Int Urol Nephrol (2014) 46:1225–1230 DOI 10.1007/s11255-013-0599-4
NEPHROLOGY - ORIGINAL PAPER
Clinical efficacy of rituximab for acute rejection in kidney transplantation: a meta-analysis Yu-gang Zhao • Bing-yi Shi • Ye-yong Qian Hong-wei Bai • Li Xiao • Xiu-yun He
•
Received: 15 September 2013 / Accepted: 30 October 2013 / Published online: 17 November 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract Objectives This meta-analysis was undertaken to compare the efficacy and safety of pretransplant treatment with rituximab in sensitized patients receiving kidney transplantation. Methods PubMed, EMBASE, and Cochrane databases were searched to identify studies that used pretransplantation rituximab in eligible patients. The major outcomes included antibody-mediated rejections (AMR) after kidney transplantation and one-year graft survival rate. The metaanalysis was performed using fixed-effects model. Results Seven studies were identified including a total of 589 patients, of whom 312 were treated without rituximab, while 277 were treated with rituximab. In our meta-analysis, patients treated with rituximab had significantly fewer AMR after kidney transplantation [odds ratio (OR) 0.52, 95 % CI 0.28, 0.98, P = 0.04] and higher rate of oneyear graft survival rates (OR 3.02, 95 % CI 1.14, 8.02, P = 0.03), indicating that rituximab is effective against acute rejection and enhances graft survival in kidney transplantation. No differences were noted in other efficacy and safety parameters in these two patient groups. Conclusions We demonstrated that preinduction with rituximab could significantly improve AMR and graft survival rates in sensitized patients undergoing kidney transplantation. Future prospective controlled studies are warranted to further understand rituximab’s role in kidney transplantation.
Y. Zhao B. Shi (&) Y. Qian H. Bai L. Xiao X. He Organ Transplantation Institute of People’s Liberation Army, 309th Hospital of Chinese People’s Liberation Army, Heishanhu Road, Haidian District, Beijing 100091, China e-mail: [email protected]
Keywords Rituximab Kidney transplantation Acute rejection Graft survival rate
Introduction For patients with end-stage renal diseases, kidney transplantation still remains as the optimal treatment option. The underlying pathogenesis of kidney transplantation rejection is still unknown. Although T cells are usually implicated in the acute rejection process, currently, acute antibody-mediated rejection (AMR) is considered to be responsible for 27–40 % of graft loss [1, 2]. AMR may occur as early as within 3 weeks of transplantation or as late as several years after the transplantation [1, 3, 4]. Traditional anti-rejection regimens, including steroids or anti-lymphocyte antibodies, are rarely effective in treating AMR. Given the growing number of sensitized renal transplantation recipients, several approaches have been used to target antibodies in AMR. Studies have been shown that plasmapheresis (PP) or intravenous immunoglobulin (IVIg) or low-dose CMV hyperimmune globulin have provided certain benefits. However, the results are not satisfactory [1, 5–7]. Rituximab is a chimeric anti-CD20 monoclonal antibody. It has been shown to target CD20 on normal and malignant B cells but not on hematopoietic stem cells, proB cells, plasma cells, or other normal tissues [8]. It is unclear whether rituximab is the ideal induction treatment for renal transplantation in sensitized recipients. In some studies, rituximab has been shown to be effective in the treatment of AMR [9]. However, in other studies, the results were not conclusive [10]. Therefore, we undertook a systemic review and quantitative meta-analysis to evaluate the available evidence from reported studies [11–13]. The
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Int Urol Nephrol (2014) 46:1225–1230
meta-analysis will summarize the various studies of rituximab induction treatment and discuss how these results could affect clinical practice.
or did not include 1 or more of the criteria, with a high risk of bias. Sensitivity analyses were performed based on whether these quality factors were adequate, inadequate, or unclear.
Materials and methods
Data extraction
Inclusion criteria
The following information was collected for our analysis: (1) first author and publication year; (2) study design and sample size; (3) treatment regimens; (4) patient source; and (5) acute antibody-mediated rejection, acute cellular-mediated rejection, graft survival rates, serum creatinine level, GFR, and infection rates.
To be included in our meta-analysis, the studies have to meet following criteria: (1) rituximab was used as study drug in renal transplantation; (2) efficacy and safety data were provided in the study, including the total number of the subjects and the values for each index; and (3) full text of the study must be accessible. A study will be excluded if these inclusion criteria were not met. Search strategy PubMed, EMBASE database, and the Cochrane Controlled Trial Register have been searched till August 2013 for available studies. In addition to full publications, abstracts presented at conferences were also included. Furthermore, all studies retrieved and the reference lists of these studies were also included in our database. The following search terms were used: sensitization, renal transplantation, antibody-mediated rejection, acute rejection, rituximab, and induction. No language restriction was placed in our search. If the same study had been published in various journals or in different years, only the most recent publication was selected for our analysis. If multiple studies had been published by the same group of researchers using different experiments, then each study was included in the analysis. If there was a disagreement in terms of whether a particular study should be included in the study, all authors participated in the discussion, and group consensus was followed. Quality assessment Each study was evaluated for methodological quality according to its randomization process, concealment of allocation procedures, blinding, data loss due to attrition, and whether the sample size meets the requirement for the statistical analysis. Guidelines in the Cochrane Handbook for Systematic Reviews of Interventions 5.0.25 was used to direct the qualitative classification of the studies. The following three broad quality categories were used for study rating and assignment based on the quality assessment criteria: (1) the study met all quality criteria adequately, with a low risk of bias; (2) the study partially met or was unclear of 1 or more quality criteria, with a moderate risk of bias; or (3) the study did not meet or inadequately met,
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Statistical analysis and ethic considerations The data were examined using Review Manager 5.0.25 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). Fixed-effect model was used in the statistical analysis of AMR and graft survival rates. There was no ethical/legal conflicts involved in the article.
