Role of double-filtration plasmapheresis in ABO- and human leukocyte antigen-incompatible kidney transplant

Smriti Sinha; Shri Ram Kabra; Saikat Mandal; Vivek Bansal; Tanuj Paul Bhatia; Sumit More; Ranjan Kumar; Vibhu Ranjan Gupta

doi:10.4103/gjtm.gjtm_7_22

SHORT COMMUNICATION

Year : 2022 | Volume : 7 | Issue : 2 | Page : 209-212

Role of double-filtration plasmapheresis in ABO- and human leukocyte antigen-incompatible kidney transplant

Smriti Sinha¹, Shri Ram Kabra¹, Saikat Mandal², Vivek Bansal¹, Tanuj Paul Bhatia³, Sumit More³, Ranjan Kumar⁴, Vibhu Ranjan Gupta⁵
¹ Department of Nephrology and Renal Transplant, Sarvodaya Hospital and Research Centre, Faridabad, Haryana, India
² Transfusion Medicine and Blood Centre, Sarvodaya Hospital and Research Centre, Faridabad, Haryana, India
³ Department of Urology and Renal Transplant, Sarvodaya Hospital and Research Centre, Faridabad, Haryana, India
⁴ Department of Pathology, Sarvodaya Hospital and Research Centre, Faridabad, Haryana, India
⁵ Department of Medical Administration, Sarvodaya Hospital and Research Centre, Faridabad, Haryana, India

Date of Submission	28-Jan-2022
Date of Decision	19-Mar-2022
Date of Acceptance	23-Jun-2022
Date of Web Publication	5-Nov-2022

Correspondence Address:
Saikat Mandal
Transfusion Medicine and Blood Centre, Sarvodaya Hospital and Research Centre, Faridabad, Haryana
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/gjtm.gjtm_7_22

Abstract

Kidney transplant has significantly improved the quality of life in end-stage renal disease patients compared to maintenance hemodialysis. Recipients can receive a living-donor or a deceased-donor kidney transplant. However, the presence of donor specific anti human leukocyte antigen (HLA) antibodies or anti A or B antibodies in the recipient makes the transplant incompatible and provokes to cause hyperacute, acute, or chronic rejection. Desensitization which is usually applied before to reduce incompatibility can be achieved by apheresis and preventing donor-specific antibody resynthesis by targeting both T and B cells. Here, we present two such cases transplanted successfully by desensitizing with double-filtration plasmapheresis (DFPP). Case 1 which was a female with high-titer anti-HLA antibody was managed with rituximab, 4 sessions of DFPP, antithymocyte globulin, and posttransplant Tacrolimus (Tac). Case 2 who had both high-titer anti-HLA and anti-A (IgG 1:256) antibody was managed with rituximab, 3 sessions of DFPP, and posttransplant Tac. In both cases, perioperative complications due to DFPP such as bleeding, thrombocytopenia, hypotension, and need of transfusion was minimal. These cases point toward successful application of DFPP in desensitization protocol, leading to successful HLA antibody-incompatible and ABO-incompatible renal transplant with minimal adverse incident and cost.

Keywords: Double-filtration plasmapheresis, double-filtration plasmapheresis in ABO-incompatible kidney transplant, double-filtration plasmapheresis in human leukocyte antigen-incompatible kidney transplant

How to cite this article:
Sinha S, Kabra SR, Mandal S, Bansal V, Bhatia TP, More S, Kumar R, Gupta VR. Role of double-filtration plasmapheresis in ABO- and human leukocyte antigen-incompatible kidney transplant. Glob J Transfus Med 2022;7:209-12

How to cite this URL:
Sinha S, Kabra SR, Mandal S, Bansal V, Bhatia TP, More S, Kumar R, Gupta VR. Role of double-filtration plasmapheresis in ABO- and human leukocyte antigen-incompatible kidney transplant. Glob J Transfus Med [serial online] 2022 [cited 2023 Mar 28];7:209-12. Available from: https://www.gjtmonline.com/text.asp?2022/7/2/209/360495

