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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 4  |  Page : 332-337

Desensitization therapy in kidney transplantation cases with positive baseline complement-dependent cytotoxicity crossmatch and high donor-specific antibodies: A retrospective study


1 Department of Nephrology and Renal Transplantation, Jaypee Hospital, Noida, Uttar Pradesh, India
2 Department of Urology and Renal Transplantation, Jaypee Hospital, Noida, Uttar Pradesh, India
3 Department of Transfusion Medicine, Jaypee Hospital, Noida, Uttar Pradesh, India
4 Department of Molecular Biology, Jaypee Hospital, Noida, Uttar Pradesh, India

Date of Submission30-Nov-2020
Date of Decision28-May-2021
Date of Acceptance03-Jun-2021
Date of Web Publication30-Dec-2021

Correspondence Address:
Dr. Ravi Kumar Singh
Department of Nephrology and Renal Transplantation, Jaypee Hospital, Noida, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_147_20

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  Abstract 

Objective: The objective of the study is to assess the graft and patient outcome after desensitization in human leukocyte antigen incompatible kidney transplantation (KT) with positive baseline complement-dependent cytotoxic (CDC) crossmatch and high mean fluorescein intensity (MFI) of donor-specific antibodies (DSA). Methods: This was a retrospective study conducted at Jaypee Hospital, Noida. This study included highly sensitized patients who were transplanted with positive CDC and DSA >10,000 MFI for single antigen or >5000 MFI for multiple donor antigens. The patient's renal outcomes were documented. The desensitization protocol consisted of rituximab, therapeutic plasma exchanges (TPE), and thymoglobulin. Results: A total of five patients who had positive CDC crossmatch with very high level of preformed DSA underwent KT. Three patients had end-stage renal disease due to diabetic kidney disease while other two due to autosomal dominant polycystic kidney disease and chronic glomerulonephritis. All the patients were on dialysis. The MFI by Luminex single antigen bead assay for Class I varied from 1657 to 23440 and for Class II varied from undetectable to 11120. The mean number of pretransplant TPE sessions given per patient was 7.8 ± 2.68 and posttransplant TPE sessions per patient was 0.8 ± 0.45. The mean follow-up period was 308.2 days. Mean creatinine on the day of discharge was 0.58 ± 0.17 mg/dL. None of the patients had any postoperative infections or rejections. Conclusion: The current report showed favorable short-term patient and graft outcomes post-KT without any postoperative infections or rejections with desensitization therapy comprising of rituximab, TPE, and thymoglobulin induction.

Keywords: Creatinine, rituximab, therapeutic plasma exchanges, thymoglobulin, transplants


How to cite this article:
Sinha VK, Singh RK, Devra AK, Choudhary LP, Singh K, Pandey P, Pande A. Desensitization therapy in kidney transplantation cases with positive baseline complement-dependent cytotoxicity crossmatch and high donor-specific antibodies: A retrospective study. Indian J Transplant 2021;15:332-7

How to cite this URL:
Sinha VK, Singh RK, Devra AK, Choudhary LP, Singh K, Pandey P, Pande A. Desensitization therapy in kidney transplantation cases with positive baseline complement-dependent cytotoxicity crossmatch and high donor-specific antibodies: A retrospective study. Indian J Transplant [serial online] 2021 [cited 2022 Aug 10];15:332-7. Available from: https://www.ijtonline.in/text.asp?2021/15/4/332/334424




  Introduction Top


Kidney transplantation (KT) is preferred over other interventions due to benefits including improved survival, better health-related quality of life, and cost-effective when compared to long-term dialysis in end-stage renal disease (ESRD) patients.[1],[2] Despite wide applicability and noteworthy advances, the impact of human leukocyte antigen (HLA) incompatibility is a major clinical challenge in KT. Thus, HLA sensitization poses a high risk of acute and chronic graft rejection and reduces allograft and patient survival.[3] This risk can be managed through several desensitization protocols adopted by different health-care centers.

