of rituximab to the protocol.

Umanath et al. (45) compared 15 CDC cross-match–positive recipients receiving rituximab and high-dose IVIg to a historic cohort of 12 patients who received high-dose IVIg only. The addition of rituximab led to a significant increase in rejection-free graft survival, but no difference was found in graft function at 1 and 12 months.

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Rituximab in Cross-Match–Negative, DSA-Positive Recipients

Two retrospective cohort studies reported on the role of rituximab in patients with DSAs detectable on single-antigen analysis (Table 3).

The larger of these studies, again from the Tokyo Women’s Medical University, compared 74 patients with low-level DSA undergoing pretransplant desensitization with rituximab, plasmapheresis, and basiliximab to 39 patients who received basiliximab only (27). Rituximab resulted in a significantly decreased incidence of AAMR (14.9% vs. 30.8%) and T-cell–mediated rejection (0.0% vs. 41.0%) at 6 months. During this period, 71.6% of the rituximab group was rejection-free, compared to 17.9% in the non-rituximab cohort. At more than 6 months, chronic antibody-mediated rejection (CAMR) was also lower among rituximab-treated patients (18.9% vs. 51.3%). The differences in CAMR can be partly explained by the prevention of de novo DSA with rituximab (0.0% vs. 12.8%). In addition, after an immediate postoperative decrease in DSA levels in both groups, the level continued to decrease in the rituximab group but began to increase year-by-year in the non-rituximab group.

Seven patients (17.9%) in the non-rituximab group suffered graft loss, all because of CAMR. This was significantly greater than the 6.8% graft loss in the rituximab group, in which the major causes of graft loss were acute rejection (one patient) or death with a functioning graft (four patients). No difference in graft function was detected between the two groups (renal function of patients with graft loss was not included in this analysis), and there was no difference in patient survival. A previous record from the same study reported a reduction in CMV viremia in those treated with rituximab (5.8% vs. 20.8%; P=0.047), but this was not associated with a significant decrease in CMV infection (5.8% vs. 16.7%; P=0.127) (28).

In the second study, Loupy et al. (51) compared 43 DSA-positive deceased donor recipients undergoing posttransplant desensitization with rituximab, plasmapheresis, and IVIg to 53 patients receiving IVIg alone. At 1 year, the incidence of AAMR was similar between the groups (23% and 24%), but there was a significant reduction in DSA positivity (56% vs. 77%; P=0.04) and CAMR (28% vs. 50%; P=0.04) and significantly improved graft function among those receiving rituximab. Previous publications with fewer patients reported no difference in patient and graft survival or adverse effects (29, 52). Again, it is difficult to separate out the effects of rituximab and plasmapheresis in this cohort.

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Rituximab in Patients With High PRAs

Four studies (one RCT and three retrospective cohort studies) reported on the use of rituximab in patients with elevated PRA (Table 4).

Vo and colleagues (53) published a small RCT in abstract form only, comparing rituximab plus IVIg to placebo plus IVIg in patients with PRA greater than 80%. Both strategies reduced DSA titres, allowing 11 of 15 enrolled patients to undergo transplantation (six in the rituximab group and five in the placebo group). However, there was a trend toward rebound of DSA levels in the placebo group after 6 months (P=0.09). The study was discontinued because of three episodes of AMR and two graft losses in the placebo group. There were no episodes of AMR (P=0.02 vs. placebo) or graft loss (P=0.08 vs. placebo) in the rituximab group and no difference in incidence of cell-mediated rejection between groups.

Vo and colleagues (54, 55) also reported a retrospective comparison of 122 recipients (PRA>80%) treated with rituximab and IVIg to 30 patients receiving IVIg alone. There was no difference in patient survival at 3-year follow-up, although significant differences in favor of rituximab were detected in incidence of acute rejection (39.3% vs. 70.0%; P=0.002), AAMR (27.9% vs. 50.0%; P=0.02), and death-censored graft survival (88% vs. 52%; P<0.0001). There was no significant difference in incidence of cell-mediated rejection (11.4% vs. 20.0%). A previous abstract from the same group found a significant reduction in incidence of viral infections with rituximab (8% vs. 14%; P=0.02) and no difference in graft function at 24 months (55).

