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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2020  |  Volume : 31  |  Issue : 6  |  Page : 1432-1438
Successful desensitization and kidney transplantation in the presence of donor-specific anti-human leukocyte antigen antibodies in kidney transplant recipients


Renal Transplant Unit, National Institute of Solid Organ and Tissue Transplantation, Dow University Hospital, Karachi, Pakistan

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Date of Web Publication29-Jan-2021
 

   Abstract 


Kidney transplantation has indisputably revamped renal medicine and restored hope among patients coming across fatal end-stage renal disease. However, sensitization of human leukocyte antigen (HLA) triggers extensive immunological fences to successful kidney transplantation and henceforth, transplant candidates are frequently demoted to the ever-growing waiting list owing to preformed donor specific antibodies (DSAs). Over the past few years, the advent of desensitization protocols has significantly overpowered the immunological barriers and enhanced the outcomes of kidney transplant recipients with DSAs against HLA. Those desensitization protocols include combination of plasmapheresis, high-dose intravenous immunoglobulin (IVIG), low-dose IVIG, rituximab, and/or bortezomib. These immunomodulatory treatments either eliminate DSAs or prevent their production. Lately, our transplant center developed and used a desensitization protocol (Two sessions of plasmapheresis on day 1 and 2 → injection rituximab on day 2 after plasmapheresis →no plasmapheresis on day 3 → eight sessions of plasmapheresis after day 3 and IVIG 100 mg/Kg/dose after each session of plasmapheresis → repeat HLA antibody detection test to confirm if DSAs are present against HLA with median fluorescence intensity (MFI)values <1000 and complement dependent cytotoxicity (CDC) crossmatch is negative for both T and B lymphocytes; if NO then continue plasmapheresis sessions with IVIG 100 mg/kg/dose till MFI values are <1000 and CDC crossmatch is negative for both T and B lymphocytes or if YES then proceed for transplantation → repeat dose of rituximab post-transplantation) to evaluate its effectiveness in improving kidney function in patients post-desensitization and kidney transplantation.

How to cite this article:
Khan MT, Hamid Rb, Sarfaraz S, Lal N, Ahmed J, Luxmi S. Successful desensitization and kidney transplantation in the presence of donor-specific anti-human leukocyte antigen antibodies in kidney transplant recipients. Saudi J Kidney Dis Transpl 2020;31:1432-8

How to cite this URL:
Khan MT, Hamid Rb, Sarfaraz S, Lal N, Ahmed J, Luxmi S. Successful desensitization and kidney transplantation in the presence of donor-specific anti-human leukocyte antigen antibodies in kidney transplant recipients. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2021 May 15];31:1432-8. Available from: https://www.sjkdt.org/text.asp?2020/31/6/1432/308365



   Introduction Top


Kidney transplantation has indisputably revamped renal medicine and restored hope among patients coming across fatal end-stage renal disease (ESRD). It offers patient with longevity and healthier quality of life. However, sensitization of human leukocyte antigen (HLA) triggers extensive immunological fences to successful kidney transplantation and henceforth, transplant candidates are frequently demoted to the ever-growing waiting list owing to preformed donor specific antibodies (DSAs). The existence of DSAs against HLA is directly proportional to poor allograft outcomes in kidney transplant candidates. The development of DSAs could be due to several reasons which include pregnancy, blood transfusion and prior kidney transplantation. Kidney transplant recipients are at inevitable risk to sustain hyperacute rejection, accelerated acute rejection, early acute antibody-mediated rejection and early graft loss, if DSAs are not sufficiently repressed.[1],[2],[3]