Desensitization procedure increases access to donor transplants and enables paired exchange transplant. However, some studies show conflicting results that may be due to differences in patient demographics, assays used, donor-specific antibodies (DSA) concentration, and complement-dependent cytotoxicity (CDC) crossmatch leaving clinicians to decide about desensitization procedure depending on their local expertise.[4],[5],[6] Clinical studies and case reports have implemented desensitizing protocols comprising of immunoglobulins intravenous (iv), rituximab, bortezomib, and basiliximab.[7],[8] Significant clinical outcomes and safety have also been reported in case of retransplantation using rituximab, plasmapheresis, and immunoglobulin iv.[9] Evidence from reported studies suggest that desensitization protocols enable to receive kidney from HLA incompatible donors leading to successful KT.[10],[11]

However, the united network for organ sharing guidelines discourage desensitization in patients with multiple antibodies if mean fluorescein intensity (MFI) is >5000. The published literature does not comment much on transplants in patients who are CDC or flow crossmatch positive and DSA identified by LUMINEX single antigen bead (SAB) having very high MFI values (>10,000) against multiple antibodies.

The present study describes case series of five patients who underwent KT, despite being positive CDC crossmatch and DSA titers >5000 MFI. The aim of the present study was to assess the graft and patient outcome after desensitization in HLA incompatible transplants with positive baseline CDC crossmatch and high MFI of DSA.


  Methods Top


Study design

This was a retrospective study conducted in the Jaypee Hospital, Noida, India from January 2018 to December 2019. Inclusion criteria- This study included highly sensitized patients who were transplanted (positive CDC crossmatch with very high positive DSA >10,000 MFI for single antigen or >5000 MFI for multiple donor antigens). Exclusion criteria- Those unwilling to give informed consent were excluded.

Study population

CDC crossmatch was sent as a part of an immunologic workup before the KT. Following a positive CDC crossmatch, the patient needed further tests in the form of flow cytometry-based crossmatch (FC-XM) and Luminex SAB crossmatch. Patients' and donors' baseline characteristics, blood groups, and immunological profiles were documented. Following this, patients were counseled regarding various options available; for example, kidney paired donation, waiting for compatible deceased donor transplant, but they insisted for transplant. After fully describing the risk of desensitization and risk of acute antibody-mediated rejection (ABMR), when they consented for the same, they underwent desensitization as per the institutional protocol. Posttransplant these patients were followed up as per the standard clinical practice immediately posttransplant, and these patients were subsequently monitored for short-term graft outcome in the form of serum creatinine, glomerular filtration rate, proteinuria, and graft biopsy in case of graft dysfunction in posttransplant period. The patient's progress and clinical outcomes were documented.

The patients of either sex or age above 18 years who underwent KT (positive CDC crossmatch with very high positive DSA >10,000 MFI for single antigen or >5000 MFI for multiple donor antigens) were included in the study while those negative for DSA and having ABO-incompatible transplants were excluded.

Treatment protocol

The protocol consisted of rituximab iv at 14–21 days before transplantation depending upon the number of therapeutic plasma exchange (TPE) planned (dose: 1.5 plasma volume) as per the highest MFI [Figure 1]. iv immunoglobulin was also used 0–6 days before transplantation. Tacrolimus (0.1 mg/kg body weight in two divided dosage) and mycophenolate (bodyweight > 40 kg: 2 g/day; body weight <40 kg 1.5 g/day) were started from the subsequent day. The CD 19/CD 20 cell count was sent after 5 days to assess the impact of rituximab iv in terms of B-cell depletion. Plasma exchanges were started 5 days from rituximab dose to allow the maximum B-cell count and hence DSA depletion. TPE was carried out on alternate days. After every five TPE sessions, Luminex DSA assay was done to estimate the depletion in preformed DSAs. After bringing down the level of preformed DSA MFI to <5000, three more sessions of TPE were done including one session on postoperative day +1. Tacrolimus dosages were monitored to keep the trough levels between 8 and 10 ng/mL. After successfully decreasing the level of preformed DSA to desired levels, KTs were carried out. A repeat CDC crossmatch was not done to avoid false-positive crossmatch due to the effect of rituximab iv (pronase treated CDC crossmatch was not available at the center). Induction with thymoglobulin iv (1.5 mg/kg body weight) was given 8–10 h before transplant.
Figure 1: Schematic illustration of our institutional desensitization protocol

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Methylprednisolone iv 500 mg for single dose was given on the day of transplantation at the time of surgery. One session of TPE was done on postoperative day +1 to remove any rebound DSA. Second dose of thymoglobulin iv was given on postoperative day 1 after completion of TPE. The third dose of thymoglobulin iv was given on postoperative day 2. Tacrolimus, mycophenolate, and oral prednisolone were continued with close monitoring of trough levels and graft functions. Graft functions were continuously monitored in the immediate posttransplant period with daily kidney function tests and urine output. A graft biopsy was planned if there was any delayed graft function or graft dysfunction. Posttransplant patients received oral trimethoprim plus sulfamethoxazole (1 tablet daily), oral valganciclovir (450 mg, 1 tablet daily), and candid mouth paint (20 drops, three times a day) for 6 months.