Laftavi and colleagues (58, 59) also found that rituximab was beneficial when comparing 14 recipients (PRA>80%) desensitized with rituximab to 23 such patients who did not receive rituximab. There was no difference in patient survival at 5 years, but rituximab was associated with prevention of development of DSA (0% vs. 35%; P=0.02), significant improvement in graft survival (92% vs. 43%; P<0.01), and decreased incidence of both AMR (0% vs. 25%) and acute cellular rejection (0% vs. 35%; P=0.0004), without an increase in adverse effects.

In contrast, Song and colleagues (30) demonstrated no benefit to the use of rituximab in a cohort of sensitized patients with lower PRA levels (≥50%). Although the lower levels of sensitization may account for the lack of benefit seen, this is confounded by the lack of a T-cell–depleting antibody in their protocol and a significantly higher pretransplant mean class I PRA level in the rituximab group.

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Rituximab in highly sensitized recipients combined

One RCT was identified that combined a variety of highly sensitized recipients (31, 60, 61) (Table 5). This was an open-label pilot study aiming to investigate the safety/toxicity of treatment and was not powered to analyze efficacy. Although this was a multiarm trial (bortezomib+ATG induction; rituximab, bortezomib+ATG induction; rituximab+ATG induction, and ATG induction alone), only two groups met our inclusion criteria (rituximab+ATG and ATG alone), each with 10 patients. At 1-year follow-up, acute rejection rates were 0% and 20% and de novo DSA 30% and 30%, respectively. No differences were detected between groups in patient and graft survivals (both 100% in both groups), graft function or adverse events, including infection rates. Unfortunately, statistical analyses were performed across all four groups, and no direct comparison of the rituximab+ATG and ATG alone groups was provided. The authors concluded that the addition of rituximab (and/or bortezomib) was associated with an acceptable safety profile and warrants further study.

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ABO-Incompatible and Highly Sensitized Recipients Combined

Two retrospective cohort studies combined ABO-incompatible and highly sensitized patients (32, 33). Although the heterogeneity in inclusion criteria precludes conclusions regarding efficacy, the data from these studies allow assessment of the impact of rituximab on infectious complications. Neither study demonstrates a significant difference in the incidence of infection between cohorts, although the incidence of infection was numerically higher in the study from Grim et al. (48% in the rituximab cohort vs. 11%, P=0.107). Of note, one third of the rituximab cohort were diabetic. Overall, the most common infections were skin and soft tissue (eight cases), bloodstream (five), esophagitis (three), peritonitis (three), pneumonia (one) and colitis (one). The authors concluded that concerns of increased infections with rituximab, coupled with the lack of improvement in patient outcomes, had prompted them to abandon its use in this setting.

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DISCUSSION

Initial attempts to perform renal transplantation across the ABO barrier were associated with high rates of acute rejection (62). However, pretransplant desensitization protocols, including splenectomy, have led to markedly improved outcomes (63), and ABO-incompatible transplants have helped to ease the organ shortage, especially in Japan where deceased donor transplant rates are low. Rituximab desensitization was first introduced by Tydén in 2001 in ABO-incompatible transplants (64) and was subsequently shown to obviate the need for splenectomy (65). The rational for peritransplant splenectomy is to remove B lymphocytes that produce DSA. However, AMR remains problematic in these patients, and systemic therapies, such as rituximab, may be more efficacious because they deplete not only splenic B lymphocytes but also those in the circulation, lymphatics, and within the graft (66).

Rituximab produces prolonged B-lymphocyte depletion but does not affect antibody-producing plasma cells. By preventing B-lymphocyte differentiation into plasma cells, rituximab precludes new alloantibody synthesis. Theoretically, it must be combined with therapies that rapidly clear pre-existing antibodies, such as plasma exchange, plasmapheresis, or antigen-specific immunoadsorption. Many protocols also include IVIg, the precise mechanism of action of which is unknown but it may bind to circulating antibodies and further prevent antibody synthesis (12). A recent study has shown that by depleting memory B cells, rituximab also prevents an anamnestic response after transplantation in antibody-negative, sensitized patients (67).

In this systematic review, most studies of ABO-incompatible recipients compared rituximab to splenectomy. No studies reported statistically significant differences in patient survival, graft survival, or graft function. One study reported a significant reduction in anti-ABO antibodies with rituximab (34) and another reduced rates of acute rejection (44). In addition to these findings, it seems that the outcomes of ABO-incompatible transplantation using rituximab-based desensitization protocols compare favorably to ABO-compatible procedures (17, 18, 68, 69). Although no strong evidence exists to support superior patient and graft outcomes with rituximab, the use of medical therapy obviously avoids the adverse effects of splenectomy, namely, risk of surgical complications, postoperative discomfort, and a lifetime risk of overwhelming post–splenectomy sepsis (70).