Results Selection of the trials The literature search with additional references obtained from the retrieved studies uncovered 46 potential articles, 23 from PubMed and 23 from EMBASE database. Based on prespecified inclusion and exclusion criteria, 37 articles were excluded after reading the titles and abstracts of the articles. Of these 37 articles, 6 were excluded due to duplication, 30 were excluded due to being either a simple case report or not directly comparing rituximab induction vs. no rituximab induction. Among the remaining 9 articles, 1 article was excluded because it is related to pediatric renal transplant. Another 1 article was also excluded since HLA mismatch yet not ABO mismatch/incompatible was used as enrollment criteria in the study. In the end, a total of 7 studies were eligible for inclusion in our analysis [10– 16] (Fig. 1). Characteristics of individual studies Table 1 summarizes the baseline characteristics of all included studies. The total number of patients per study ranged from 40 to 144, with a total of 589 patients accrued. Three hundred and twelve patients were treated without rituximab, while 277 patients were treated with rituximab. The dosing of rituximab ranged from 100 to 1,000 mg one dose to 375 mg/m2 repeated based on CD19? cell count. In some studies, IVIg, PP, mycophenolate mofetil (MMF),
Int Urol Nephrol (2014) 46:1225–1230
1227
Graft survival rate Total 46 articles identified: -- Pubmed:23 -- EMBASE: 23
On the bases of title and abstracts, 37 articles were excluded according to the inclusion and exclusion criteria
9 relevant articles included
1 article was excluded because it is about pediatric renal transplant
8 relevant articles included
1 article was excluded because the patients were HLA – mismatch not ABO mismatch/incompatible
7 studies were included in the final analysis
Fig. 1 Flow chart illustrating the selection of studies for this metaanalysis
tacrolimus (TAC), or rabbit anti-thymocyte globulin were used in the control groups or in the rituximab-treated groups, or both. In most studies, rejection episodes, especially acute antibody-mediated rejection and/or acute cellular-mediated rejection, were reported. Transplantation survival rates, renal functions, and CMV infection incidence were also reported in some studies. Among the seven studies included in the analysis, four were specified as retrospective studies [10–12, 14]; one was reported as long-term outcome [13]; two did not specify its prospective or retrospective design [15, 16]. Efficacy Acute AMR Antibody-mediated rejections were reported in 5 studies [10–13, 16]. For the induction before renal transplantation, the AMR ranged from 0 to 30 % in patients treated with rituximab versus 7.4–50 % in patients without rituximab induction. More specifically, AMR were experienced by 17 of 182 subjects in the rituximab group and 37 of 212 in the control groups. In our meta-analysis, patients treated with rituximab had significantly fewer AMR (i.e., acute rejection) after kidney transplantation [odds ratio (OR) 0.52, 95 % CI 0.28, 0.98, P = 0.04], indicating that rituximab is effective against acute rejection in kidney transplantation (Fig. 2).
Four of the seven studies [13–16] reported one-year graft survival rate, ranged from 90 to 100 % in the rituximabtreated groups versus 60–100 % in the control groups. In another study, two-year graft survival rate was reported as 100 % in the rituximab-treated patients versus 98 % in the control group [10]. Data revealed that 160 out of 165 patients in the rituximab group versus 167 out of 183 patients in the control groups survived at one-year followup. Our meta-analysis showed that patients treated with rituximab had higher rate of one-year graft survival after kidney transplantation (OR 3.02, 95 % CI 1.14, 8.02, P = 0.03), indicating that rituximab enhances the survival of grafts in kidney transplantation (Fig. 3). Patient survival data were only available in one of the studies included in our meta-analysis. In this study, survival rate was reported as 90 % in patients treated with rituximab (n = 20) and 80–100 % in patients treated without rituximab induction (n = 20) [16]. Publication bias assessment Begg’s funnel plot was performed to access qualitative publication bias of the studies. The results showed that there was no evidence of obvious asymmetry (Fig. 4). Therefore, no bias of publications was found.
Discussion It is known that AMR is likely to occur in highly sensitized patients who develop de novo allospecific antibodies [17]. Acute AMR is associated with acute tissue injury and is likely to be antibody- and complement-mediated. A recent study showed a decreased risk of acute AMR with terminal complement pathway inhibition. However, despite the advancement of knowledge of the diagnosis and pathophysiology of AMR, evidence that support existing treatments is poor. Several treatment modalities have been recommended by KIDNEY DISEASE | IMPROVING GLOBAL OUTCOMES guidelines, including corticosteroids, PP, IVIg, anti-CD20 antibodies, and lymphocytedepleting antibodies [18]. In addition, various recent reviews have discussed advantage and disadvantages of treatment options for AMR. However, no consensus has been reached based on randomized control trials. In addition to treating acute AMR, achieving long-term graft survival is another important goal for renal transplantation. It has been demonstrated that even in patients without AMR, graft survival rate of patients with positive donorspecific alloantibodies (DSA) remains lower compared with those without DSAs [19].
