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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 1  |  Page : 101-106

Efficacy and safety of bortezomib in the treatment of active antibody-mediated rejection in adult kidney-transplant recipients: A single-center retrospective study


Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission10-Dec-2020
Date of Acceptance24-May-2021
Date of Web Publication31-Mar-2022

Correspondence Address:
Dr. Dharmendra Bhadauria
Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_155_20

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  Abstract 


Introduction: The management of active antibody-mediated rejection (ABMR) is evolving, and optimal treatment remains uncertain due to incomplete understanding of pathogenesis. Bortezomib is found to be useful in the treatment of active ABMR. We studied the efficacy and safety of bortezomib in renal-transplant recipients with active ABMR. Materials and Methods: We retrospectively included renal-transplant recipients with active ABMR, who received bortezomib as main management. Results: Eighteen live-related renal-transplant recipients of active ABMR were included. C4d was positive in 14 patients and negative in eight patients. Patients with active ABMR had a mean improvement in glomerular filtration rate (GFR) of 7, 10.5, and 15 ml/min/1.73 m2 at 3, 6, and 12 months, respectively, from baseline GFR. Improvement was significant at 3 (P = 0.009) and 6 months (P = 0.018) of follow-up. Conclusion: Bortezomib may be a safe and effective therapy in patients with active ABMR in patients.

Keywords: Active antibody-mediated rejection, antibody-mediated rejection, bortezomib, donor-specific antibodies


How to cite this article:
Bhadauria D, Kumar S, Yachha M, Kaul A, Patel MR, Kushwaha RS, Behera MR, Prasad N. Efficacy and safety of bortezomib in the treatment of active antibody-mediated rejection in adult kidney-transplant recipients: A single-center retrospective study. Indian J Transplant 2022;16:101-6

How to cite this URL:
Bhadauria D, Kumar S, Yachha M, Kaul A, Patel MR, Kushwaha RS, Behera MR, Prasad N. Efficacy and safety of bortezomib in the treatment of active antibody-mediated rejection in adult kidney-transplant recipients: A single-center retrospective study. Indian J Transplant [serial online] 2022 [cited 2022 May 25];16:101-6. Available from: https://www.ijtonline.in/text.asp?2022/16/1/101/342433




  Introduction Top


Active antibody-mediated rejection (ABMR) is a main and most important cause of allograft loss in renal-transplant recipients; it is responsible for around three-fourth of death-censored allograft failures after 1 year of renal transplant.[1] The management of active ABMR is evolving, and optimal treatment remains uncertain due to incomplete understanding of pathogenesis and still evolving criteria for diagnosis.[2],[3]

The current standard of care for active ABMR is primarily based on the data accumulated through some pilot and retrospective studies and includes the use of plasmapheresis and intravenous immunoglobulin (IvIg) such as rituximab and bortezomib.[4],[5] Maintenance immunosuppressive regimen containing tacrolimus and mycophenolate mofetil (MMF) will cause decrease in donor-specific antibody (DSA) production, which may be relevant in the prevention of chronic antibody rejection.[6] Use of these therapies is not based on sound evidence, and their true benefits and side effects remain yet to be proved.

Bortezomib is a proteasome inhibitor that can deplete plasma cells by inducing apoptosis and thereby decreasing DSA production and therefore has been found to be useful in the treatment of active ABMR in adults[7] as well as pediatric kidney-transplant recipients.[8] These studies were uncontrolled, and overall, there is a paucity of data for its true benefits and side effects in patients of active ABMR. Hence, we aim to observe the outcomes, treatment response, and adverse effects of the bortezomib in active ABMR.


  Materials and Methods Top


This is a single-center retrospective study descriptive in nature, which was conducted among renal-transplant recipients who were diagnosed with active ABMR. The study was conducted in a nephrology transplant unit of a tertiary care referral hospital in North India from January 2016 to December 2018.

Data were collected regarding age, sex, comorbidities, donor age, donor sex, relation, HLA matching, pretransplant DSA, flow cytometry (FXM), type of induction, type of immunosuppressive drugs, number of rejection episodes, baseline serum creatinine, and glomerular filtration rate (GFR) (by modification of diet in renal disease [MDRD] equation).

