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Volume: 14 Issue: 2 April 2016

FULL TEXT

ARTICLE
Rituximab Therapy and Infection Risk in Pediatric Renal Transplant Patients

Objectives: Rituximab is a monoclonal antibody directed against the CD20 molecule on pre-B and mature B cells and is used in transplant recipients for the prevention and treatment of alloantibody-mediated rejection or for the treatment of disease recurrence after transplant. In most patients, rituximab has been safe and well-tolerated, but the long-term adverse effects of rituximab are currently unknown.

Materials and Methods: We retrospectively eval­uated 78 pediatric renal transplant recipients for the occurrence of infectious disease. Patients who received rituximab therapy were divided into 2 groups: those who developed an infection and those who did not. The 2 groups were compared for serious infections, hospitalization, graft loss, and death rates.

Results: Eighteen transplant patients received rituximab therapy for various causes. The number of rituximab courses given varied according to the cause and ranged from 1 to 8 courses. The dose at each course was 375 mg/m2. Median age of all recipients was 16.00 years (min-max:, 5.00-22.00 y), and median follow-up time was 2.00 years (min-max:, 1.00-3.00 y). Serious infections (bacterial sepsis, tuberculosis, Cytomegalovirus infection, varicella-zoster virus infection, Polyomavirus-associated nephropathy, and acute pyelonephritis) were observed in 8 patients who received rituximab therapy. We observed that patients with antibody-mediated rejection had significantly increased infection rate. Patients who had used rituximab combined with antithymocyte globulin and higher rituximab course number and higher pretreatment CD19 and CD20 levels had higher risk of infection (P < .05).

Conclusions: The combined use of rituximab with additional treatments such as antithymocyte glob­ulin, intravenous immunoglobulin, and repeated plasma exchange may be associated with high risk of infectious disease. Especially for those patients who required intensive and repetitive treatment, such as antibody-mediated rejection, rituximab treatment should be used with caution. Infection risk should be closely monitored, although mainly in patients who receive T-cell-depleting agents.


Key words : Renal transplant, Infectious disease, Rejection, CD20

Introduction

Rituximab is a monoclonal antibody directed against the CD20 molecule on pre-B and mature B cells. Rituximab is used in sensitized organ transplant patients to decrease preformed anti-HLA antigen antibodies, in patients with a donor-specific-positive crossmatch, in patients requiring treatment for antibody-mediated allograft rejection, and in patients who have disease recurrence after transplant.1,2

In most patients, rituximab has been safe and well tolerated, but the long-term adverse effects of rituximab are currently unknown. Rituximab use results in depletion of normal B cells for several months, but immunoglobulin levels remain unaltered in most patients. This is because long-living plasma cells do not express CD20. The lack of effect on immunoglobulin levels has suggested that rituximab use could have an effect on the occurrence of infections.3 Continued administration of rituximab may be associated with increased risk of infection in immunosuppressed patients.

The aim of our study was to evaluate the long-term safety of rituximab for infection risk in pediatric renal transplant patients.

Materials and Methods

We retrospectively evaluated 78 pediatric renal trans­plant recipients for the occurrence of infectious disease and compared outcomes in patients who received rituximab therapy with those who did not receive rituximab. In our evaluated patients, 60 transplant patients did not receive rituximab therapy, and 18 transplant patients received rituximab therapy for various causes. The study was approved by the Ethical Review Committee of our hospital.

The immunosuppressive protocol for renal trans­plant consisted of prednisolone, calcineurin inhibitor (cyclosporine A or tacrolimus), and mycophenolate mofetil and oral prednisolone. Renal biopsy was performed in 16 patients because of elevated creatinine levels or severe proteinuria during routine follow-up, and acute rejection or relapse of the original glomerulopathy was proven with biopsy.

The number of rituximab courses given varied according to the reason for administration and ranged from 1 to 8 courses. The dose at each course was 375 mg/m2. Each dose was preceded by intravenous methylprednisolone (2 mg/kg) and intravenous pheniramine maleate (45.5 mg). In addition to rituximab, the patients received intravenous methylprednisolone (30 mg/kg/d for 3 d consecutively) and plasmapheresis (1.5 plasma volumes). Patients with rejection also received intravenous immunoglobulin (2 g/kg). T-cell-depleting agents (antithymocyte globulin) were administered in 4 patients with acute rejection. T hese 4 patients were given anti-Cytomegalovirus prophylaxis based on valganciclovir for 100 days.

