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Volume: 20 Issue: 7 July 2022


Rituximab Administered for Recurrent Membranous Nephropathy in a Kidney Transplant Recipient Did Not Eliminate Donor-Specific Antibodies

Chronic active antibody-mediated rejection is the leading cause of kidney transplant failure. Although various immunosuppressive agents have been tested, rituximab included, presently there is no effective treatment. There are reports about the beneficial role of certain immunosuppressive protocols that include rituximab to reduce donor-specific antibodies, the cause of chronic active antibody-mediated rejection. If an immunosuppressive agent reduces donor-specific antibodies, its administration before the occurrence of chronic active antibody-mediated rejection may be beneficial. We describe a case of a renal transplant recipient with recurrent membranous nephropathy and recent development of donor-specific antibodies but without histological evidence of active antibody-mediated rejection. The patient received 3 weekly doses of rituximab for recurrent membranous nephropathy, and complete remission was achieved. One year after, he has preserved an excellent renal function without proteinuria. However, repeated measurements of donor-specific antibodies revealed that rituximab only modestly reduced donor-specific antibodies. Donor-specific antibody levels remained considerably higher than the laboratory reference value. Thus, rituximab alone may not have a role to prevent chronic active antibody-mediated rejection in patients with donor-specific antibodies.

Key words : Anti-CD20 antibody, Antibody-mediated rejection, Recurrent glomerulonephritis, Renal transplantation


Chronic active antibody-mediated rejection (cAMR) is the leading cause of death-censored kidney transplant failure.1 Although various immunosup-pressive agents have been tested, rituximab included, presently there is no effective treatment.2 There are reports about the beneficial role of certain immunosuppressive protocols that include rituximab to reduce donor-specific antibodies (DSA),3-5 the cause of cAMR. If an immunosuppressive agent reduces DSA, then its administration before the occurrence of cAMR may be proved beneficial.

In this report, we describe a case of a renal transplant recipient with recurrent membranous nephropathy and recent development of DSA but without histological evidence of AMR. The patient received rituximab for recurrent membranous nephropathy.6 Although complete remission was achieved, DSA levels remained considerably higher than the laboratory reference value.

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent for submitting this case report was obtained from the patient.

Case Report

A 42-year-old male kidney transplant recipient presented at the outpatient clinic with stable sufficient renal function (serum creatinine 1.15 mg/dL) but with new-onset proteinuria of 2.1 g/day. He received the transplant 3 years ago from a biologically unrelated living donor (his wife). Before that, he was on hemodialysis for 3 years. The cause of the end-stage renal disease was membranous nephropathy. At the time of transplant, he had no antibodies against human leukocyte antigen (HLA), and he received basiliximab as part of the induction therapy. The transplant functioned immediately, and there were no events of acute rejection. After that, he was given methylprednisolone, mycophenolate, and tacrolimus, with the levels of tacrolimus kept at 6 to 8 ng/mL. Routine tests for cytotoxic antibodies were negative.

A kidney biopsy was performed and detected a typical image of membranous nephropathy with intense granular positivity for the phospholipase A2 receptor (PLA2R) in all glomerular capillaries but an absence of the related staining in podocytes. No histological evidence for T-cell-mediated rejection or AMR was revealed. Serum anti-PLA2R antibodies were negative. Screening and identification of anti-HLA panel reactive antibodies (PRA) were performed by the bead array (Luminex) method using a commercial kit (One Lambda). The PRA results were negative for HLA class I but were 84% for HLA class II. The anti-HLA II antibodies were specific for DR51, DQ4, DQ5, DQ6, and DQA1*03:02, with DR51 and DQ5 being DSA. The mean fluorescence intensity (MFI) cutoff is 1000 for PRA identification with single-antigen kits (LS1A04 and LS2A01; One Lambda).

The patient continued the triple immunosup-pressive regimen; in addition, he received 3 weekly doses of 375 mg/m2 rituximab. His creatinine level remained stable, and proteinuria remised rapidly and completely. One year after the rituximab administration, creatinine level was 1.25 mg/dL and urine protein was 141 mg/day (Figure 1A). However, rituximab failed to eliminate DSA levels as shown by the MFI values, which remained high throughout this period. More precisely, before rituximab administration, anti-HLA DR51 MFI was 15 383, whereas 1 year after the treatment, MFI remained considerably high at 13 273. Regarding anti-HLA DQ5, its initial MFI was 3068, and 1 year after rituximab administration the MFI was 2397 (Figure 1B). As noted, the MFI cutoff for PRA identification is 1000.


Chronic active AMR remains a challenge for kidney transplant physicians since there is presently no effective treatment. Rituximab has also been tested among various factors, albeit in small, randomized trials, and no clear benefit has been detected.2,7

In some but not all trials for AMR or recipient desensitization, an immunosuppressive regimen that included rituximab was found to reduce anti-HLA antibodies.2-4,7,8 Periodic testing of patients may detect DSA before the occurrence of changes in cAMR histology. In such cases, an immunosup-pressive agent that reduces DSA may prevent the occurrence of cAMR. However, it is difficult to perform such clinical trials because of the risks of potent immunosuppression and the relatively good prognosis in patients whose kidney biopsy shows DSA but not cAMR. To our knowledge, there is a case of a kidney transplant recipient with DSA but without histological evidence of AMR who received an intense immunosuppressive regimen that inclu-ded rituximab and achieved clearance of DSA and an excellent subsequent course.5

Our patient appeared with a recurrence of mem-branous nephropathy and concurrent development of DSA. Because rituximab is indicated to treat recurrent membranous nephropathy,6 the patient received 3 weekly doses of this agent. Complete remission of membranous nephropathy was achieved rapidly. However, DSA levels decreased modestly, and the associated MFI values were always significantly higher than the laboratory cutoff values. From a pathophysiological point of view, the failure of rituximab to reduce DSA may result from its inability to affect plasma cells. Although rituximab destroys the precursors of plasma cells, the B cells, when a humoral immune response has been established, the source of antibodies are the long-lived plasma cells.9,10 Plasma cells lack CD20 and consequently are not vulnerable to rituximab. Interestingly, this explanation raises questions about the exact mechanisms involved to treat membranous nephropathy with rituximab.

In conclusion, the present case report indicates that the addition of rituximab alone in the usual immunosuppressive regimen of kidney transplant recipients with DSA but not histological lesions of cAMR may be inefficient for a clinically relevant reduction of DSA levels. Thus, rituximab alone may not have a role to prevent cAMR in such patients.


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Volume : 20
Issue : 7
Pages : 695 - 697
DOI : 10.6002/ect.2022.0146

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From the 1Department of Nephrology and the 2Department of Immunology-Histocompatibility, Evangelismos General Hospital, Athens; and the 3Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa, Greece
Acknowledgements: This study was funded only by the resources of our departments. Other than described, the authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Theodoros Eleftheriadis, Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece
Phone: +30 241 350 1665