Over the past few years, the advent of desensitization protocols has significantly overpowered the immunological barriers and enhanced the outcomes of kidney transplant recipients with DSAs against HLA. A handful of research studies have reported various desensitization protocol experiences in their kidney transplant centers. Those desensitization protocols include combination of plasma-pheresis, high-dose intravenous immunoglobulin (IVIG), low-dose IVIG, Rituximab and/or Bortezomib [Table 1].[1],[2],[4],[5],[6] These immuno-modulatory treatments either eliminate DSAs or prevent their production. To the best of our literature search, the only report regarding successful implementation of desensitization protocol and kidney transplantation from Pakistan was lately published by Mirza et al of Shifa International Hospital, Islamabad, Pakistan.[1] Our objective was to evaluate the improvement in kidney function in patients post-desensitization and kidney transplantation. For the second time in Pakistan, we successfully performed desensitization therapy and HLA-incompatible kidney transplantation in a DSAs-positive cohort.
Table 1: Definitions of most common desensitizing agents.

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   Case Series Top


Case 1

A 37-year-old male patient with ESRD secondary to chronic membranoproliferative glomerulonephritis presented for kidney transplant workup on November 2017. The patient was on hemodialysis (HD) for the past two years. He had a comorbid hepatitis C. His blood group was O positive which matched with his cousin’s blood group. The Luminex technology was used to detect IgG antibodies against the HLA which revealed moderate levels of DSAs against DQ2 with median fluorescence intensity (MFI) value of 12245. Lymphocyte crossmatch was performed by complement-dependent cytotoxicity (CDC) assay. The CDC crossmatch was also positive for both T and B lymphocytes. The immunological characteristics of the kidney transplant recipients’ pre-and post-desensitization therapy are shown in [Table 2] and [Table 3]. We then performed desensitization therapy (described below) to achieve MFI values <1000 and negative CDC crossmatch for both T and B lymphocytes before proceeding for kidney transplantation. With our desensitization therapy, his MFI values were significantly reduced to 695 for DQ2 and CDC crossmatch for both T and B lymphocytes was also negative prior to transplant. The patient was successfully transplanted on February 2018. It was patient’s first transplant. No significant clinical events were observed on follow-up.
Table 2: Predesensitization therapy immunological characteristics of kidney transplant recipients.

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Table 3: Postdesensitization therapy immunological characteristics of kidney transplant recipients

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Case 2

A 23-year-old young male patient with ESRD secondary to focal segmental glomerulo-sclerosis presented on January 2018 for kidney transplant workup. The patient never had transplant. He was on HD for the past three months and had a history of hypertension, hepatitis B virus and hepatitis C virus infection along with blood transfusions. His blood group was A positive which matched with his sister’s blood group. A significantly high number of DSAs were present against A26 with MFI value of 17692. The CDC crossmatch was also positive for both T and B lymphocytes. The desensitization protocol was performed to remove DSAs and make patient eligible for kidney transplantation. The patient required nine sessions of plasmapheresis before transplant. Our transplant recipient responded well to desensitization protocol with MFI values of 889 for A26 and negative CDC crossmatch for both T and B lymphocytes. The patient was successfully transplanted with kidney on April 2018. On follow up, no remarkable transplant events were noted.

Case 3

A 50-year-old woman with ESRD secondary to chronic hypertension visited for kidney transplant workup on February 2018. The patient was on HD for the past five years. No co-morbidities were found, however, she had a history of previous renal transplant from her brother in 2007. The previous allograft was rejected because of chronic interstitial fibrosis and tubular atrophy. For second transplant, her blood group matched with his sister’s blood group; A positive. The Luminex technology found moderate levels of DSAs against DQ11 with MFI value of 10355. The CDC crossmatch was also positive for both T and B lymphocytes. The desensitization protocol was performed to remove DSAs prior to transplant procedure. Our desensitization protocol was administered and her MFI values were successfully reduced to 867 for D11 and CDC crossmatch for both T and B lymphocytes was also negative. The patient was transplanted on April 2018 successfully. Patient follow up did not notice any significant transplant events.

