Abstract
Background
Rituximab induces long-lasting B cell depletion in the peripheral blood and increases the levels of proinflammatory cytokines associated with regulatory B cell depletion. Previous reports showed that B cell-related cytokine release after administration of rituximab may induce acute cellular rejection (ACR) and delayed-onset neutropenia. The present study was conducted to investigate the correlation between acute rejection and delayed-onset neutropenia in ABO-incompatible renal transplant recipients who underwent administration of rituximab for 1 year after transplantation.
Material/Methods
From June 2006 to July 2015, 47 patients with chronic renal failure received ABO-incompatible renal transplant with rituximab induction at Osaka City University Hospital. All 47 patients underwent plasmapheresis due to removal of anti-A/B antibodies and administration of rituximab, and their transplants were carried out successfully. We investigated the correlation between ACR and delayed-onset neutropenia in ABO-incompatible renal transplant recipients who underwent administration of rituximab for 1 year after transplantation.
Results
Fourteen patients (29.8%) experienced ACR (group A), and 33 recipients did not develop ACR (group B). The frequency of delayed-onset neutropenia was higher in group A than in group B (p=0.0503). Multivariate logistic regression analysis revealed that the frequency of ACR correlated significantly with the prevalence of delayed-onset neutropenia.
Conclusions
Our results indicated that ACR in ABO-incompatible renal transplant recipients receiving rituximab was associated with delayed-onset neutropenia.
MeSH Keywords: ABO Blood-Group System, Graft Rejection, Kidney Transplantation, Neutropenia
Background
Living donor renal transplantation across the blood group barrier has become an alternative to ABO-compatible renal transplantation due to the insufficiency of deceased donors in Japan [1,2]. Several reports have shown that the clinical outcome of ABO-incompatible renal transplantation is not inferior to ABO-compatible renal transplantation [2,3]. It has been reported that in Japan, graft survival rates of ABO-incompatible renal transplantation were 71% and 59% at 5 and 9 years, respectively, while in the historical control, graft survival rates were 81% and 57% at 5 and 9 years, respectively [2].
Rituximab has been applied in immunosuppressive protocols for ABO-incompatible renal transplantation [1,4] and as rescue treatment for antibody-mediated rejection [5,6]. Using rituximab, we have performed successful ABO-incompatible renal transplants in recipients without splenectomy and in those with high anti-A/B antibody titers [1,3,4,7].
Rituximab induces long-lasting B cell depletion in the peripheral blood and increases the levels of proinflammatory cytokine associated with regulatory B cell depletion [8]. Patients receiving rituximab have been observed to have a higher frequency of acute cellular rejection (ACR) compared to recipients who had not received induction therapy [9]. Moreover, a recent report demonstrated a marked elevation in the levels of serum B cell activating factor, a B cell-related cytokine, in ABO-incompatible renal transplant recipients with delayed-onset neutropenia [10]. ACR in ABO-incompatible renal transplant recipients who underwent administration of rituximab may be associated with delayed-onset neutropenia [11]. Our present study was conducted to investigate the correlation between ACR and delayed-onset neutropenia in ABO-incompatible renal transplant recipients who underwent administration of rituximab for 1 year after transplantation.
Material and Methods
Patients
From June 2006 to July 2015, 47 patients with chronic renal failure underwent ABO-incompatible renal transplant with rituximab induction at our institution. These 47 recipients were enrolled as the targets in the present study. We retrospectively analyzed the relationship between ACR and delayed-onset neutropenia in ABO-incompatible renal transplant recipients receiving rituximab for 1 year after transplantation.
Immunosuppressive protocols
Previously, we reported on our standard, elderly, and high-titer immunosuppressive protocols for ABO-incompatible renal transplantation using rituximab at our institution from June 2006 to March 2012. Briefly, for the immunosuppressive protocol without splenectomy, the patients with anti-A/B titers less than 1: 512 underwent administration of 2 doses of rituximab (150 mg/m2) at 2 weeks before and on the day of transplantation (standard protocol: Figure 1) [1,3]. The recipients aged 65 years and older underwent administration of only a single dose of rituximab (150 mg/m2) at 2 weeks before transplantation to reduce its adverse events (elderly protocol: Figure 2) [12,13]. The patients with titers more than 1: 512 or with donor-specific antibody underwent both a splenectomy at transplantation and administration of 2 doses of rituximab (high-titer protocol: Figure 3) [4,7]. For removal of antibodies, the patients received 1–12 sessions (over 1 session) of plasma exchange (PE) and/or double-filtration plasmapheresis (DFPP) before renal transplantation. Adverse events due to plasmapheresis were monitored. The pretransplant desensitization regimen contained 4 weeks of mycophenolate mofetil (MMF) 1 g/day. The patients aged 65 years and older underwent administration of 0.5 g/day of MMF for 4 weeks. Post-transplant immunosuppression consisted of calcineurin inhibitor (tacrolimus or cyclosporine), MMF, steroid, and 2 doses of basiliximab. Tacrolimus or cyclosporine was initiated 3 days prior to transplantation. Tacrolimus was given to maintain a blood trough concentration of 10–13 ng/ml during the first month, and cyclosporine was given to so as to maintain a blood trough concentration of 250–300 mg/dl during the first month after transplantation. The MMF dosage after transplantation was maintained at pretransplant doses. However, it was decreased to 0.5 g/day at 2 weeks after transplantation for the recipients with anti-A/B titers less than 1: 512 to avert over-immunosuppression.