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123 ATG, OKT3, or Campath, PP
rATG
TAC, MMF, mPD, and basiliximab
27 16 72 69 10 10 10 10 28 26 20g 10g 50g 30g NR
7.4 0 NR
8.3 6.8
15.9 4.0
19.6 16.6
AMR, acute (%)
32 8
14.8 18.8 9.7 5.2 NR
23.3 8.2
9.5 4.0
NR
CMR, acute (%)
100 98.3 90 90 80 90 60h 90j
NR
1 year: 96.8 versus 100 %; 3 year: 94.9 versus 100 %; 5 year: 90.3 versus 100 %
NR
Graft survival rate
1.4 1.4 1.8 1.3 1.8 1.8
NR
NR
± ± ± ± ± ±
0.4 0.3 1.3 0.2 2.6 1.2
1.27 ± 0.43 1.31 ± 0.48
1.33 1.23
NR
Serum creatinine (mg/dL), 1 year
31.3 ± 30.01 42.0 ± 22.3
NR
NR
NR
59 ± 10.5e 52.7 ± 17.0e NR NR
29 26
44.4 26
No difference between two groups
CMV infection
NR
NR
43 ± 16 54 ± 16
GFR (mL/min/ 1.73 m2), 1 year
ACR acute cellular rejection, AMR antibody-mediated rejection, CKT compatible, GFR glomerular filtration rate, IKT incompatible, MMF mycophenolate mofetil, mPD methylprednisolone, NR not reported, PP plasmapheresis, TAC tacrolimus, rATG rabbit anti-thymocyte globulin a At 1 year post-transplantation, patients had lower chronic AMR (41.3 vs. 13.3 %, P = 0.03). Four patients in IVIg group and 2 patients in the IVIg ? rituximab group lost their grafts during follow-up period GFR b No differences were found in BK virus infections (0 vs. 2.6 %, P = 0.53) and leukopenia (24 vs. 23 %, P = 0.25) (in the control group vs rituximab group). For ABO-CKT patients, rituximab-treated patients had significantly less the number of total rejection (4.3 vs. 34 %, P \ 0.05) and AMR (4.3 vs. 24 %, P = 0.05) versus control group c Two-year graft survival rates were 100 versus 98 % d Acute rejection episodes occurred in the control group versus rituximab group were 29.6 versus 18.8 %, P = 0.494 e Reported as 9-month data f All patients except 11 were treated with a combination of tacrolimus (FK506), MMF, and methylprednisolone (mPD) after two doses of basiliximab g Reported as acute rejection rates h Reported as two-year rates
Kaposztas 2008
Ejaz2013
Baek 2011f
Song 2012d NR
66 78
PP
Takagi 2010b,c
Control, rituximab 200 mg (n = 50), 300 mg (n = 1), 600 mg (n = 27) Control, rituximab (375 mg/m2 one dose) Control, rituximab (200 mg or 500 mg) rATG, rATG ? rituximab, rATG ? bortezomib, rATG ? bortezomib ? rituximab PP without rituximab PP with rituximab
63 50
NR
Fuchinoue 2011
36 18
10 days ATG or intravenous basiliximab
IVIg, IVIg ? PP ? rituximab (375 mg/m2 repeated depending on CD19? cell count) Control, rituximab 100 mg (n = 6) 200 mg (n = 26) 500 – 1,000 mg (n = 18)
Loupy 2010a
N
Additional induction therapy
Interventions
Study
Table 1 Basic characteristics of included studies
1228 Int Urol Nephrol (2014) 46:1225–1230
Int Urol Nephrol (2014) 46:1225–1230
1229 Rituximab
Control
Odds Ratio
Events Total Events Total Weight
Study or Subgroup Ejaz 2013
4
20
7
20
20.1%
0.46 [0.11, 1.94]
Fuchinoue 2011
2
50
10
63
30.5%
0.22 [0.05, 1.06]
Loupy 2010
3
18
7
36
13.9%
0.83 [0.19, 3.67]
Song 2012
3
16
8
27
17.3%
0.55 [0.12, 2.46]
Takagi 2010
5
78
5
66
18.2%
0.84 [0.23, 3.02]
212 100.0%
0.52 [0.28, 0.98]
182
Total (95% CI)
M-H, Fixed, 95% CI
37
17
Total events
Odds Ratio
M-H, Fixed, 95% CI
Heterogeneity: Chi 2 = 2.07, df = 4 (P = 0.72); I 2 = 0%
0.01
Test for overall effect: Z = 2.01 (P = 0.04)
0.1
1
10
100
Favours [Rituximab] Favours [control]
Fig. 2 Forest plot of meta-analysis on AMR episodes. The diamond stood for pooled effect
Rituximab
Control
Odds Ratio
Events Total Events Total Weight
Study or Subgroup Baek 2011
68
69
72
72
30.3%
0.31 [0.01, 7.86]
Ejaz 2013
18
20
17
20
33.9%
1.59 [0.24, 10.70]
Fuchinoue 2011
50
50
61
63
10.7%
4.11 [0.19, 87.48]
Kaposztas 2009
24
26
17
28
25.1%
7.76 [1.52, 39.62]
183 100.0%
3.02 [1.14, 8.02]
165
Total (95% CI)
M-H, Fixed, 95% CI
167
160
Total events
Odds Ratio
M-H, Fixed, 95% CI
Heterogeneity: Chi 2 = 3.66, df = 3 (P = 0.30); I2 = 18%
0.01
Test for overall effect: Z = 2.22 (P = 0.03)
0.1
1
10
100
Favours [Rituximab] Favours [control]
Standard error/Mean difference
Fig. 3 Forest plot of meta-analysis on graft survival rates. The diamond stood for pooled effect
0
SE(log[OR])
0.2
0.4
0.6
0.8
OR 1 0.01
0.1
1
10
100
Mean difference
Fig. 4 Funnel plot of the studies represented in the meta-analysis
With improved understanding of the role of B cells in graft rejection, rituximab has been explored for its roles in the treatment of acute allograft rejection [20–24]. Recent pilot experience with rituximab, aimed at depleting this B-cell pool, has demonstrated efficacy in ABO-incompatible transplantation [25–28]. Furthermore, rituximab with adjunctive immunosuppression may have been effective in improving the Banff grade of rejection and may positively impact graft function recovery [29]. It has been hypothesized that the beneficial effects of rituximab in AMR were associated with a
different mechanism. Therefore, rituximab may be able to be effective in treating both cellular and humoral rejections. However, recently several studies showed conflict data of rituximab in early AMR and long-term survival in kidney transplantation. None of these published studies were prospective randomized controlled study. For some studies, the sample sizes were not large enough to obtain significant results. Therefore, we conducted a systematic review of the literature to determine the efficacy of rituximab treatments for acute AMR in kidney transplantation, with the hope to provide directions for clinical practice. We also wish to identify priorities for future research in the treatment of AMR. In our meta-analysis, we demonstrated that patients treated with rituximab had significantly fewer AMR after kidney transplantation (OR 0.52, 95 % CI 0.28, 0.98, P = 0.04). In addition, patients treated with rituximab had higher rate of one-year graft survival after kidney transplantation (OR 3.02, 95 % CI 1.14, 8.02, P = 0.03). Our results indicated that rituximab is not only effective against acute rejection but also enhances the survival of grafts in kidney transplantation. On the other hand, no significant differences were noted in renal functions and infection rates. While we believe our analysis is valid and credible, as with all meta-analyses, it is important to consider certain caveats.