Among highly sensitized recipients, there is stronger evidence for a benefit of rituximab-based protocols, although the other components of the desensitization strategies were variable, making assessment of the direct effects of rituximab difficult. Retrospective studies using rituximab in cross-match–positive patients and cross-match–negative patients with positive DSAs on single-antigen assays all showed benefit with the introduction of rituximab to desensitization protocols, particularly in AAMR and CAMR. Rituximab may also have some benefit in reducing risk and improving outcomes in patients with high PRA levels (>80%). Recently, rituximab-based desensitization in this setting has been shown to be superior to long-term dialysis with respect to overall survival and cost-effectiveness at 3-year follow-up (71).

The optimal dose and number of infusions of rituximab is still unknown. ‘Standard dosing’ (375 mg/m2) is based on the treatment of lymphoma (72), but this may be excessive in the setting of transplantation. Furthermore, body surface area may not be the optimal method of calculating the required dose (73). Therefore, studies have investigated using lower doses of rituximab to improve safety and cost-effectiveness. Tydén reported that a single 375 mg/m2 dose of rituximab was capable of long-term depletion of all circulating B lymphocytes as well as those in renal tissue and 50% within lymph nodes (74, 75), suggesting that multiple infusions are not necessary. A subsequent study by Toki et al. (76) indicated that single doses less than 375 mg/m2 are also effective at depleting B lymphocytes in the spleen and peripheral blood. Takagi et al. (77) found that there was no difference in incidence of AMR or acute cellular rejection between ABO-incompatible patients receiving a single 150 mg/m2 or 375 mg/m2 dose. Another report from the same unit found no difference in graft function in ABO-incompatible patients administered single doses of 100 mg, 200 mg, and 500 mg (18). Therefore, it is likely that ‘standard dosing’ is excessive.

Infusion-related reactions are a recognized consequence of administration of rituximab. Fever is the most common adverse effect in nontransplant patients (78) and may relate to cytokine release (79). Concomitant corticosteroids may prevent some of the adverse effects caused by this inflammatory storm. Zarkhin et al. (80) reported hypotension and dyspnea as other infusion-related side-effects, both resolved by slowing the infusion rate.

The risk of infectious complications in the immunosuppressed transplant population is also of concern. Kamar and colleagues (81) reported that although the overall incidence of infection in those receiving rituximab is not increased, infection-related mortality was significantly greater in the rituximab group when compared to retrospective controls (9.1% vs. 1.6%; P=0.0007). In this current systematic review, none of the studies found a statistically significant higher incidence infectious of complications with rituximab. Indeed, significantly lower rates of CMV viremia (28) and viral infections (55) were identified. It has been speculated that a reduction in viral infections may relate to fewer episodes of rejection and associated steroid therapy (18). Our findings are in agreement with two retrospective reviews of infectious complications in renal transplant recipients (82, 83) and a study among rheumatoid arthritis patients (84). However, a recent study reports that the combination of rituximab and plasmapheresis for desensitization does increase the rate of infection (85), whereas another suggests that desensitization with rituximab and IVIg results in a greater incidence of BKV viremia after transplantation (86). Thus, some caution should be expressed regarding the risk of infection with the use of rituximab.

Another concern is the development of progressive multifocal leukoencephalopathy secondary to impaired cellular immunity and reactivation of latent JC virus. In a study screening 73 solid organ recipients treated with rituximab, JC virus was detected in 5.5% (87). Significantly, these patients also received T lymphocyte–depleting therapies. All responded to a reduction in immunosuppression with none developing progressive multifocal leukoencephalopathy.