Figure 1.
Standard protocol for ABO-incompatible kidney transplantation without splenectomy. MMF – mycophenolate mofetil; PE – plasma exchange; DFPP – double filtration plasmapheresis.
Figure 2.
High-titer protocol for ABO-incompatible high-titer (more than 1: 512) kidney transplantation. MMF – mycophenolate mofetil; PE – plasma exchange; DFPP – double-filtration plasmapheresis.
Figure 3.
Elderly protocol for ABO-incompatible kidney transplantation without splenectomy in elderly recipients. MMF – mycophenolate mofetil; PE – plasma exchange; DFPP – double-filtration plasmapheresis.
Since January 2012, all patients with titers less than 1: 512 underwent administration of a single dose of rituximab at 2 weeks before transplantation (modified standard protocol: Figure 4), and MMF (1 g/day) or everolimus (1.5 mg/day or 3.0 mg/day) was started after transplantation. For removal of the anti-A/B antibodies, the patients received 1–5 sessions of PE and/or DFPP before renal transplantation [14]. All the patients provided informed consent, and the study was approved by the Institutional Review Board of Osaka City University Hospital and was in accordance with the Declaration of Helsinki (1975).
Figure 4.
Modified standard protocol for ABO-incompatible kidney transplantation without splenectomy. MMF – mycophenolate mofetil; PE – plasma exchange; DFPP – double-filtration plasmapheresis.
Adverse events in the plasma exchange procedure
For the removal of anti-A/B antibody titers, the patients underwent not only double-filtration plasmapheresis but also plasma exchange at least once. Plasma exchange was performed using fresh frozen plasma as the replacement fluid. The common adverse events in the plasma exchange procedure included symptoms due to hypercalcemia, hypovolemia, and anaphylactoid reaction. All adverse effects due to plasma exchange were collected retrospectively.
Diagnosis and treatment of acute rejection
Surveillance biopsies after renal transplantation were performed once within 3 months after transplantation in all recipients. Rejection was diagnosed by histological findings. Immunostaining for C4d in the peritubular capillaries was applied for diagnosis of antibody-mediated rejection (AMR). If rejection was suspected, we performed episode biopsy. ACR and acute AMR were confirmed based on the Banff ‘09 classification. The first line of ACR episodes consisted of methylprednisolone 500 mg/day for 3 days or in combination with deoxyspergualin (5 mg/kg/day; 5–7 days). Steroid and/or deoxyspergualin-resistant rejections were treated with muromonab CD3 (OKT-3) or anti-human thymocyte immunoglobulin. AMR was treated with plasmapheresis in combination with administration of rituximab.
Delayed-onset neutropenia and other adverse events during the 1st year after transplantation
Delayed-onset neutropenia was diagnosed as grade III to IV neutropenia occurring at least 4 weeks after the last administration of rituximab in the absence of any alternative reason to explain its occurrence. All adverse events were collected retrospectively for 1 year after transplantation.
Statistical analysis
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Australia). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics. The results are presented as mean values ± standard deviations and as proportions for categorical variables. Changes were evaluated using Student’s t-test or Mann-Whitney U-test. Categorical variables were compared using chi-squared analysis or Fisher’s exact test. Univariate associations between variables were assessed using logistic regression. Multiple logistic regression analysis using ACR as categorical variables was performed to determine the factors related to ACR. Statistical significance was defined as p<0.05.
Results
Patient characteristics
The median age of the recipients and donors was 50 years (range, 15–74 years) and 57 years (range, 25–67 years), respectively. The median HLA mismatches were 4 antigens (range, 0–6 antigens). The median dialysis period was 14 months (range, 0–180 months). The causes of chronic renal failure were chronic glomerulonephritis (n=10), diabetes mellitus nephropathy (n=4), IgA nephropathy (n=4), autosomal dominant polycystic kidney disease (n=3), and others (n=26). The median anti-A/B IgG and IgM titers were 1: 64 (range, 1: 2–1: 8196) and 1: 32 (range, 1: 2–1: 512), respectively. The patient characteristics are shown in Table 1.