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Publication bias may exist and influence the results. Even though our funnel plot did not provide any evidence of publication bias, it is likely that some relevant negative data had not been published. The quality of the studies used for the meta-analysis is low. As mentioned above, none of the studies included were prospective randomized study. In addition, we analyzed the efficacy and safety of rituximab induction in sensitized patients receiving kidney transplantation regardless of additional induction regimen. Even though some induction regimens were captured in some studies (Table 1), due to the small eligible study amount, it is not feasible for additional analysis based on different induction therapies. A more detailed analysis may further direct treatment decisions once more clinical data are available. In conclusion, we demonstrated that pretransplantation induction with rituximab could significantly decrease AMR and increase graft survival rates in sensitized patients undergoing kidney transplantation. Future prospective controlled studies are warranted to further understand rituximab’s role in kidney transplantation. Combination with existing treatment regimens may be an effective strategy to decrease complications, inconvenience, and expenses. Acknowledgments This work was supported by the Key Projects in the National Science and Technology Pillar Program in the Eleventh Five-year Plan Period (2008BAI60B04) from Chinese ministry of science and technology.
References 1. Mauiyyedi S, Colvin RB (2002) Humoral rejection in kidney transplantation: new concepts in diagnosis and treatment. Curr Opin Nephrol Hypertens 11:609–618 2. Faguer S, Kamar N, Guilbeaud-Frugier C et al (2007) Rituximab therapy for acute humoral rejection after kidney transplantation. Transplantation 83:1277–1280 3. Mauiyyedi S, Crespo M, Collins AB et al (2002) Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification. J Am Soc Nephrol 13:779 4. Sun Q, Liu ZH, Ji S et al (2006) Late and early C4d-positive acute rejection: different clinico-histopathological subentities in renal transplantation. Kidney Int 70:377–383 5. White NB, Greenstein SM, Cantafio AW et al (2004) Successful rescue therapy with plasmapheresis and intravenous immunoglobulin for acute humoral renal transplant rejection. Transplantation 78:772–774 6. Lehrich RW, Rocha PN, Reinsmoen N et al (2005) Intravenous immunoglobulin and plasmapheresis in acute humoral rejection: experience in renal allograft transplantation. Hum Immunol 66:350–358 7. Jordan SC, Quartel AW, Czer LS et al (1998) Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action. Transplantation 66:800–805 8. Becker YT, Becker BN, Pirsch JD et al (2004) Rituximab as treatment for refractory kidney transplant rejection. Am J Transplant 4:996–1001
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Int Urol Nephrol (2014) 46:1225–1230 9. Lefaucheur C, Nochy D, Andrade J et al (2009) Comparison of combination plasmapheresis/IVIg/anti-CD20 versus high-dose IVIg in the treatment of antibody-mediated rejection. Am J Transplant 9:1099–1107 10. Takagi T, Ishida H, Shirakawa H et al (2010) Evaluation of lowdose rituximab induction therapy in living related kidney transplantation. Transplantation 89(12):1466–1470 11. Song YH, Huh KH, Kim YS et al (2012) Impact of pretransplant rituximab induction on highly sensitized kidney recipients: comparison with non-rituximab group. J Korean Surg Soc 82(6):335–359 12. Loupy A, Suberbielle-Boissel C, Zuber J et al (2010) Combined posttransplant prophylactic IVIg/anti-CD 20/plasmapheresis in kidney recipients with preformed donor-specific antibodies: a pilot study. Transplantation 89(11):1403–1410 13. Fuchinoue S, Ishii Y, Sawada T et al (2011) The 5-year outcome of ABO-incompatible kidney transplantation with rituximab induction. Transplantation 91(8):853–857 14. Kaposztas Z, Podder H, Mauiyyedi S et al (2009) Impact of rituximab therapy for treatment of acute humoral rejection. Clin Transplant 23(1):63–73 15. Baek CH, Park KS, Han DJ et al (2011) Lower dose of mycophenolate mofetil is enough for rituximab treated renal transplant patients. Transpl Int 24(Suppl 2):341 16. Ejaz N, Shields A, Alloway R, et al. (2013) Prospective, randomized pilot study of B-cell targeted induction therapy in sensitized kidney transplant recipients: final report. Presented at American Transplant Congress, Abstract number: 175 17. Cornell LD (2013) Renal allograft pathology in the sensitized patient. Curr Opin Organ Transplant 18(3):327–336 18. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group (2009) KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 9(Suppl 3):S1–S155 19. Colvin RB (2007) Antibody-mediated renal allograft rejection: diagnosis and pathogenesis. J Am Soc Nephrol 18:1046–1056 20. Sis B, Halloran PF (2010) Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection. Curr Opin Organ Transplant 15(1):42–48 21. Kayler LK, Kiss L, Sharma V et al (2008) Acute renal allograft rejection: diagnostic significance of focal peritubular capillary C4d. Transplantation 85(6):813–820 22. Montgomery RA, Zachary AA, Racusen LC et al (2000) Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation 70(6):887–895 23. Stegall MD, Diwan T, Raghavaiah S et al (2011) Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant 11(11):2405–2413 24. Crespo M, Pascual M, Tolkoff-Rubin N et al (2001) Acute humoral rejection in renal allograft recipients: I. Incidence, serology and clinical characteristics. Transplantation 71(5):652–658 25. Egawa H, Teramukai S, Haga H et al (2008) Present status of ABO-incompatible living donor liver transplantation in Japan. Hepatology 47:143–152 26. Tanabe K, Takahashi K, Sonda K et al (1998) Long-term results of ABO incompatible living kidney transplantation: a singlecenter experience. Transplantation 65:224–228 27. Watson R, Kozlowski T, Nickeleit V et al (2006) Isolated donor specific alloantibody-mediated rejection after ABO compatible liver transplantation. Am J Transplant 6:3022–3029 28. Usuda M, Fujimori K, Koyamada N et al (2005) Successful use of anti-CD20 monoclonal antibody (rituximab) for ABO-incompatible living related-liver transplantation. Transplantation 79:12–16 29. Zarkhina V, Lia V, Kambhamb N et al (2008) A randomized, prospective trial of rituximab for acute rejection in pediatric renal transplantation. Am J Transplant 8:2607–2617
NEPHROLOGY - ORIGINAL PAPER
Clinical efficacy of rituximab for acute rejection in kidney transplantation: a meta-analysis Yu-gang Zhao • Bing-yi Shi • Ye-yong Qian Hong-wei Bai • Li Xiao • Xiu-yun He
•
Received: 15 September 2013 / Accepted: 30 October 2013 / Published online: 17 November 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract Objectives This meta-analysis was undertaken to compare the efficacy and safety of pretransplant treatment with rituximab in sensitized patients receiving kidney transplantation. Methods PubMed, EMBASE, and Cochrane databases were searched to identify studies that used pretransplantation rituximab in eligible patients. The major outcomes included antibody-mediated rejections (AMR) after kidney transplantation and one-year graft survival rate. The metaanalysis was performed using fixed-effects model. Results Seven studies were identified including a total of 589 patients, of whom 312 were treated without rituximab, while 277 were treated with rituximab. In our meta-analysis, patients treated with rituximab had significantly fewer AMR after kidney transplantation [odds ratio (OR) 0.52, 95 % CI 0.28, 0.98, P = 0.04] and higher rate of oneyear graft survival rates (OR 3.02, 95 % CI 1.14, 8.02, P = 0.03), indicating that rituximab is effective against acute rejection and enhances graft survival in kidney transplantation. No differences were noted in other efficacy and safety parameters in these two patient groups. Conclusions We demonstrated that preinduction with rituximab could significantly improve AMR and graft survival rates in sensitized patients undergoing kidney transplantation. Future prospective controlled studies are warranted to further understand rituximab’s role in kidney transplantation.
Y. Zhao B. Shi (&) Y. Qian H. Bai L. Xiao X. He Organ Transplantation Institute of People’s Liberation Army, 309th Hospital of Chinese People’s Liberation Army, Heishanhu Road, Haidian District, Beijing 100091, China e-mail: [email protected]
Keywords Rituximab Kidney transplantation Acute rejection Graft survival rate
Introduction For patients with end-stage renal diseases, kidney transplantation still remains as the optimal treatment option. The underlying pathogenesis of kidney transplantation rejection is still unknown. Although T cells are usually implicated in the acute rejection process, currently, acute antibody-mediated rejection (AMR) is considered to be responsible for 27–40 % of graft loss [1, 2]. AMR may occur as early as within 3 weeks of transplantation or as late as several years after the transplantation [1, 3, 4]. Traditional anti-rejection regimens, including steroids or anti-lymphocyte antibodies, are rarely effective in treating AMR. Given the growing number of sensitized renal transplantation recipients, several approaches have been used to target antibodies in AMR. Studies have been shown that plasmapheresis (PP) or intravenous immunoglobulin (IVIg) or low-dose CMV hyperimmune globulin have provided certain benefits. However, the results are not satisfactory [1, 5–7]. Rituximab is a chimeric anti-CD20 monoclonal antibody. It has been shown to target CD20 on normal and malignant B cells but not on hematopoietic stem cells, proB cells, plasma cells, or other normal tissues [8]. It is unclear whether rituximab is the ideal induction treatment for renal transplantation in sensitized recipients. In some studies, rituximab has been shown to be effective in the treatment of AMR [9]. However, in other studies, the results were not conclusive [10]. Therefore, we undertook a systemic review and quantitative meta-analysis to evaluate the available evidence from reported studies [11–13]. The
123
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Int Urol Nephrol (2014) 46:1225–1230
meta-analysis will summarize the various studies of rituximab induction treatment and discuss how these results could affect clinical practice.
or did not include 1 or more of the criteria, with a high risk of bias. Sensitivity analyses were performed based on whether these quality factors were adequate, inadequate, or unclear.