Patients who received rituximab treatment were divided into 2 groups: those who developed an infection and those who did not. Of 18 patients, 8 had serious infectious disease and 10 had no infectious disease. In these groups, we recorded age, gender, induction therapy used at transplantation (antithymocyte globulin, monoclonal anti-CD25 antibodies, or no induction therapy), immuno­suppressive therapy given at discharge, acute rejection rate, patient and graft survival rates, and type of infectious complication.

Results

Patient characteristics
Seventy-eight pediatric renal transplant recipients (32 males, 46 females) were included in the study. Patients’ median age was 16.00 years (min-max: range, 5.00-22.00 y). Mean follow-up time after transplant was 3.02 ± 0.74 years. Eighteen patients (7 males, 11 females) received rituximab therapy for various causes. These included antibody-mediated acute or chronic rejection in the presence of donor-specific anti-HLA antigen antibodies (n = 11), relapse of the original glomerulopathy on the kidney allograft (n = 5), and highly sensitized patients (n = 2). Median follow-up time after rituximab use was 2.00 years (min-max: range, 1.00-3.00 y). There were no statistically significant differences between patients who received rituximab treatment and those who did not with respect to demographic features (Table 1). The type of immunosuppressive therapy after transplant consisted of prednisolone, calcineurin inhibitor (cyclosporine A or tacrolimus), and mycophenolate mofetil, with similar therapy for both groups.

The number of rituximab courses varied according to the reason for administration. Two patients with acute rejection received only 1 dose of rituximab. Four patients with acute rejection and 1 patient with relapse of original glomerulopathy received rituximab 2 times. Three patients with acute rejection, 2 patients with relapse of original glomerulopathy, and 2 highly sensitized patients received rituximab 4 times. Two patients with acute rejection and 2 patients with relapse of original glomerulopathy received rituximab 8 times (Table 1).

Outcomes and infection rates
After a median follow-up of 2.00 years (range, min-max: 1.00-3.00 y), the incidence of serious infection after rituximab therapy was 38%. Serious infection rate in the group that did not receive rituximab was 18%. There was a significant difference between the 2 groups (P < .05).

T-cell-depleting agents (antithymocyte globulin) were used in 5 patients with acute rejection. These 5 patients received anti-Cytomegalovirus prophylaxis based on valganciclovir for 100 days. All patients received anti-Pneumocystis prophylaxis during the first 6 months after transplant with sulfamethoxazole trimethoprim. Three patients with serious infections received a combination of antithymocyte globulin and rituximab therapy. The median time between the first rituximab infusion and the first infection was 6 months (min-max:range, 0.00-18.00 mo).

Hospitalization rate was 22% in patients who received rituximab therapy. Infection-related reasons for hospitalization were life-threatening or graft function-threatening infections such as bacterial sepsis, tuberculosis, Cytomegalovirus infection, varicella-zoster virus infection, Polyomavirus-associated nephropathy, and acute pyelonephritis. One patient died as a result of severe bacterial sepsis and chronic hepatic failure, and 1 patient had graft loss related to Polyomavirus nephropathy. Hospitalization rate (16%) was significantly lower in patients who did not receive rituximab therapy (P < .05) (Table 1 and Table 2).

When we compared patients who did versus who did not develop a severe infection after rituximab therapy, we observed that patients with antibody-mediated rejection had significantly increased infection rate. We did not observe severe infection in patients who had recurrence of primary disease. Patients who had used rituximab combined with antithymocyte globulin and who had higher rituximab course number and higher CD19, CD20 (pretreatment), also had higher risk of infection (Table 3).

Discussion

Rituximab is effective in a variety of nephrologic diseases. The efficacy of rituximab to deplete B cells prompted its consideration as therapy in renal transplant where these cells are considered to have a significant role, including acute rejection, in highly sensitized patients and in relapse of the original glomerulopathy on the kidney allograft.1,2

Depletion of B cells would be expected to result in poor antibody responses to new antigens more so than to recall antigens.3 Besides their role in antibody synthesis, B cells may act as antigen-presenting cells and may be important cofactors of effective immune responses.4 Higher serious infection and hospitalization rates in the rituximab-treated group versus the control group may have been related to this condition. In addition, antithymocyte globulin use may have increased the risk of infection.