Table 1.
Patient characteristics.
| n | 47 |
| Age at transplant (year) | 50 (15–74) |
| Gender (Male/Female) | 28/19 |
| Dialysis duration (months) | 14 (0–180) |
| Donor father/mother/son/daughter brother/sister spouse | 5/10/1/1 2/1 27 |
| Donor age (year) | 57 (25–67) |
| HLA mismatch | 4 (0–6) |
| Anti A/B antibody titer (IgG) | 64 (2–8192) |
| Anti A/B antibody titer (IgM) | 32 (2–512) |
Immunosuppressive protocols (Table 2)
Table 2.
Desensitization and immunosuppressive protocol.
| Standard protocol | 14 |
| A→B; 5, A→O; 1, B→A; 1, B→O; 1, AB→A; 3, AB→B; 3 | |
| Elderly protocol | 6 |
| A→O; 1, AB→B; 1, AB→O; 1, B→A; 3 | |
| High titer protocol | 10 |
| A→O; 6, A→B; 1, B→A; 1, B→O; 1 | |
| AB→A; 1 | |
| Modified standard protocol | 17 |
| A→B; 3, A→O; 3, B→A; 3, B→O; 3, AB→A; 3, AB→B; 2 | |
| Plasmapheresis (session) | 4 (1–13) |
| Dose of rituximab | 2 (1–2) |
| Splenectomy (+/−) | 10/37 |
| CsA/Tac | 28/19 |
CsA; cyclosporine, Tac; tacrolimus
Fourteen patients received the standard protocol, 10 received the high-titer protocol including both splenectomy and rituximab administration, 6 received the elderly protocol, and 17 received the modified standard protocol. The median number of plasmapheresis sessions was 4 (range, 1–13). Twenty-four recipients of the standard and high-titer protocol received 2 doses of rituximab, and 23 recipients of the elderly and modified standard protocol received a single dose of rituximab. Twenty-eight patients were under cyclosporine treatment and 19 under tacrolimus treatment.
Adverse events in the plasma exchange procedure
Adverse events were categorized as plasma exchange-related when plasma exchange was performed, the most frequent of which were pruritus (48.9%), urticaria (36.2%), hypotension (14.9%), tetany (23.4%), vomiting (14.9%), and laryngeal edema (8.5%). Among the 47 recipients, 35 (74.5%) experienced adverse events in the plasma exchange procedure.
Outcomes and rejections (Table 3)
Table 3.
Outcomes and complications.
| Serum creatinine 1year after Tx (mg/dl) | 1.195 (0.61–3.50) |
| Acute cellular rejection | 29.8% (14/47) |
| Antibody-mediated rejection | 6.4% (3/47) |
| Cytomegalovirus infection | 38.3% (18/47) |
| Other complications | ureteral stenosis; 1, subcutaneous abscess; 2, lymphocele; 3, pelvic hemorrhage; 3, brain infarction; 1, PCP; 2, PLS; 1 late onset neutropenia; 19 |
Tx – transplantation; PCP – pneumocystis pneumonia; PLS – passenger lymphocyte syndrome.
All 47 patients with administration of rituximab underwent successful transplantation with a median serum creatinine of 1.195 mg/dl (range, 0.61–3.50 mg/dl) at 1 year after transplantation. Patient and graft survivals were 100% at 1 year after transplantation. Fourteen recipients (29.8%) experienced ACR (Banff classification, borderline; 1, IA; 5, IB; 6, IIA; 1, IIB; 1) during the first year after transplantation, while 33 patients did not develop ACR. Six recipients experienced steroid and/or deoxyspergualin-resistant rejections. Two recipients developed AMR due to anti-A/B antibodies and 1 developed AMR due to donor-specific antibody.
Delayed-onset neutropenia and other adverse events during the first year after transplantation
Nineteen patients (40.4%) experienced delayed-onset neutropenia after transplantation due to the administration of rituximab. However, delayed-onset neutropenia did not induce fatal bacterial and opportunistic infections in this study, and they recovered from neutropenia by granulocyte-colony stimulating factor administration.