Definition and management protocol

The diagnosis of active ABMR was based on Banff 2017 update.[9] The diagnosis was made if at least 2 of the 3 criteria were present:

  1. Histopathological evidence of acute tissue injuries such as (i) acute tissue injury and/or presence of neutrophils and/or mononuclear cells in peritubular capillaries (PTCs) and/or glomeruli, (ii) acute tubular injury or capillary thrombosis, and (iii) intimal arteritis/fibrinoid necrosis/intramural or transmural inflammation in arteries
  2. Evidence of recent antibody interaction with the endothelium including 1 or more of the following:


    • Linear C4d staining in PTC (C4d2 or C4d3 by immunofluorescence on frozen sections, or C4d >0 by immunohistochemistry on paraffin sections)
    • At least moderate microvascular inflammation ([g + PTC] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute T cell-mediated rejection, borderline infiltrate, or infection, PTC ≥2 alone is not sufficient and g must be ≥1
    • Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated.


  3. Presence of DSA.


Cutoff of 12 months was taken to define early versus late ABMR; early occurring within 12 months while late occurring after 12 months.

DSA had been identified by the cell-based luminex method (lysate assay) because of cost constraints to afford single-antigen bead assay, and more than 2000 mean fluorescent index (MFI) was taken as positive. In most of the patients, DSA could not be done after completion of therapy due to financial constraints and nonavailability of the donor in some cases.

Pretransplant HLA typing was done by DNA-based methods (sequence-specific oligonucleotide method).

Pretransplant FXM-mean channel shift >150 was taken as positive.

Treatment protocol for active antibody-mediated rejection

All active ABMR was treated with IV methylprednisolone 500 mg 3–5 doses. The standard of care for patients with active ABMR is plasmapheresis (5 sessions usually) with IVIg (total dose of 2 g/kg).

The treatment modalities include enhancing maintenance immunosuppression by increasing dose or substitution to the stronger immunosuppressive agent (cyclosporine to tacrolimus or azathioprine to MMF).

Bortezomib treatment protocol

Currently, we are using bortezomib in patients who are not affordable for plasmapheresis ± IVIg due to financial constraints. It was given for 1 cycle subcutaneously at a dose of 1.3 mg/m2 on day 1, 4, 8, and 11 along with prophylaxis for herpes zoster (acyclovir) and cotrimoxazole. These patients were followed up, and details were collected regarding the clinical course, renal outcomes, and side effects of bortezomib.

Treatment responses

They were analyzed for active ABMR as improvement or decline in estimated GFR calculated by using MDRD equation at 1, 3, 6, and 12 months after the therapy. The study was conducted in accordance with prevailing ethical principles and reviewed by our own institutional review board.

Statistical analysis

Baseline characteristics were reported as mean ± standard deviation (SD) for normally distributed continuous variables and proportions for categorical variables. To test the mean difference between paired observations among five time points, repeated-measures ANOVA was used. As repeated-measures ANOVA takes a number of concurrent pairs over the time, the effective sample size was reduced from 22 to 12. To overcome this issue, paired-samples t-test was used to test the mean difference between the observations on two-time point (instead of multiple comparisons of repeated measures ANOVA). Error bar graph was used to present the mean ± 1 SD over time. A P < 0.05 was considered statistically significant. Statistical analyses were performed using the Statistical Package for the Social Sciences, version-23 (SPSS-23, IBM, Chicago, Illinois, USA).

Declaration of patient consent

The patient consent has been taken for participation in the study and publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

Good clinical practice guidelines were followed. As it was a data analysis study, ethics committee approval was not deemed necessary. The study was carried out as per the Declaration of Helsinki.


  Results Top


All the 18 patients included in this study had live-related ABO-compatible renal transplant.

Baseline characteristics

The baseline characteristics are summarized in [Table 1].
Table 1: Baseline characteristics at the time of presentation

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The mean age was 38.05 ± 10.06 years, and most of them were male (89%) and most of the donors were female (83%).

Immunological status

Pretransplant complement-dependent cytotoxicity crossmatch was negative in all the patients and pretransplant flow crossmatch was done in 12 patients (three patients had positive T cell crossmatch and one patient had a positive B cell crossmatch). Pretransplant DSA was available in 11 patients (one patient positive for only Class I and three patients positive for only Class II).

Immunosuppression

Of all the 18 patients, 10 patients received no induction, six patients received basiliximab induction, and two patients received anti-thymocyte globulin (one patient received a single dose of 1.5 mg/kg and one patient received 2 doses of 1.5 mg/kg). All patients were on standard tacrolimus, MMF, and prednisolone regimen. Prior episodes of acute rejection were present in five patients. Three patients had a prior active ABMR and two patients had prior acute cellular rejection.