Background

In the last two decades, both in developing and developed countries, the number of patients affected by end-stage renal disease (ESRD) is increasing sharply. Among them, many are suitable for kidney transplant. Compared to maintenance hemodialysis (MHD), kidney transplant is associated with significantly better quality of life and life expectancy.^[1],[2] Recipients can receive a living-donor (the best option) or a deceased-donor kidney transplant. However, the presence of donor-specific anti-ABO blood group or anti-human leukocyte antigen (HLA) antibodies in the recipient makes the transplant incompatible and provokes to cause hyperacute, acute, or chronic rejection. Desensitization is usually applied at before transplant although in some cases after transplant to remove donor-specific antibodies (DSAs) or to at least reduce their strength. Desensitization relies on removing the culprit DSAs, which can be achieved by apheresis, and preventing DSA resynthesis by targeting both T and B cells.^[3],[4] In the last few decades, improved desensitization protocol successfully helped overcome the hurdle of anti-ABO antibody as well as anti-HLA antibodies.

Double-filtration plasmapheresis (DFPP) method uses a plasma separator (a primary membrane filter/centrifuge) to separate plasma from the cell components and a plasma fractionator (a secondary filter) to remove plasma immunoglobulin from the filtered plasma. Compared to regular plasma exchange, this procedure enables better and selective removal of high molecular-weight proteins from plasma (plasma-immunoglobulin fraction) and reinfuses the patient's plasma and other blood cells. Some studies have reported the success of DFPP in ABO/HLA-incompatible kidney transplantation with and without a regimen of rituximab, bortezomib, and/or splenectomy.^{[5],[6],[7],[8]}

Here, we present two cases; one of successful HLA-incompatible renal transplantation in patient with the donor-specific anti-HLA antibody and another with high-titer anti-A antibody using desensitization protocol that included rituximab, antithymocyte globulin, and DFPP.

Case 1: Human leukocyte antigen-incompatible transplant

A 32-year-old female, parity-2 living issue-2, known case of ESRD on MHD for the last 1 year with a history of 5 blood transfusions was worked up for kidney transplant with cousin as donor. Her pretransplant immunological workup showed her to be sensitized. Luminex single antigen bead (SAB) was positive for DSA of Class 1 (A*02:06 Mean Fluorescence Index(MFI) 9485; C*01:02 -MFI 5082; B*15:02 MFI 958). The patient was counseled regarding high rejection risks despite desensitization. Her repeat DSA lysate testing was found positive for Class 1 with Mean fluorescence Index (MFI) of 861 and negative for Class 2, and flow cytometric HLA cross-match was positive for T and B cells. Hence, the patient was desensitized with rituximab 500 mg. Following that, tacrolimus (Tac) and mycophenolate mofetil (MMF) were started 1 week later. Four sessions of DFPP were done on alternative days except the last one which was performed on the day of surgery [Figure 1]. During DFPP, target exchange volume was kept to 2 log plasma volume clearance. As efflux volume was minimal, 500 ml 4% albumin solution was used as the replacement fluid. Filter used was Evaflux (Manufactured by Kawasumi Laboratories, Japan). Acid citrate dextrose which was used as anticoagulant was used keeping a ratio of 1:13–1:14 with inlet. The rate of infusion was kept 60–90 ml/min. Postplasmapheresisis, we monitored ionized serum calcium levels, prothrombin time, international normalized ratio (INR), and activated partial thromboplastin time (APTT), as well as complete blood count, serum electrolytes, and serum albumin level. As repeat flow cytometry-based HLA crossmatch performed after third DFPP was found negative, it was planned to go for a kidney transplant on the next day after a 4^th session of DFPP in the morning of transplant day following the same DFPP protocol. Pretransplant induction was given with thymoglobulin, total dose 3 mg/kg divided over 3 days. During renal transplant, the warm ischemia time was 5 minutes and cold ischemia time was 25 minutes. The allograft was placed in the right illiac fossa and there was good post operative diuresis. Postoperatively, there was no increased oozing from suture site or perirenal hematoma. Flow crossmatch done on the postoperative day (POD) 2 (without pronase digestion) was weak positive for B cell. In view of good urine output and decreasing serum creatinine, further DFPP was not done. Flow crossmatch done on POD 4 was negative for both B and T cells. Serum Tac levels were monitored regularly, and Tac dose was adjusted to maintain a level above 8 μg/l. At the time of discharge, the patient had good urine output and nadir creatinine of 0.9 mg/dl. On further follow-up till 2 months, the patient was maintaining good urine output, urea, creatinine, and Tac level.