Materials and methods
Data extraction
Inclusion criteria
The following information was collected for our analysis: (1) first author and publication year; (2) study design and sample size; (3) treatment regimens; (4) patient source; and (5) acute antibody-mediated rejection, acute cellular-mediated rejection, graft survival rates, serum creatinine level, GFR, and infection rates.
To be included in our meta-analysis, the studies have to meet following criteria: (1) rituximab was used as study drug in renal transplantation; (2) efficacy and safety data were provided in the study, including the total number of the subjects and the values for each index; and (3) full text of the study must be accessible. A study will be excluded if these inclusion criteria were not met. Search strategy PubMed, EMBASE database, and the Cochrane Controlled Trial Register have been searched till August 2013 for available studies. In addition to full publications, abstracts presented at conferences were also included. Furthermore, all studies retrieved and the reference lists of these studies were also included in our database. The following search terms were used: sensitization, renal transplantation, antibody-mediated rejection, acute rejection, rituximab, and induction. No language restriction was placed in our search. If the same study had been published in various journals or in different years, only the most recent publication was selected for our analysis. If multiple studies had been published by the same group of researchers using different experiments, then each study was included in the analysis. If there was a disagreement in terms of whether a particular study should be included in the study, all authors participated in the discussion, and group consensus was followed. Quality assessment Each study was evaluated for methodological quality according to its randomization process, concealment of allocation procedures, blinding, data loss due to attrition, and whether the sample size meets the requirement for the statistical analysis. Guidelines in the Cochrane Handbook for Systematic Reviews of Interventions 5.0.25 was used to direct the qualitative classification of the studies. The following three broad quality categories were used for study rating and assignment based on the quality assessment criteria: (1) the study met all quality criteria adequately, with a low risk of bias; (2) the study partially met or was unclear of 1 or more quality criteria, with a moderate risk of bias; or (3) the study did not meet or inadequately met,
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Statistical analysis and ethic considerations The data were examined using Review Manager 5.0.25 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). Fixed-effect model was used in the statistical analysis of AMR and graft survival rates. There was no ethical/legal conflicts involved in the article.
Results Selection of the trials The literature search with additional references obtained from the retrieved studies uncovered 46 potential articles, 23 from PubMed and 23 from EMBASE database. Based on prespecified inclusion and exclusion criteria, 37 articles were excluded after reading the titles and abstracts of the articles. Of these 37 articles, 6 were excluded due to duplication, 30 were excluded due to being either a simple case report or not directly comparing rituximab induction vs. no rituximab induction. Among the remaining 9 articles, 1 article was excluded because it is related to pediatric renal transplant. Another 1 article was also excluded since HLA mismatch yet not ABO mismatch/incompatible was used as enrollment criteria in the study. In the end, a total of 7 studies were eligible for inclusion in our analysis [10– 16] (Fig. 1). Characteristics of individual studies Table 1 summarizes the baseline characteristics of all included studies. The total number of patients per study ranged from 40 to 144, with a total of 589 patients accrued. Three hundred and twelve patients were treated without rituximab, while 277 patients were treated with rituximab. The dosing of rituximab ranged from 100 to 1,000 mg one dose to 375 mg/m2 repeated based on CD19? cell count. In some studies, IVIg, PP, mycophenolate mofetil (MMF),
Int Urol Nephrol (2014) 46:1225–1230
1227
Graft survival rate Total 46 articles identified: -- Pubmed:23 -- EMBASE: 23
On the bases of title and abstracts, 37 articles were excluded according to the inclusion and exclusion criteria
9 relevant articles included
1 article was excluded because it is about pediatric renal transplant
8 relevant articles included
1 article was excluded because the patients were HLA – mismatch not ABO mismatch/incompatible
7 studies were included in the final analysis
Fig. 1 Flow chart illustrating the selection of studies for this metaanalysis
tacrolimus (TAC), or rabbit anti-thymocyte globulin were used in the control groups or in the rituximab-treated groups, or both. In most studies, rejection episodes, especially acute antibody-mediated rejection and/or acute cellular-mediated rejection, were reported. Transplantation survival rates, renal functions, and CMV infection incidence were also reported in some studies. Among the seven studies included in the analysis, four were specified as retrospective studies [10–12, 14]; one was reported as long-term outcome [13]; two did not specify its prospective or retrospective design [15, 16]. Efficacy Acute AMR Antibody-mediated rejections were reported in 5 studies [10–13, 16]. For the induction before renal transplantation, the AMR ranged from 0 to 30 % in patients treated with rituximab versus 7.4–50 % in patients without rituximab induction. More specifically, AMR were experienced by 17 of 182 subjects in the rituximab group and 37 of 212 in the control groups. In our meta-analysis, patients treated with rituximab had significantly fewer AMR (i.e., acute rejection) after kidney transplantation [odds ratio (OR) 0.52, 95 % CI 0.28, 0.98, P = 0.04], indicating that rituximab is effective against acute rejection in kidney transplantation (Fig. 2).