Parameters at the time of graft dysfunction

The time of presentation varied from 2 to 132 (33 ± 37) months. Twelve patients had early ABMR and six had late ABMR. Data on DSA at the time of graft dysfunction were present in 17 patients (1 positive for only Class I, 10 positive for only Class II, and 6 positive for Class I and II). In the remaining five patients, DSA could not be done due to unavailability of the donor or financial constraints.

At the time of graft dysfunction, the mean serum creatinine was 2.05 ± 0.58 mg/dl and the mean GFR was 39.42 ± 11.37 ml/min/1.73 m2. The mean proteinuria in patients with active ABMR was 2288 mg/dl.

C4d was positive in 14 out of 18 patients.

Fourteen of these patients had received concurrent IV methylprednisolone (3 doses).

Treatment response

Active antibody-mediated rejection

In 18 patients with active ABMR, all 13 patients had 6 months of follow-up and 5 had 12 months of follow-up. The mean serum creatinine at the time of graft dysfunction was 2.05 ± 0.58 mg/dl, and it improved to 1.85 ± 1.33 mg/dl at the end of 1-year follow-up and the decline of serum creatinine was not significant, as shown in [Figure 1]. The mean GFR in this group at time of graft dysfunction, 1 month, 3 months, 6 months, and 1 year was 41.53, 48.63, 53.70, 52.10, and 56.56 ml/min/1.73 m2, respectively, as shown in [Table 2].
Figure 1: Mean difference of serum creatinine over time in active antibody-mediated rejection shown by error plot graph, n = 22. ABMR: Antibody-mediated rejection

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Table 2: Mean glomerular filtration rate at times of graft dysfunction and at different times in patients with active antibody-mediated rejection (P-value done by paired t-test)

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In this group, there was a mean improvement of 7, 10.5, and 15 ml/min/1.73 m2 at 3, 6, and 12 months as compared to the GFR at the time of graft dysfunction. However, this improvement was statistically significant only at 3 and 6 months [Table 2]. However, overall, the mean improvement of GFR by repeated-measure ANOVA test showed that P value is not significant (P = 0.058) as shown in [Figure 2].
Figure 2: Mean difference of glomerular filtration rate over time in active antibody-mediated rejection shown by error plot graph. ABMR: Antibody-mediated rejection, GFR: Glomerular filtration rate

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Early versus late antibody-mediated rejection

Twelve patients had early ABMR and six had late ABMR. The mean serum creatinine in early ABMR at the time of graft dysfunction and at 1, 3, 6, and 12 months was 1.75, 1.55, 1.37, 1.34, and 1.1 mg/dl, respectively. The mean serum creatinine in late ABMR at the time of graft dysfunction and at 1, 3, 6, and 12 months was 2.12, 2.07, 1.95, 1.92, and 2.07 mg/dl, respectively, as shown in [Table 3].
Table 3: Mean serum creatinine at the time of graft dysfunction and after 1, 3, 6, and 12 months after bortezomib

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Graft survival and patient survival

The mean follow-up of our patients was 14.8 ± 8.5 months. In our series, none of the patients had graft loss until the study completion.

Side effect profile

Most common side effects observed were gastrointestinal including nausea, vomiting, and diarrhea. There was no death, and episode of severe infection requiring hospitalization was observed during bortezomib therapy.


  Discussion Top


The major finding of this study was that bortezomib was useful in active and early ABMR but not in late ABMR with minimal side effect profile.

In our study, there was improvement in GFR in active ABMR till 1 year and there is an improvement of 7, 10.5, and 15 ml/min/1.73 m2 at 3, 6, and 12 months, respectively; this is in contrast to 5 ml/min/1.73 m2 in patients in bortezomib arm versus 5.2 ml/min/1.73 m2 in placebo arm at 1-year GFR difference seen in the BORTEJECT study[10] which is not significant. In the same study at 24 months of follow-up, there was no significant difference between bortezomib and placebo-treated groups in median GFR at 24 months (33 vs. 42 ml/min/1.73 m2; P = 0.31). In the BORTEJECT study, there were also no differences in 2-year graft survival (81% vs. 96%; P = 0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes at 24 months of follow-up.