Case 4

A 50-year-old male patient with ESRD secondary to IgA nephropathy was on HD for the past three years. The patient presented for kidney transplant workup on April 2018. He had a positive history of chronic hypertension. His blood group was O positive which matched with his wife’s blood group. The Luminex technology showed significantly elevated DSAs against B61 with MFI value of 14286 along with positive CDC crossmatch for both T and B lymphocytes. The desensitization protocol was successfully implemented to remove DSAs and make patient eligible for kidney transplantation. His MFI values were significantly reduced to 543 for B61 and CDC crossmatch for both T and B lymphocytes was also negative prior to transplant. A total of 13 sessions of plasmapheresis were required before transplantation. The patient was successfully transplanted on July 2018. It was patient’s first renal transplant. No significant clinical events were noticed afterward.

Case 5

A 26-year-old male patient with ESRD secondary to focal segmental glomerulo-sclerosis presented for kidney transplant workup on June 2018. The patient was on HD for the past five months. He had a history of hypertension. His blood group was B positive which matched with his cousin’ s blood group. A moderate level of DSAs against B27 with MFI value of 13499 was found on Luminex technology. The CDC crossmatch was also positive for both T and B lymphocytes. The desensitization protocol was performed to remove DSAs and make patient eligible for kidney transplantation. The desensitization therapy described below was administered and his MFI values were diminished to 422 for B27 and CDC crossmatch was also negative for both T and B lymphocytes before proceeding for kidney transplant. The patient was successfully transplanted on August 2018.The patient never had a history of renal transplant. No subsequent clinical events were evidenced on follow-up.

Case 6

A 32-year-old male patient with ESRD secondary to chronic membranoproliferative glomerulonephritis presented for kidney transplant workup on October 2018. The patient was on HD for the past two years. He had a comorbid diabetes and hypertension. His blood group was B positive which matched with his brother’s blood group. The Luminex technology revealed moderate number of DSAs against A1 with MFI value of 10547. The CDC crossmatch was also positive for both T and B lymphocytes. The desensitization protocol was executed to eliminate DSAs and progress for kidney transplantation. His MFI values were significantly reduced to 724 for A1 and CDC crossmatch for both T and B lymphocytes was also negative prior to transplant upon implementing desensitization protocol. The patient was successfully transplanted on December 2018. It was patient’s first renal transplant. On patient follow-up, no remarkable transplant complications were witnessed.

Desensitization Protocol

Desensitization protocol in our transplant center encompassed below mentioned strategy to achieve MFI values <1000 and negative CDC crossmatch for both T and B lymphocytes before proceeding for kidney transplantation:

  1. Two sessions of plasmapheresis on day 1 and 2
  2. Injection rituximab on day 2 after plasma-pheresis
  3. No plasmapheresis on day 3
  4. Eight sessions of plasmapheresis after day 3 and IVIG 100 mg/Kg/dose after each
  5. session of plasmapheresis
  6. Repeat HLA antibody detection test to confirm if DSAs are present against HLA with MFI values <1000 and CDC crossmatch is negative for both T and B lymphocytes; if NO then continue plasma-pheresis sessions with IVIG 100 mg/Kg/dose till MFI values are <1000 and CDC crossmatch is negative for both T and B lymphocytes or if YES then proceed for transplantation; and
  7. Repeat dose of rituximab post-transplantation.


Written informed consents were obtained from the patients before publishing the case reports.


   Discussion Top


A positive CDC crossmatch for both T and B lymphocytes is long been regarded as a big “NO” to kidney transplantation.[7] Highly HLA sensitized kidney transplant recipients’ present puzzling situation as they produce numerous preformed antibodies against donor antigens that subsequently results in positive CDC crossmatch and therefore extended duration of wait to be considered for transplantation. In such circumstances, cadaveric transplantation and kidney paired donation come to rescue. However, Pakistan is yet to evidence both the aforementioned transplantation program and transplants here are exclusively dependent on living kidney donation.[1],[2],[3] Therefore, desensitization therapy is a sustainable and cost effective choice and breaks the immunological barrier for transplant candidates who might have to endure prolonged dialysis and waiting otherwise.