Four of the seven studies [13–16] reported one-year graft survival rate, ranged from 90 to 100 % in the rituximabtreated groups versus 60–100 % in the control groups. In another study, two-year graft survival rate was reported as 100 % in the rituximab-treated patients versus 98 % in the control group [10]. Data revealed that 160 out of 165 patients in the rituximab group versus 167 out of 183 patients in the control groups survived at one-year followup. Our meta-analysis showed that patients treated with rituximab had higher rate of one-year graft survival after kidney transplantation (OR 3.02, 95 % CI 1.14, 8.02, P = 0.03), indicating that rituximab enhances the survival of grafts in kidney transplantation (Fig. 3). Patient survival data were only available in one of the studies included in our meta-analysis. In this study, survival rate was reported as 90 % in patients treated with rituximab (n = 20) and 80–100 % in patients treated without rituximab induction (n = 20) [16]. Publication bias assessment Begg’s funnel plot was performed to access qualitative publication bias of the studies. The results showed that there was no evidence of obvious asymmetry (Fig. 4). Therefore, no bias of publications was found.
Discussion It is known that AMR is likely to occur in highly sensitized patients who develop de novo allospecific antibodies [17]. Acute AMR is associated with acute tissue injury and is likely to be antibody- and complement-mediated. A recent study showed a decreased risk of acute AMR with terminal complement pathway inhibition. However, despite the advancement of knowledge of the diagnosis and pathophysiology of AMR, evidence that support existing treatments is poor. Several treatment modalities have been recommended by KIDNEY DISEASE | IMPROVING GLOBAL OUTCOMES guidelines, including corticosteroids, PP, IVIg, anti-CD20 antibodies, and lymphocytedepleting antibodies [18]. In addition, various recent reviews have discussed advantage and disadvantages of treatment options for AMR. However, no consensus has been reached based on randomized control trials. In addition to treating acute AMR, achieving long-term graft survival is another important goal for renal transplantation. It has been demonstrated that even in patients without AMR, graft survival rate of patients with positive donorspecific alloantibodies (DSA) remains lower compared with those without DSAs [19].
123
123 ATG, OKT3, or Campath, PP
rATG
TAC, MMF, mPD, and basiliximab
27 16 72 69 10 10 10 10 28 26 20g 10g 50g 30g NR
7.4 0 NR
8.3 6.8
15.9 4.0
19.6 16.6
AMR, acute (%)
32 8
14.8 18.8 9.7 5.2 NR
23.3 8.2
9.5 4.0
NR
CMR, acute (%)
100 98.3 90 90 80 90 60h 90j
NR
1 year: 96.8 versus 100 %; 3 year: 94.9 versus 100 %; 5 year: 90.3 versus 100 %
NR
Graft survival rate
1.4 1.4 1.8 1.3 1.8 1.8
NR
NR
± ± ± ± ± ±
0.4 0.3 1.3 0.2 2.6 1.2
1.27 ± 0.43 1.31 ± 0.48
1.33 1.23
NR
Serum creatinine (mg/dL), 1 year
31.3 ± 30.01 42.0 ± 22.3
NR
NR
NR
59 ± 10.5e 52.7 ± 17.0e NR NR
29 26
44.4 26
No difference between two groups
CMV infection
NR
NR
43 ± 16 54 ± 16
GFR (mL/min/ 1.73 m2), 1 year
ACR acute cellular rejection, AMR antibody-mediated rejection, CKT compatible, GFR glomerular filtration rate, IKT incompatible, MMF mycophenolate mofetil, mPD methylprednisolone, NR not reported, PP plasmapheresis, TAC tacrolimus, rATG rabbit anti-thymocyte globulin a At 1 year post-transplantation, patients had lower chronic AMR (41.3 vs. 13.3 %, P = 0.03). Four patients in IVIg group and 2 patients in the IVIg ? rituximab group lost their grafts during follow-up period GFR b No differences were found in BK virus infections (0 vs. 2.6 %, P = 0.53) and leukopenia (24 vs. 23 %, P = 0.25) (in the control group vs rituximab group). For ABO-CKT patients, rituximab-treated patients had significantly less the number of total rejection (4.3 vs. 34 %, P \ 0.05) and AMR (4.3 vs. 24 %, P = 0.05) versus control group c Two-year graft survival rates were 100 versus 98 % d Acute rejection episodes occurred in the control group versus rituximab group were 29.6 versus 18.8 %, P = 0.494 e Reported as 9-month data f All patients except 11 were treated with a combination of tacrolimus (FK506), MMF, and methylprednisolone (mPD) after two doses of basiliximab g Reported as acute rejection rates h Reported as two-year rates
Kaposztas 2008
Ejaz2013
Baek 2011f
Song 2012d NR
66 78
PP
Takagi 2010b,c
Control, rituximab 200 mg (n = 50), 300 mg (n = 1), 600 mg (n = 27) Control, rituximab (375 mg/m2 one dose) Control, rituximab (200 mg or 500 mg) rATG, rATG ? rituximab, rATG ? bortezomib, rATG ? bortezomib ? rituximab PP without rituximab PP with rituximab
63 50
NR
Fuchinoue 2011
36 18
10 days ATG or intravenous basiliximab
IVIg, IVIg ? PP ? rituximab (375 mg/m2 repeated depending on CD19? cell count) Control, rituximab 100 mg (n = 6) 200 mg (n = 26) 500 – 1,000 mg (n = 18)
Loupy 2010a
N
Additional induction therapy
Interventions
Study
Table 1 Basic characteristics of included studies
1228 Int Urol Nephrol (2014) 46:1225–1230
Int Urol Nephrol (2014) 46:1225–1230