In a single-center case series from Mexico,[11] five patients with ABMR were treated with 1 cycle of bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11) along with plasmapheresis. In this series, all patients had maintenance immunosuppression consisting of cyclosporin, MMF, and prednisolone. This is in contrast to our study where a majority of patients were on tacrolimus, MMF, and prednisolone regimen. The average time for rejection was 952 days posttransplant which is similar to 1002 days (33 months) in our study. In this series, three patients had active ABMR and two patients had active and chronic ABMR, and after 24 months of follow-up, the two patients who had chronic active ABMR had graft loss and three patients who had active ABMR had stabilization of serum creatinine levels.

In a single-center experience from Thailand,[12] 15 patients with chronic active ABMR were treated with standard protocol of plasma exchange, immunoglobulin, and rituximab, and in 13 patients, bortezomib was added to the standard protocol, and they found that addition of bortezomib to standard protocol had lower rate of GFR declination (−4.20 ± 4.89 mL/min/y vs. −12.33 ± 10.44 mL/min/y; P = 0.014), a higher rate of disappearance of DSA (69.2% vs. 25%; P = 0.03), a lower rate of allograft loss (15.4% vs. 66.7%; P = 0.006), and better allograft survival (P = 0.006) after a medial follow-up of 41.8 months; however, in our study, patients with chronic active ABMR had stabilization of GFR up to 1 year, but there is no significant improvement from baseline GFR. This may be explained partly by the fact that chronic active ABMR is predominantly caused by Class II DSAs that are persistent and difficult to treat and bortezomib has less effect on Class II DSA reduction when compared to Class I.[13] Another study showed that bortezomib was effective in decreasing the levels of HLA-B and -DR antibodies but was not successful in depleting HLA-A and -DQ DSA.[14]

Recently, it was found that in patients with chronic active ABMR, the use of terminal complement blockade using eculizumab[15] was found to have stabilization of graft function. It suggests that both complement-dependent and -independent mechanisms play a role in chronic active ABMR which may be a target for future therapies of chronic active ABMR that is difficult to treat.

In early ABMR, there was statistically significant improvement in serum creatinine at 1, 3, 6, and 12 months when compared to serum creatinine at the time of graft dysfunction as shown in [Table 4], but in late ABMR, even though there was not statistically significant decline in serum creatinine, yet stabilization of serum creatinine was seen. As there are no beneficial treatment options for late ABMR, bortezomib may be considered a good treatment option.

The dose of bortezomib in ABMR is not fixed and varies from center to center. In our study, we used 1 cycle of bortezomib (4 doses at 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11); this is in contrast to 2 cycles used intravenously in BORTEJECT study.[10] Although IV route is the standard route of administration for bortezomib, in our study, we had chosen subcutaneous route rather than IV route because previous studies in multiple myeloma demonstrated noninferiority in efficacy and relatively good safety profile with subcutaneous route when compared with IV route as shown by Moreau et al.[16] and also for the ease of administration by the patient on outpatient basis.

Bortezomib is also less costly when compared to plasmapheresis. In our institute, each cycle of 4 doses of bortezomib costs around 10,000/- while plasmapheresis (5 sessions) with IVIg (total dose of 2 g/kg) costs around 500,000/. Hence, in a developing country like India where patients are not affordable for costly therapy like plasmapheresis with IVIg, bortezomib may a cheaper alternative (at 50 times less cost) for active ABMR.

Bortezomib is a relatively safe drug in our study group. Gastrointestinal side effects and hematological toxicity were the major side effects as seen in the BORTEJECT study,[10] and they were not present in our patients. Indeed, in BORTEJECT study, average daily doses of MMF were significantly lower in the bortezomib arm due to hematological side effects of bortezomib. None of the patients developed severe side effects warranting discontinuation of bortezomib in our study.

Strengths

Strengths of our study include the homogenous nature of the population of active ABMR and follow-up of 1 year and could be of merit in patients of resource-constrained areas.

Limitations

Limitations of our study include small sample size, lack of posttherapy DSA and kidney biopsy in the majority of the patients, lack of MFI values to see the extent of improvement, and use of plasmapheresis in four patients, so treatment response may be biased in those patients. Further large randomized controlled trials are needed in patients of active ABMR comparing bortezomib head to head with plasmapheresis/IVIg and/or rituximab.