One of the patients in the rituximab-treated group was diagnosed with tuberculosis. Recent studies have shown that peripheral B cells are important in the host defense against Mycobacterium tuberculosis. However, it is not clear whether rituximab promoted disease progression or caused tuberculosis.5

Cytomegalovirus infection is one of the most frequent viral infections after renal transplant. Cytomegalovirus reactivation occurring after rituximab treatment has been recently discussed in a case report, with rituximab considered to impair humoral immunity, which does not play a key role in defending against Cytomegalovirus infection.6 Cytomegalovirus infection was not seen in the rituximab-treated group. Only 1 of the patients in the control group was diagnosed as having Cytomegalovirus infection during follow-up.

An increased incidence of Polyomavirus has also been described in transplant patients who received rituximab.7 In our study, 1 patient in the rituximab-treated group and 2 patients in the group that did not receive rituximab were diagnosed with Polyomavirus nephropathy, and 1 in the rituximab-treated group and 1 in the group without rituximab treatment had graft loss related to Polyomavirus nephropathy. In our study group, there was no difference regarding Polyomavirus nephropathy between the 2 groups.

Rituximab has increasingly been used for the treatment of nephrologic disease, especially in pediatric transplant patients. We observed that patients with antibody-mediated rejection had significantly increased infection rate. The combined use of rituximab and additional treatments such as antithymocyte globulin, intravenous immuno­globulin, and repeated plasma exchange may be associated with high risk of infectious disease. Additional treatment may increase immuno­suppression, perhaps facilitating infection develop­ment in these patients. Acute rejection is itself an immune system reaction, which disrupts the entire host defense and perhaps decreases the immune response to infection.

For those patients who require intensive and repetitive treatment like antibody-mediated rejection, rituximab treatment should be especially used with caution. The possibility of infection should be closely monitored, although mainly in patients who receive T-cell-depleting agents. It is not possible to say whether rituximab only increased the risk of infection. Further and larger studies are needed to clarify the association between rituximab and infection.


References:

  1. Kamar N, Milioto O, Puissant-Lubrano B, et al. Incidence and predictive factors for infectious disease after rituximab therapy in kidney-transplant patients. Am J Transplant. 2010;10(1): 89-98.
    CrossRef - PubMed
  2. Becker YT, Becker BN, Pirsch JD, Sollinger HW. Rituximab as treatment for refractory kidney transplant rejection. Am J Transplant. 2004;4(6):996-1001.
    CrossRef - PubMed
  3. Gea-Banacloche JC. Rituximab-associated infections. Semin Hematol. 2010;47(2):187-198.
    CrossRef - PubMed
  4. Lund FE, Hollifield M, Schuer K, Lines JL, Randall TD, Garvy BA. B cells are required for generation of protective effector and memory CD4 cells in response to Pneumocystis lung infection. J Immunol. 2006;176(10):6147-6154.
    CrossRef - PubMed
  5. Kelesidis T, Daikos G, Boumpas D, Tsiodras S. Does rituximab increase the incidence of infectious complications? A narrative review. Int J Infectious Dis. 2011;15(1):e2-e16.
    CrossRef - PubMed
  6. Suzan F, Ammor M, Ribbag V. Fatal reactivation of cytomegalovirus infection after use of rituximab for a post-transplantation lymphoproliferative disorder. N Engl J Med. 2001;345 (13):1000.
    CrossRef - PubMed
  7. Aksoy S, Harputluoglu H, Kilickap S, et al. Rituximab-related viral infections in lymphoma patients. Leuk Lymphoma 2007;48(7): 1307-1312.
    CrossRef - PubMed


Volume : 14
Issue : 2
Pages : 172 - 175
DOI : 10.6002/ect.2014.0156


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From the Departments of 1Pediatric Nephrology, 2General Surgery, 3Pathology, and 4Infectious Diseases, Baskent University, Ankara, Turkey
Acknowledgements: The authors declare having no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Kaan Gulleroglu, Baskent University Pediatric Nephrology Department, 54. Cadde No: 72/3, Bahcelievler-Cankaya 06490, Ankara, Turkey
Phone: +90 312 223 4936
Fax: +90 312 215 7597 E-mail: kaangulleroglu@yahoo.com