1229 Rituximab
Control
Odds Ratio
Events Total Events Total Weight
Study or Subgroup Ejaz 2013
4
20
7
20
20.1%
0.46 [0.11, 1.94]
Fuchinoue 2011
2
50
10
63
30.5%
0.22 [0.05, 1.06]
Loupy 2010
3
18
7
36
13.9%
0.83 [0.19, 3.67]
Song 2012
3
16
8
27
17.3%
0.55 [0.12, 2.46]
Takagi 2010
5
78
5
66
18.2%
0.84 [0.23, 3.02]
212 100.0%
0.52 [0.28, 0.98]
182
Total (95% CI)
M-H, Fixed, 95% CI
37
17
Total events
Odds Ratio
M-H, Fixed, 95% CI
Heterogeneity: Chi 2 = 2.07, df = 4 (P = 0.72); I 2 = 0%
0.01
Test for overall effect: Z = 2.01 (P = 0.04)
0.1
1
10
100
Favours [Rituximab] Favours [control]
Fig. 2 Forest plot of meta-analysis on AMR episodes. The diamond stood for pooled effect
Rituximab
Control
Odds Ratio
Events Total Events Total Weight
Study or Subgroup Baek 2011
68
69
72
72
30.3%
0.31 [0.01, 7.86]
Ejaz 2013
18
20
17
20
33.9%
1.59 [0.24, 10.70]
Fuchinoue 2011
50
50
61
63
10.7%
4.11 [0.19, 87.48]
Kaposztas 2009
24
26
17
28
25.1%
7.76 [1.52, 39.62]
183 100.0%
3.02 [1.14, 8.02]
165
Total (95% CI)
M-H, Fixed, 95% CI
167
160
Total events
Odds Ratio
M-H, Fixed, 95% CI
Heterogeneity: Chi 2 = 3.66, df = 3 (P = 0.30); I2 = 18%
0.01
Test for overall effect: Z = 2.22 (P = 0.03)
0.1
1
10
100
Favours [Rituximab] Favours [control]
Standard error/Mean difference
Fig. 3 Forest plot of meta-analysis on graft survival rates. The diamond stood for pooled effect
0
SE(log[OR])
0.2
0.4
0.6
0.8
OR 1 0.01
0.1
1
10
100
Mean difference
Fig. 4 Funnel plot of the studies represented in the meta-analysis
With improved understanding of the role of B cells in graft rejection, rituximab has been explored for its roles in the treatment of acute allograft rejection [20–24]. Recent pilot experience with rituximab, aimed at depleting this B-cell pool, has demonstrated efficacy in ABO-incompatible transplantation [25–28]. Furthermore, rituximab with adjunctive immunosuppression may have been effective in improving the Banff grade of rejection and may positively impact graft function recovery [29]. It has been hypothesized that the beneficial effects of rituximab in AMR were associated with a
different mechanism. Therefore, rituximab may be able to be effective in treating both cellular and humoral rejections. However, recently several studies showed conflict data of rituximab in early AMR and long-term survival in kidney transplantation. None of these published studies were prospective randomized controlled study. For some studies, the sample sizes were not large enough to obtain significant results. Therefore, we conducted a systematic review of the literature to determine the efficacy of rituximab treatments for acute AMR in kidney transplantation, with the hope to provide directions for clinical practice. We also wish to identify priorities for future research in the treatment of AMR. In our meta-analysis, we demonstrated that patients treated with rituximab had significantly fewer AMR after kidney transplantation (OR 0.52, 95 % CI 0.28, 0.98, P = 0.04). In addition, patients treated with rituximab had higher rate of one-year graft survival after kidney transplantation (OR 3.02, 95 % CI 1.14, 8.02, P = 0.03). Our results indicated that rituximab is not only effective against acute rejection but also enhances the survival of grafts in kidney transplantation. On the other hand, no significant differences were noted in renal functions and infection rates. While we believe our analysis is valid and credible, as with all meta-analyses, it is important to consider certain caveats.
123
1230
Publication bias may exist and influence the results. Even though our funnel plot did not provide any evidence of publication bias, it is likely that some relevant negative data had not been published. The quality of the studies used for the meta-analysis is low. As mentioned above, none of the studies included were prospective randomized study. In addition, we analyzed the efficacy and safety of rituximab induction in sensitized patients receiving kidney transplantation regardless of additional induction regimen. Even though some induction regimens were captured in some studies (Table 1), due to the small eligible study amount, it is not feasible for additional analysis based on different induction therapies. A more detailed analysis may further direct treatment decisions once more clinical data are available. In conclusion, we demonstrated that pretransplantation induction with rituximab could significantly decrease AMR and increase graft survival rates in sensitized patients undergoing kidney transplantation. Future prospective controlled studies are warranted to further understand rituximab’s role in kidney transplantation. Combination with existing treatment regimens may be an effective strategy to decrease complications, inconvenience, and expenses. Acknowledgments This work was supported by the Key Projects in the National Science and Technology Pillar Program in the Eleventh Five-year Plan Period (2008BAI60B04) from Chinese ministry of science and technology.
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