Several desensitization protocols have been developed and successfully implemented by research groups with improved kidney allograft and patient survival in patients with DSAs and a positive CDC crossmatch.[3],[4],[5],[6],[7] Lately, Mirza et al for the very first time in Pakistan, successfully transplanted three HLA sensitized kidney transplant patients using low-dose IVIG, plasmapheresis, rituximab and bortezomib.[1] Green et al concluded improved kidney function outcomes after desensitization therapy with IVIG, plasmapheresis and rituximab in kidney transplant recipients with high levels of DSAs.[2] Similarly, Ide et al reported effectiveness of phased desensitization therapy with Rituximab followed by Bortezomib along with IVIG and Plasma-pheresis in kidney transplant patients.[6] According to the British Transplant Society, DSAs with MFI value <5000 and negative CDC crossmatch for both T and B lymphocytes is associated with lower susceptibility to allograft rejection.

In our study, all the six cases had moderate levels of DSAs against HLA except for one case with MFI value of 17962. The Luminex technology was used to detect IgG antibodies against the HLA. With implementation of our desensitization protocol, we achieved low levels of DSAs with MFI value <1000. Similarly, all our patients had positive crossmatch for both T and B lymphocytes prior to transplant. Lymphocyte crossmatch was performed by CDC assay. It is a classical technique for the detection of preformed antibodies in the recipient against potential donor. Recipient and donor T and B lymphocytes were separated by magnetic beads. Complement fixation reaction was observed under inverted phase contrast light microscope. Scoring was performed according to the American Society of Histopathology and Immunogenetic guidelines (Laboratory Manual USA, 2nd Edition). Our patients were exposed to desensitization therapy till the crossmatches become negative for both T and B lymphocytes. The high levels of DSA and a positive CDC crossmatch for both T and B lymphocyte is considered an absolute contraindication to kidney transplantation which can cause hyperacute rejection, accelerated acute rejection, early acute antibody-mediated rejection and early allograft loss. Lately, studies have confirmed that high levels of DSAs are linked with allograft rejection.[2],[3],[7]

As mentioned earlier that numerous desensitization protocols have been developed and used by different kidney transplant centers.[3],[4],[5],[6],[7] Our desensitization therapy encompassed plasmapheresis, IVIG and Rituximab. Plasma-pheresis removes harmful antibodies from the blood circulation. The number sessions required to remove antibodies are based on DSA titer. Our patients did not suffer from any of the adverse effects of plasmapheresis such as itching, rash, flushing, headache, tachycardia, nausea, vomiting, shortness of breath, paresthesia and hypotension or hypertension.[8] Postdesensitization therapy and posttransplantation kidney function has been depicted in [Table 4]. DSA rebound has been reported in the past with plasmapheresis discontinuation and could result in allograft dysfunction and rejection.[8],[9] However, in combination with low-dose IVIG, plasmapheresis provides lasting eradication of DSAs.[11] IVIG antagonizes T and B lymphocytes, regulates B lymphocyte antibody production, induces anti-inflammatory response through up-regulation of T-helper cells 2 cytokine production and nullifies alloantibodies.[1],[2] We used low dose IVIG; 100 mg/kg/dose as part of desensitization protocol. Rituximab is a monoclonal antibody and it targets a CD-20 protein on the surface of the pre-B and mature B lymphocytes.[1],[4] It inhibits the B lymphocyte proliferation and triggers cellular apoptosis through antibody dependent cell-mediated cytotoxicity facilitated by activation of complement cascade.[10] A study by Fuchinoue et al demonstrated that pre-transplant rituximab significantly reduces the incidence of antibody mediated rejection and improves five year allograft outcome.[14] In addition, research studies have also mentioned that IVIG and rituximab avert DSA rebound, hence thwarting transplant related glomerulopathy and acute humoral allograft rejection.[6],[15]
Table 4: Postdesensitization therapy and posttransplantation kidney function.