  Conclusion Top


In this study, it was found that bortezomib may be safe and cheaper therapy in patients with active ABMR and early active ABMR in whom plasmapheresis cannot be done due to financial constraints or due to limited resources. However, it is not effective in treating late active ABMR for which still the definitive treatment is controversial.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
ANZDATA Registry. 39th Report, Chapter 8: Transplantation. Australian and New Zealand Dialysis and Transplant Registry, Adelaide, Australia; 2017. Available from: http://www.anzdata.org.au. [Last accessed on 2021 Jan 03].  Back to cited text no. 1
    
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Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant 2018;18:293-307.  Back to cited text no. 2
    
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Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M. Diagnosis and management of antibody-mediated rejection: Current status and novel approaches. Am Transplant 2014;14:255-71.  Back to cited text no. 3
    
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Billing H, Rieger S, Süsal C, Waldherr R, Opelz G, Wühl E, et al. IVIG and rituximab for treatment of chronic antibody-mediated rejection: A prospective study in paediatric renal transplantation with a 2-year follow-up. Transpl Int 2012;25:1165-73.  Back to cited text no. 4
    
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Walsh RC, Alloway RR, Girnita AL, Woodle ES. Proteasome inhibitor-based therapy for antibody-mediated rejection. Kidney Int 2012;81:1067-74.  Back to cited text no. 5
    
6.
Theruvath TP, Saidman SL, Mauiyyedi S, Delmonico FL, Williams WW, Tolkoff-Rubin N, et al. Control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic rejection. Transplantation 2001;72:77-83.  Back to cited text no. 6
    
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Moreno Gonzales MA, Gandhi MJ, Schinstock CA, Moore NA, Smith BH, Braaten NY, et al. 32 doses of bortezomib for desensitization is not well tolerated and is associated with only modest reductions in anti-HLA antibody. Transplantation 2017;101:1222-7.  Back to cited text no. 7
    
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Kizilbash S, Claes D, Ashoor I, Chen A, Jandeska S, Matar RB, et al. Bortezomib in the treatment of antibody-mediated rejection in pediatric kidney transplant recipients: A multicenter Midwest Pediatric Nephrology Consortium study. Pediatr Transplant 2017;21:e12873.  Back to cited text no. 8
    
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Haas M, Sis B, Racusen LC, Solez K, Glotz D, Colvin RB, et al. Banff 2013 meeting report: Inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant 2014;14:272-83.  Back to cited text no. 9
    
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Eskandary F, Regele H, Baumann L, Bond G, Kozakowski N, Wahrmann M, et al. A randomized trial of bortezomib in late antibody-mediated kidney transplant rejection. J Am Soc Nephrol 2018;29:591-605.  Back to cited text no. 10
    
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Bahena Méndez J, López Y López LR, Sebastián Díaz MA, Trejo Curiel I, Galindo-Lopéz R, Baca Córdova A, et al. Antibody-mediated rejection treatment with bortezomib in renal transplant recipients: A single-center 24-month follow-up case report. Transplant Proc 2020;52:1123-6.  Back to cited text no. 11
    
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Larpparisuth N, Skulratanasak P, Premasathian N, Vongwiwatana A. Efficacy of bortezomib as an adjunctive therapy for refractory chronic active antibody-mediated rejection in kidney transplant patients: A single-center experience. Transplant Proc 2019;51:3293-6.  Back to cited text no. 12
    
13.
Philogene MC, Sikorski P, Montgomery RA, Leffell MS, Zachary AA. Differential effect of bortezomib on HLA Class I and Class II antibody. Transplantation 2014;98:660-5.  Back to cited text no. 13
    
14.
Slatinska J, Slavcev A, Honsova E, Hruba P, Kratochvilova I, Rohal T, et al. Efficacy and safety of BORTEZOMIB treatment for refractory acute antibody-mediated rejection – A pilot study. HLA 2018;92:47-50.  Back to cited text no. 14
    
15.
Kulkarni S, Kirkiles-Smith NC, Deng YH, Formica RN, Moeckel G, Broecker V, et al. Eculizumab therapy for chronic antibody-mediated injury in kidney transplant recipients: A pilot randomized controlled trial. Am J Transplant 2017;17:682-91.  Back to cited text no. 15
    
16.
Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: A randomised, phase 3, non-inferiority study. Lancet Oncol 2011;12:431-40.  Back to cited text no. 16
    


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