Outcomes

The primary outcome was to look at the incidence of delayed graft function (dialysis during 1st week of KT); graft function at 1-, 3-, 6-, and 12-month posttransplant; and incidence of acute rejection (biopsy-proven borderline, cellular, and ABMR).

Statistical analysis

As there were only 5 patients included in this study, no statistical analysis was done. All the data is presented in [Table 1].
Table 1: Demographic characteristics of sensitized patients

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Patient consent

Patient consent was waived by the IEC considering retrospective nature of the study.

Ethics statement

The procedure was carried out in accordance with the Declaration of Helsinki and International Council for Harmonization-Good Clinical Practice (ICH-GCP). The study was approved by the institutional ethics committee (Jaypee Hospital, EC approval no. EC09/20/1165, 04/06/2020).


  Results Top


A total of five patients underwent KT who had positive CDC crossmatch with very high level of preformed DSA [Table 1]. Patients were of south East-Asian ethnicity. These patients belonged to age group between 33 years and 62 years. Three patients had ESRD due to diabetic kidney disease while other two due to autosomal dominant polycystic kidney disease and chronic glomerulonephritis. All the patients were on dialysis differing in the duration from 2 to 96 months.

Complement-dependent cytotoxicity-based crossmatch (CDC-XM), Luminex-based crossmatch (LM-XM), and FC-XM were performed in all the cases. If any of these tests turned out positive, SAB assay was performed to detect MFI. The CDC-XM for B-cells was positive in three cases and for T-cells, it was positive in all the cases. The results of FC-XM were positive for T-cells and B-cells in four patients.

All the cases were subjected to a SAB assay which gave antibody specificity against donor A locus in four cases, against donor B locus in two cases, against donor C locus and donor DQ each in only one case, against donor DP in eight (13.56%) cases, against donor and against DR in two cases. The HLA mismatches in all the five patients are shown below in [Table 1].

The MFI by Luminex SAB for Class I varied from 1657 to 23440 and for Class II varied from undetectable to 11120. Rituximab, 500 mg, was administered in four patients and 200 mg in one patient. All the patients were on dialysis and underwent TPE pretransplant and posttransplant, except for two patients who did not undergo TPE posttransplant. The mean number of pretransplant TPE sessions given per patient was 7.8 ± 2.68 and posttransplant TPE sessions per patient was 0.8 ± 0.45. Induction immunotherapy was given in all the five patients using antithymocyte globulin infusion. Maintenance therapy was administered with tacrolimus, mycophenolate mofetil, and prednisolone.

Mean creatinine on the day of discharge was 0.58 ± 0.17 mg/dL. The mean (standard deviation) follow-up period for these five patients was 308.2 (76.98) days (longest follow-up was of 12 months).


  Discussion Top


KT is superior to other modes of renal replacement therapy even in sensitized patients. In case of live donor KT, novel immunosuppressive protocols are implemented to curb the sensitization. This study presented case series of five immunologically high-risk patients with high DSA and positive CDC crossmatch who underwent living-related KT using desensitization protocol comprising of TPE, immunoglobulin iv, and rituximab iv.

All the patients in this study responded well and achieved immediate graft function. The serum creatinine was stable at 1 month, 3 months, 6 months, 9 months, and 12 months for all the patients. None of the patients had any postoperative infections or rejections. The graft and patient outcome at the time of writing this report were excellent.

Nondesensitized patients exhibit a higher incidence of clinical and subclinical T-cell-mediated rejection and high DSA leading to graft loss.[12] Several studies have demonstrated the prevention of ABMR of a kidney allograft using desensitization procedures and increasing the success rate of transplantation in sensitized patients.