Figure 1: HLA Antibody Desensitization and Treatment protocol of Case 1, HLA = Human leukocyte antigen, DFPP = Double-filtration plasmapheresis, MMF = Mycophenolate mofetil, Inj = Injection, Cap = Capsule, POD = Postoperative day, Tab = Tablet

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Case 2: ABO- and human leukocyte antigen-incompatible transplant

A 25-year-old male who was a known case of chronic kidney disease 5 stage on MHD for the last 1 year was admitted for ABO-incompatible renal transplant with anti-A titer IgG 1:256 dilution. His pretransplant immunological workup for donor anti-HLA antibodies was also positive. Luminex SAB was positive for anti-HLA antibodies of Class 1 MFI <1000 and Class 2 MFI >2 lac, but virtual crossmatch with donor HLA (DSA) was negative. Desensitization [Figure 2] was done with rituximab 500 mg 2 weeks before transplant date. He was started on tablet (Tab) Tac 2.5 mg (0.1 mg/kg/day) and Tab MMF sodium 720 mg twice daily 1 week before. Three sessions of DFPP were performed on alternate days. We achieved 2 log plasma volume clearance in every DFPP session, and 4% albumin was used as replacement fluid (volume around 500 ml). After 3 sessions of DFPP, his titers anti-A IgG reduced to 1:2 and IgM titer became nil, and the patient was taken for kidney transplant. Posttransplant induction was given with basiliximab 40 mg. Periprocedural patient's Hb level dropped from 7.9 g/dl, and he was transfused 1 Packed red blood cell (PRBC). Patient's vascular access was tunneled dialysis catheter which was removed pretransplant. As per protocol, blood culture sent from tunnelled cuffed dialysis catheter, which grew Candida for which injection caspofungin was started. However, clinically, the patient did not develop signs of septic shock. Subsequent blood and urine culture sent was found negative. Anti-A titers were sent on alternate days; IgG anti-A titers were stable at 1:2 dilution. The patient's renal function was good postoperatively with no risk of excessive bleeding, and there was no need for fresh frozen plasma (FFP) transfusion. He was discharged on POD 8 with serum creatinine 1.6 mg/dl which on 1-month follow-up reduced to 0.9 mg/dl.

Figure 2: ABO and HLA Antibody Desensitization and Treatment protocol of Case 2, HLA = Human leukocyte antigen, DFPP = Double-filtration plasmapheresis, POD = Postoperative day, Ig = Immunoglobulin

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Discussion

DFPP has been used for diverse indications, and few studies had analyzed the efficiency of removal of target plasma molecules and its complications.^[6],[9] Agishi et al. showed that there is significant removal of serum immunoglobulin, but the assessment of the efficiency of removal in serial treatment sessions was not elaborated, and replacement fluids were either not used or used minimally.^[9] Tanabe showed that the percentage of removal of IgM and IgG per session was 70% and 60%, respectively, with 8% albumin used as a replacement solution.^[6] Hebibi et al., on the other hand, showed suboptimal removal of serum IgG, IgA, and IgM (37.8%, 52.8%, and 61.5%, respectively) and found that one of the major reasons for poor tolerability could be not using the replacement solutions during the procedure.^[10] In the Indian scenario study done by Jagdish et al on 15 patients, mentioned that proportional removal efficiency after the 1st and 4th session of plasma exchange with cascade filtration were 55% and 72% for IgG, 74% and 89% for IgA, 85% and 96% for IgM, respectively.^[7] Although we did not assess serial the IgG and IgM level, flow cytometry-based HLA crossmatch compatibility on serial testing and IgM/IgG anti-A titration gave an indirect estimation regarding high level of extraction of immunoglobulins during this procedure. Due to financial issues and as flow cytometry-based HLA crossmatch was compatible on serial testing, and on posttransplant period, the patient had good urine output and maintaining urea and creatinine level, it was not possible to repeat the Luminex-based SAB DSA testing immediately before to transplant and on further follow-up. Kidney transplant was performed based on flow cytometric HLA compatibility testing.

Sieving coefficient of albumin quoted by most manufacturers is 0.6 (Hebibi et al. and Agishi et al.). In other words, 60% of the albumin will be retained in the circulation after each DFPP session. The proportion of serum albumin removal in our study was 21.30%, with 36.35% for standard 5% albumin replacement solution and 11.9% for effluent concentration albumin used as replacement solution, respectively.^[9],[10] Agishi et al. initially described the procedure without replacement solution.^[9] Subsequently, Tanabe started using 7.5% albumin as a replacement solution which roughly contains the albumin content of 2.5–3 l of plasma.^[6] Nishi et al. came up with the idea of using 12.5% albumin in which there is a significant deficiency of globulins with higher post-DFPP albumin, and there were no hypotensive episodes.^[11] In our case also, we have used 5% albumin solution as a replacement; as a result, we have noted minimal hypotensive episodes.