This systematic review is limited by a number of factors. In a narrative review of this type, it is not possible to formally assess for the presence of publication bias, and so it is possible that the identified studies are biased toward those with positive findings in favor of rituximab. We have attempted to minimize this effect by performing a thorough literature search across several databases and searching trial registries for ongoing or abandoned studies. The review is also limited by the quality of existing evidence. Only two small RCTs were identified, with the vast majority of evidence being derived from retrospective cohort studies containing relatively small numbers of patients. In addition, the diversity of therapeutic protocols, using a variety of complex medications, means that it is difficult to confidently attribute outcomes solely to the administration of rituximab. Finally, 28 of 45 included records were abstracts. Because of their brevity, such records are likely to omit significant amounts of information, and it is impossible to accurately assess their methodological quality, increasing the risk of bias and limiting the conclusions that we can draw from their results. This systematic review highlights the need for high-quality RCTs to better define the role of rituximab in addition to standard desensitization protocols in ABO-incompatible, HLA-incompatible and high-risk renal transplant recipient, and to better define its long-term safety profile and optimal dosing regimen.

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MATERIALS AND METHODS

Protocol and Registration

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (88) and is registered with the International Prospective Register of Systematic Reviews (registration number: CRD42012002101).

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Eligibility Criteria

Inclusion criteria specified all comparative studies of ABO-incompatible and highly sensitized adult or pediatric renal transplant recipients in which rituximab-based desensitization protocols were compared with alternative protocols not including rituximab. Highly sensitized recipients were defined as those with a positive CDC cross-match, DSA (any level), or a high PRA level as defined in the original study. Exclusion criteria included nonrenal solid organ and bone marrow transplant studies, comparative studies against ABO-compatible or nonsensitized patients, use of more than one B-cell depleting agent, case series, and case reports. No date or language limits were applied.

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Literature Search

A systematic literature search was performed in Ovid MEDLINE and Embase, The Cochrane Library, and The Transplant Library. Search terms included keywords and free text terms for rituximab and its aliases, along with keywords and free text alternatives for renal transplantation (SDC 2,http://links.lww.com/TP/B38). The final date for searches was April 15, 2014. Reference lists of identified studies were assessed for relevant records not identified by the initial search.

To identify unpublished or in-progress studies, we searched ClinicalTrials.gov (http://clinicaltrials.gov), the International Standard Randomized Controlled Trial Number Register (http://www.isrctn.org) and the World Health Organisation International Clinical Trials Registry Platform (http://apps.who.int/trialsearch). We also contacted the pharmaceutical companies that manufacture rituximab (Roche [European Union and Canada], Biogen Idec/Genentech [United States of America], and Chugai Pharmaceutical [Japan]).

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Study Selection

Duplicates were discarded from initial search results. The remaining titles and abstracts were screened independently by two authors (PSM and SRK). Full text of potentially relevant studies was reviewed before confirming their inclusion. Any discrepancies that could not be resolved were dealt with by discussion with the third author (PJM).

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Data Abstraction and Analysis

Studies are identified by the first author and year of the first full publication (if available) or published abstract. Demographic, outcome and methodological quality data for included studies were abstracted into a database by means of a pro forma. Timing of reported outcomes is recorded as specified in each study; if not specified, average time of patient follow-up is recorded instead. All outcomes are recorded as reported by each study. All SCr values were converted to the International System of Units (μmol/L). Data are presented as mean (±standard deviation) or median (minimum-maximum), and all values are expressed to one decimal place unless the original article did not provide this degree of accuracy. The exceptions to this are P values, which are presented as stated in the published record.

Primary study outcomes focus on efficacy, including patient and graft survivals, incidence of rejection, graft function, and reduction in sensitization level. Secondary outcomes focus on safety.

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Risk of Bias in Individual Studies

The methodological quality of included studies was evaluated by the Downs and Black Quality Index (89) (SDC 3,http://links.lww.com/TP/B38), one of only six tools to evaluate the quality of nonrandomized studies deemed appropriate for use in systematic reviews (90). Quality assessment was performed on the most recent full publication for each study. Where studies were only reported in abstract form, quality assessment was not possible.

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Synthesis of Results

A narrative synthesis was performed because a lack of high-quality randomized studies precluded meta-analysis. Results are presented in a hierarchical order based on the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence (91).

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ACKNOWLEDGMENT

The authors thank Professor Kazunari Tanabe (Tokyo Women’s Medical University, Tokyo, Japan), Professor Gunnar Tydén (Karolinska University Hospital, Stockholm, Sweden) and Dr Santosh Waigankar and Professor Shriram Joshi (Jaslok Hospital and Research Centre, Mumbai, India) for responding to their requests for further information relating to their experiences of the use of rituximab.

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Keywords:

Renal; Transplantation; Rituximab; Desensitization

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