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The present research study characterizes the data of six kidney transplant patients with high DSAs; therefore, a longitudinal study with large sample size would be a better alternative in terms of elucidating the effectiveness of desensitization therapy for such transplant candidates. Nevertheless, this study emphasizes that kidney transplants are practical even in high risk patients presenting with immunological barriers; preformed DSAs and ABO incompatibility which is regarded as an absolute contraindication for successful kidney transplant under the contemporary scenario, given that effective desensitization therapy and appropriate posttransplant DSA monitoring is provided.


   Conclusion Top


The advent of desensitization therapy has indeed advanced the dynamics of kidney transplantation and offered a lasting way out for the ordeal of immunologically underprivileged patients with moderate to high DSAs, especially for countries like Pakistan where kidney transplants are solely driven by living kidney donation and where cadaveric transplantation and kidney paired donation are still hypothetical. In our transplant center, we success fully desensitized and transplanted six HLA sensitized kidney transplant candidates with moderate and high DSAs and T and B lymphocyte positive CDC crossmatch. Our desensitization protocol comprised of multiple plasmapheresis sessions with simultaneous low-dose IVIG and Rituximab, an immuno-modulatory drug. Upon follow-up, we did not witness any significant transplant-related event such as allograft dysfunction or rejection.

Conflict of interest: None declared.



 
   References Top

1.
Sethi S, Choi J, Toyoda M, Vo A, Peng A, Jordan SC. Desensitization: Overcoming the immunologic barriers to transplantation. J Immunol Res 2017;2017:6804678.  Back to cited text no. 1
    
2.
Vo AA, Choi J, Cisneros K, et al. Benefits of rituximab combined with intravenous immuno-globulin for desensitization in kidney transplant recipients. Transplantation 2014;98(3):312-9.  Back to cited text no. 2
    
3.
Ide K, Tanaka Y, Sasaki Y, et al. A Phased Desensitization Protocol With Rituximab and Bortezomib for Highly Sensitized Kidney Transplant Candidates. Transplantation Direct 2015;1(5):e17.  Back to cited text no. 3
    
4.
Mirza S, Mahmud SN, Abideen ZU, Aziz T, Akhter S, Baloch BK. Overcoming the Immunological Barrier in Highly HLA Sensitized Renal Transplant Recipients -A Desensitization Experience from a Transplant Center in Pakistan. Journal Pak Med Assoc 2019;69(4):584-7.  Back to cited text no. 4
    
5.
Green H, Nesher E, Aizner S, et al. Long-term results of desensitization protocol with and without rituximab in sensitized kidney transplant recipients. Clin Transplant 2019: e13562.  Back to cited text no. 5
    
6.
Jeong JC, Jambaldorj E, Kwon HY, et al. Desensitization Using Bortezomib and High-dose Immunoglobulin Increases Rate of Deceased Donor Kidney Transplantation. Medicine (Baltimore) 2016;95(5):e2635.  Back to cited text no. 6
    
7.
Stegall MD, Gloor J, Winters JL, Moore SB, Degoey S. A comparison of plasmapheresis versus high-dose IVIG desensitization in renal allograft recipients with high levels of donor specific alloantibody. Am J Transplant 2006; 6(2):346-51.  Back to cited text no. 7
    
8.
Susal C, Opelz G, Morath C. Role and Value of Luminex(®)-Detected HLA Antibodies before and after Kidney Transplantation. Transfus Med Hemother 2013;40:190-5.  Back to cited text no. 8
    
9.
Morath C, Opelz G, Zeier M, Susal C. Prevention of antibody-mediated kidney transplant rejection. Transpl Int 2012;25(6): 633-45.  Back to cited text no. 9
    
10.
Shin M, Kim SJ. ABO Incompatible Kidney Transplantation-Current Status and Uncertainties. J Transplant 2011;2011:970421.  Back to cited text no. 10
    

Top
Correspondence Address:
Muhammad Tassaduq Khan
Renal Transplant Unit, National Institute of Solid Organ and Tissue Transplantation, Dow University Hospital, Karachi
Pakistan
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DOI: 10.4103/1319-2442.308365

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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    Abstract
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