In these cases, any dyselectrolytemia was not there. Need of correction and the calcium replacement were based on the ionic calcium value measured. Moreover, it was given with repeated calcium replacements during conventional plasmapheresis.

Spontaneous bleeding diathesis is rare and observed in our study only when fibrinogen is <50 mg/dl, which can be mitigated by spacing DFPP.^[12] During this procedure, for both the patients, PT/INR and APTT were closely monitored, but there was no deviation from normal values and there was no significant bleeding during surgery or postoperative period.

The major advantage of DFPP over routine plasmapheresis is first lesser need for replacement. If regular plasmapheresis had been done in above cases, we would have needed at an average of 8–10 L of 4% albumin replacement along with 6–8 FFP transfusion as the incidence of coagulopathy is much higher. Transfusion of FFP in ABO- or HLA-incompatible transplant patient is particularly problematic as it can increase the antibody levels. Second, there was barely any peri- or post-operative bleeding complication that occurred. Immunoadsorbtion may offer similar benefit; however, in countries like ours where the cost of transplant is borne primarily out of pocket by the patient, DFPP is a much cheaper option with the same efficacy.

Conclusion

These cases underline successful application of DFPP in desensitization protocol, leading to successful HLA-antibody incompatible and ABO-incompatible renal transplant with lesser episodes of complications such as minimal need of transfusion, coagulopathy, hypotension, and postoperative complications with cost-effectivity.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Niu SF, Li IC. Quality of life of patients having renal replacement therapy. J Adv Nurs 2005;51:15-21.
2.	Ingsathit A, Kamanamool N, Thakkinstian A, Sumethkul V. Survival advantage of kidney transplantation over dialysis in patients with hepatitis C: A systematic review and meta-analysis. Transplantation 2013;95:943-8.
3.	Wongsaroj P, Kahwaji J, Vo A, Jordan SC. Modern approaches to incompatible kidney transplantation. World J Nephrol 2015;4:354-62.
4.	Jordan SC, Choi J, Vo A. Kidney transplantation in highly sensitized patients. Br Med Bull 2015;114:113-25.
5.	Sawada T, Fuchinoue S, Teraoka S. Successful A1-to-O ABO-incompatible kidney transplantation after a preconditioning regimen consisting of anti-CD20 monoclonal antibody infusions, splenectomy, and double-filtration plasmapheresis. Transplantation 2002;74:1207-10.
6.	Tanabe K. Double-filtration plasmapheresis. Transplantation 2007;84 Suppl 12:S30-2.
7.	Jagdish K, Jacob S, Varughese S, David VG, Mohapatra A, Valson A, et al. Effect of double filtration plasmapheresis on various plasma components and patient safety: A prospective observational cohort study. Indian J Nephrol 2017;27:377-83. [PUBMED] [Full text]
8.	Aggarwal G, Tiwari AK, Dorwal P, Chauhan R, Arora D, Dara RC, et al. Successful renal transplantation across HLA barrier: Report from India. Indian J Nephrol 2017;27:210-4. [PUBMED] [Full text]
9.	Agishi T, Kaneko I, Hasuo Y, Sanaka T, Sudo N, Hayasaka Y, et al. DFPP utilizing new membrane technology. J Jpn Soc Dial Ther 1981;14:61-5.
10.	Hebibi H, Weclawiak H, Rostaing L, Beaudreuil S, Allal A, François H, et al. Non-tolerability of double-filtration plasmapheresis in antibody-incompatible kidney transplant candidates. Saudi J Kidney Dis Transpl 2015;26:297-301. [PUBMED] [Full text]
11.	Nishi S, Hasegawa S, Gejyo F, Saito K, Nakagawa Y, Takahashi K. The safety measures for double filtration plasma apheresis (DFPP) before ABO-incompatible kidney transplantation. Int Congr Ser 2006;1292:91-5.
12.	Yeh JH, Chen WH, Chiu HC. Complications of double-filtration plasmapheresis. Transfusion 2004;44:1621-5.