Eighteen cases experienced cytomegalovirus reactivation revealed by cytomegalovirus antigenemia. However, no obvious invasive tissue disease occurred. Two experienced subcutaneous infection, which was treated by wound washing. Three experienced lymphocele, which was treated with sclerotherapy. One experienced acute optic neuritis and was treated by steroid administration. Two patients experienced an elevation of β-D-glucan, for which Pneumocystis jiroveci infection was suspected. Interstitial pneumonitis was treated by the administration of sulfamethoxazole/trimethoprim. In 3 recipients, significant postoperative diffuse hemorrhage occurred, needing surgical intervention. One recipient experienced ureteral stenosis and was treated with balloon dilation. Other adverse events are shown in Table 4.
Table 4.
Characteristics of recipients with and without acute cellular rejection.
| With acute rejection | Without acute rejection | p Value | |
|---|---|---|---|
| n | 14 | 33 | |
| Age at transplant (year) | 43.5 (15–66) | 52 (23–74) | NS |
| Dialysis duration (months) | 12 (0–121) | 25 (0–180) | NS |
| Donor father/mother/son/daughter brother/sister spouse | 1/3/1/0 1/0 8 | 4/7/0/1 1/1 19 | NS |
| Donor age (year) | 53 (25–67) | 58 (37–67) | NS |
| HLA mismatch (antigen) | 4 (2–6) | 4 (0–6) | NS |
| Anti-A/B antibody (IgG) | 48 (8–4096) | 64 (2–8192) | NS |
| Anti-A/B antibody (IgM) | 32 (8–256) | 32 (2–512) | NS |
| Plasmapheresis (sessions) | 4 (2–12) | 4 (1–13) | NS |
| Dose of rituximab | 1 (1–2) | 2 (1–2) | NS |
| Splenectomy (+/−) | 2/12 | 8/25 | NS |
| CsA/Tac | 7/7 | 21/12 | NS |
| Cytomegalovirus infection | 42.9% (6/14) | 36.4% (12/33) | NS |
| Serum creatinine 1 year after Tx (mg/dl) | 1.20 (0.61–3.50) | 1.08 (0.75–1.51) | NS |
| Antibody-mediated rejection | 7.1% (1/14) | 6.1% (2/33) | NS |
| Late-onset neutropenia | 64.3% (9/14) | 30.3% (10/33) | p=0.0502 |
Comparison of patient characteristics between group A and B (Table 4)
The recipients were divided into 2 groups, group A (n=14): patients who experienced ACR and group B: patients who did not develop ACR (n=33). There were no significant changes in the age at transplant, distribution of the underlying kidney diseases, sex ratio, donor age, and cyclosporine/tacrolimus ratio between the 2 groups. The number of plasmapheresis sessions and the dose of rituximab did not differ significantly between the 2 groups. Nine of the 14 patients (64.3%) who developed ACR had delayed-onset neutropenia, as compared with 10 of the 33 patients (30.3%) who did not experience ACR. Five of 9 patients experienced steroid and deoxyspergualin-resistant ACR requiring anti-human thymocyte immunoglobulin or OKT3. The frequency of delayed-onset neutropenia was greater in group A than in group B (p=0.0503).
Relationship between ACR and delayed-onset neutropenia
Univariate logistic analysis identified that delayed-onset neutropenia was independently associated with ACR. We selected delayed-onset neutropenia and variables associated with acute cellular rejection in the multivariate analysis by the backward model. Delayed-onset neutropenia was also an independent risk factor for ACR by multiple logistic regression analysis (Table 5).
Table 5.
Logistic regression analysis of risk factors associated with acute cellular rejection.
| Variable | Unit increase | Univariate | Multivariate | ||
|---|---|---|---|---|---|
| Odds ratio (95%CI) | p value | Odds ratio (95%CI) | p value | ||
| Age at transplant | 1 year | 0.973 (0.931–1.02) | 0.216 | ||
| Gender | 0.867 (0.244–3.08) | 0.825 | |||
| HLA mismatch | 1 antigen | 1.230 (0.761–2.000) | 0.393 | 1.30 (0.723–2.350) | 0.4337 |
| CsA/Tac | 1.67 (0.469–5.930) | 0.43 | 2.17 (0.516–9.120) | 0.29 | |
| Number of plasmapheresis | 1 session | 0.796 (0.580–1.09) | 0.158 | ||
| Late-onset neutropenia | 4.140 (1.10–15.50) | 0.0351 | 5.21 (1.22–22.3) | 0.0262 | |
Discussion
This study demonstrated that delayed-onset neutropenia was an independent risk factor for ACR by multiple regression analysis. ACR in ABO-incompatible renal transplant recipients receiving rituximab may therefore be associated with delayed-onset neutropenia. Nine of the 14 patients (64.3%) who developed ACR had delayed-onset neutropenia, and 5 of 9 patients experienced steroid- and deoxyspergualin-resistant ACR requiring anti-human thymocyte immunoglobulin or OKT-3. Moreover, ACR associated with delayed-onset neutropenia in ABO-compatible renal transplantation may be intractable.
