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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2015  |  Volume : 26  |  Issue : 2  |  Page : 297-301
Non-tolerability of double-filtration plasmapheresis in antibody-incompatible kidney transplant candidates


1 Department of Nephrology, Dialysis and Organ Transplantation, CHU, Kremlin Bicêtre, Paris, France
2 Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, France
3 Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil; INSERM U1043, IFR-BMT, CHU Purpan Toulouse, France
4 Department of Nephrology, Dialysis and Organ Transplantation, CHU, Kremlin BicÍtre, Paris; INSERM U1014, CHU Kremlin BicÍtre, France
5 Department of Nephrology, Dialysis and Organ Transplantation; INSERM U1014, CHU Kremlin Bicêtre, France

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Date of Web Publication3-Mar-2015
 

   Abstract 

Few studies have reported the use of double-filtration plasmapheresis (DFPP) in antibody-incompatible kidney transplantation. To assess the efficiency and tolerability of DFPP, we prospectively studied four chronic hemodialysis patients from two centers undergoing antibody-incompatible kidney transplantation. DFPP was used for ABO-incompatible transplantation (n = 1), for high human leukocyte antigen (HLA) immunization levels (n = 2) or for the presence of a donor-specific antibody (DSA) against a potential living donor (n = 1). In all the patients, the DFPP program was discontinued because of the adverse effects. Low blood pressure occurred during the first hour of the session in all the patients. A significant loss of plasma proteins, clotting factors and immunoglobulins also occurred during this treatment. In addition, fistula thrombosis was diagnosed in two patients. Three patients experienced gastrointestinal symptoms. The DFPP reduced the titers of the anti-B antibodies and reduced the levels of DSA in one patient, but had no effect on anti-HLA antibodies in the remaining two patients. Our study highlights the non-tolerability and poor efficacy of DFPP prior to antibody-incompatible kidney transplantation that limit its extensive use in the desensitization protocols.

How to cite this article:
Hebibi H, Weclawiak H, Rostaing L, Beaudreuil S, Allal A, François H, Durrbach A, Kamar N. Non-tolerability of double-filtration plasmapheresis in antibody-incompatible kidney transplant candidates. Saudi J Kidney Dis Transpl 2015;26:297-301

How to cite this URL:
Hebibi H, Weclawiak H, Rostaing L, Beaudreuil S, Allal A, François H, Durrbach A, Kamar N. Non-tolerability of double-filtration plasmapheresis in antibody-incompatible kidney transplant candidates. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2019 Nov 15];26:297-301. Available from: http://www.sjkdt.org/text.asp?2015/26/2/297/152435

   Introduction Top


Several methods have been developed to remove plasma immunoglobulins prior to anti-body-incompatible kidney transplantation [antibodies against human leukocyte antigen (HLA) or against AB antigens] over the past 20 years. Many studies have reported the success of plasmapheresis or protein A immunoadsorption to prevent acute humoral rejection. [1],[2],[3] Another plasmapheresis method, called double-filtration plasmapheresis (DFPP), has been poorly studied in antibody-incompatible kidney transplant patients. This method uses a plasma separator (a primary filter) to separate plasma from the cell components and a plasma fractionator (a secondary filter) to remove plasma immunoglobulins from the filtered plasma. Compared with regular plasma exchange, this regimen enables selective removal of high molecular-weight proteins from plasma (plasma-immunoglobulin fraction) and reconstitutes the patient's plasma and other protein components.

A few studies have reported the success of DFPP prior to ABO-incompatible kidney transplantation with and without a regimen of rituximab and/or splenectomy, [4],[5] and in patients with a relapse of focal and segmental glomerulosclerosis (FSGS) after kidney transplantation. [6] More recently, DFFP has been evaluated to desensitize kidney transplant candidates against HLA antigens without any other pre-conditioning regimen. [7] This latter study showed that DFPP was unable to reduce donor-specific antibody (DSA) levels during the post-transplant period. Moreover, cross-match of complement-dependent lymphocytoxicity (CDC) and flow cytometry (FC) remained positive in a high proportion of patients at the end of the DFPP course. In terms of tolerability, the DFPP sessions were only discontinued in a small fraction of patients because of hemodynamic instability.