[Figure 2] summarizes various HLA-incompatible desensitization protocols. Desensitization protocol, similar to our study, including immunoglobulin iv, rituximab, and TPE was studied by Pandey et al. in Indian setting with inclusion of 55 sensitized KT recipients. Graft and patient survival of 45 patients at 12 months were 100%, and preconditioning with TPE was reported to be the most beneficial in HLA sensitized transplant recipients.[13]
Figure 2: Various human leukocyte antigen-incompatible desensitization protocols (adapted from Sharif A, et al. QJM. 2012;105:1141-50)

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Another case series of three patients exhibiting positive outcomes with desensitization therapy employing plasma exchange, immunoglobulin iv, and rituximab. They reported three cases, of which two were females and all had ESRD due to diabetic nephropathy that is in line with the present study. Furthermore, they used CDC-XM and FC-XM and panel reactive antibodies to detect the presence of DSA. These assays are used in many institutions, and the present study too has used the same assays.[14]

Another case series of five female patients with high panel reactive antibodies and DSA titers but negative CDC and MFI >1000 underwent living donor KT. Their protocol implemented mycophenolate mofetil, tacrolimus, and prednisolone and desensitized with TPE, immunoglobulin iv, and rituximab, along with an additional agent basiliximab. Postdesensitization, MFI titers decreased but three patients experienced acute rejection. Although successful KT was performed in sensitized patients displaying DSA, they warranted more studies to elucidate the safe MFI titer of the DSA and optimum doses of immunoglobulin iv and TPE.[15]

Lim et al. reported a retrospective study of 548 patients with incompatible HLA, ABO, or both. They used a pretransplant DSA MFI target of <3000 in HLA incompatible KT and anti-A/B antibody titer of <16 in ABO-incompatible KT. They showed comparable outcomes in all types of incompatible KTs with nonsensitized KTs.[16]

In the present study, a protocol consisting of iv rituximab, iv thymoglobulin, and TPE was adopted as a desensitization therapy. Rituximab is a monoclonal antibody that is precise for CD20 has demonstrated clinically important results in combination with immunoglobulin, TPE, and bortezomib against HLA sensitization.[8],[17],[18] Although few evidences report its action as a single agent, it has shown significant efficacy and safety in combination with other desensitizing agents.[19] Correspondingly, TPE is the most commonly used approach in desensitizing protocol. Several clinical studies report its important role in overcoming a positive crossmatch in KT recipients; thus, reducing ABMR and improving survival.[4],[10] Thymoglobulin showed excellent patient and graft survival and graft function and importantly, risk of infections and malignancies observed was very low with this agent.[20]

Subsequently, the patients were put on mycophenolate mofetil, tacrolimus, and prednisolone as a part of maintenance therapy. During the follow-up, all the patients showed stable graft function and creatinine levels after 1-, 3-, 6-, and 12-month posttransplant. This has been proven by Jalalonmuhali et al.[21] and Shaffer et al.[22] Vo et al. has studied the efficacy, outcomes, and cost-effectiveness of desensitization using high-dose immunoglobulin iv and rituximab in 146 patients. The patient and graft survival were 95% and 87.5%, respectively, at 48 months that were superior to the patients who were on dialysis during the study period.[8]

Limitations of the study

The present study is in accordance with the reported literature demonstrating the successful implementation of desensitization therapy in sensitized transplant recipients.[23],[24] However, the limitations of the study include short-term follow-up and smaller sample size. The fear of posttransplant infections can be decreased with adequate prophylaxis and therapeutic dose monitoring; nevertheless, long-term follow-up and large case series are needed to establish substantial outcomes. In addition, care must be taken when generalizing the outcomes considering this was a single-center study.


  Conclusion Top


The current report showed favorable short-term patient and graft outcomes without any postoperative infections or rejections with desensitization therapy that comprised of iv rituximab, TPE, and iv thymoglobulin induction. The fear of multiple preformed antibodies with high MFI values should not be a deterrent for transplantation in HLA incompatible recipients provided a suitable desensitization protocol is tailor-made.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Fujisawa M, Ichikawa Y, Yoshiya K, Isotani S, Higuchi A, Nagano S, et al. Assessment of health-related quality of life in renal transplant and hemodialysis patients using the SF-36 health survey. Urology 2000;56:201-6.  Back to cited text no. 2
    
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Kauke T, Klimaschewski S, Schoenermarck U, Fischereder M, Dick A, Guba M, et al. Outcome after desensitization in HLA or ABO-incompatible kidney transplant recipients: A single center experience. PLoS One 2016;11:e0146075.  Back to cited text no. 5
    
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