Previous reports have suggested that rituximab administration induces elevated levels of proinflammatory cytokines associated with regulatory B cell depletion [8]. The report by Clatworthy et al. showed that B cell-related cytokines releases were associated with higher frequency of acute rejection in rituximab-treated patients [9]. Moreover, a previous report showed that delayed-onset neutropenia after administration of rituximab was associated with the elevation of serum B cell activating factor (BAFF) [10]. In this study, elevated levels of B cell-related cytokines may have induced ACR and delayed-onset neutropenia in the rituximab-treated patients, although the measurement of B cell-related cytokines was not analyzed.
In this study, 74.5% of the patients with rituximab desensitization had adverse events in the plasma exchange procedure for removal of anti-A/B antibody. The most common adverse reactions associated with plasma exchange were of the anaphylactoid type. Presenting symptoms included pruritus, urticaria, hypotension, and laryngeal edema. In general, most reports on large series of patients treated with plasma exchange have low total complication rates (5–12%). In this study, the rate of adverse events in the plasma exchange procedure was higher than that of previous reports [15]. This finding may reflect the reaction of cytokine release due to regulatory B cell depletion after administration of rituximab. A recent report by Kamburova et al. revealed that rituximab-treated patients had higher serum levels of interleukin-10 and macrophage inflammatory protein-18 compared to placebo-treated patients at 2 h after start of rituximab infusion [16]. There were various doses of rituximab and a varied number of plasmapheresis sessions in our 4 desensitization protocols for ABO-incompatible renal transplantation, and 10 elderly patients older than 60 years of age were included in this study. Certain conditions of some of the B cell-related cytokines may have induced delayed-onset neutropenia and/or ACR in different recipients receiving ABO-incompatible renal transplantation in this study.
The efficacy of rituximab induction in transplant rejection is controversial. Recently, a randomized control study revealed that rituximab induction in ABO-compatible renal transplantation had no beneficial effects on transplant outcome [17]. However, the above-mentioned report by Clatworthy et al. was prematurely terminated after the inclusion of 13 patients because of an excess incidence of acute rejection in rituximab-treated patients [9]. In ABO-incompatible renal transplantation, any cytokine release would have been resolved by plasmapheresis and steroid administration before transplantation, and increase in the risk of rejection would not be expected [9]. ACR is considered a major risk factor for chronic rejection and a strong predictor of long-term graft survival [18]. A recent systematic review revealed that the frequency of biopsy-proven acute rejection was 32.9% in ABO-incompatible renal transplantation [19], which was similar to the results of our present study. A previous report showed that the rate of delayed-onset neutropenia was 42.3% in ABO-incompatible renal transplant recipients receiving rituximab, which was similar to the results of our present study [10]. We need to develop an appropriate desensitization and immunosuppression therapy to minimize ACR and delayed-onset neutropenia in ABO-incompatible renal transplantation.
ABO-incompatible renal transplantation is an immunologically high-risk procedure, and powerful immunosuppressant drug combinations including rituximab and MMF are needed for desensitization. As such, there may be an increase in the incidence and severity of infections, including opportunistic infections. The cytomegalovirus (CMV) antigenemia-positive rate was 38.2% in this study, but no recipients experienced CMV disease. CMV infection was successfully treated with ganciclovir as preemptive therapy. Two patients experienced Pneumocystis jiroveci infection. There may be a need for immune monitoring to prevent infections and to reduce the risk of acute rejection in ABO-incompatible renal transplantation, and everolimus may be used as an immunosuppressant in these patients [20–23].
The main limitation of this study might be the small number of patients and its retrospective design. Moreover, the measurement of B cell-related cytokines was not analyzed in the present study. However, this study demonstrated the frequency of adverse events in the plasma exchange procedure, and it may represent the B cell-related cytokine storm after rituximab administration. Although this was a pilot study, this is the first multivariate analysis comparing ACR and delayed-onset neutropenia in ABO-incompatible renal transplantation with rituximab desensitization.
Conclusions
Delayed-onset neutropenia in ABO-incompatible renal transplant recipients receiving rituximab was an independent risk factor for ACR as shown by multiple regression analysis. ACR in ABO-incompatible renal transplant recipients receiving rituximab may be associated with delayed-onset neutropenia. In addition, B cell-related cytokines may play a role in the development of ACR and/or delayed-onset neutropenia in these recipients.
Footnotes
Source of support: Departmental sources
References
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