In this study, we describe the experience with DFPP as a pre-conditioning regimen in the HLA- and ABO-incompatible kidney transplant candidates. We report on the hemodynamic complications that occurred in those patients related to this procedure.


   Patients and Methods Top


We performed a prospective study in two medical centers (CHU Bicêtre Hospital, AP-HP, Paris, France and CHU Rangueil, Toulouse, France) to assess the efficacy of the DFPP prior to antibody-incompatible kidney transplantation.

Four patients with end-stage renal disease treated with chronic hemodialysis and on the waiting list for a kidney transplant were included in this study. One patient had an ABO incompatibility with his donor, two other patients had high HLA immunization levels, i.e. panel-reactive alloantibodies (PRA) of >80%, and the fourth patient, for whom living donor transplantation was planned, experienced DSA against his potential living donor. Reactivity of serum to specific HLA antigens was measured using a microbead assay (One lambda, Canoga Park, CA, USA) and was analyzed with the Luminex technique. This assay was performed before and after each DFPP session to determine whether the treatment could remove the anti-HLA antibodies.

Five DFPP pre-transplant sessions were planned on alternate days. The DFPP was performed using Plasmaflo TM OP-05W (Asahi Kasei Medical, Tokyo, Japan) as the first filter to separate the blood into plasma and blood-cell components. Cascadeflo TM EC-20W (Asahi Kasei Medical, Tokyo, Japan) was used as the second filter to remove plasma immunoglobulins from the separated plasma. The volume of plasma processed during each session was 50 mL/kg. The blood-flow rate was 200 mL/min and the plasma-separation rate was ~20% of the blood-flow rate. Unfractionated heparin was used as the anticoagulant for all the patients. An arteriovenous fistula was used as the vascular access for the DFPP in all the patients. Each session was followed by perfusion of human polyvalent immunoglobulins (1 g/kg). Substitution fluid (either albumin replacement or fresh frozen plasma) was not routinely used.

The patients for whom the kidney transplantation was planned with a living donor (cases 3 and 4) were pre-treated with rituximab therapy at Days 15 or 21, respectively, prior to the DFPP (one dose of rituximab 375 mg/m 2 given 15 days before the DFPP, followed by the conventional triple-drug immunosuppression consisting of tacrolimus, mycophenolate mofetil and prednisolone starting one week before the DFPP). Conversely, no rituximab therapy was given in the other two patients for whom no living kidney donor was available and for whom the aim of the DFPP was to decrease the anti-HLA allo-antibodies.


   Results Top


The patients' characteristics are summarized in [Table 1]. All the patients were male, with an average age of 32 years. The average duration of the DFPP was 2 h 30 min and we used fistulas as the access for the procedure. Hemodynamic instability occurred in all the patients, and most of them had abdominal pain. However, all patients could be dialyzed the next day to the DFPP. However, there were no bleeding complications due to the DFPP.
Table 1: Patients' characteristics included in this study.

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Other biological parameters were quantified before and after each session: Plasma-albumin level, hemoglobin and hematocrit levels, plasma-immunoglobulin level, serum calcium and coagulation factors. The mean variations of the biological parameters before and after each DFPP session are summarized in [Table 2]. There were significant decreases in the immunoglobulin, coagulation factors and fibrinogen, plasma proteins and hemoglobin levels. Two patients experienced a significant decrease in anti-B antibodies or DSA anti-DQ4 after two sessions. For the other two patients, one had no significant decrease of anti-HLA antibodies after one session and the other had no reduction after two sessions.
Table 2: Mean variation and standard deviation of selected parameters during the DFPP sessions

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   Discussion Top


Our study was initially designed to assess the efficacy of the DFPP to remove plasma immunoglobulins prior to the antibody-incompatible kidney transplantation with or without combined rituximab therapy. Our patients did not tolerate this plasmapheresis method and, consequently, we could not perform the scheduled DFPP course. However, our results do show that the decrease of the antibodies with the DFPP was not uniform and some patients did not have a significant drop in the antibodies.

Hypotension was the main adverse effect observed in this study. Hemodynamic complications occurred mainly during the first hour of the session. A loss of plasma albumin through the second filter might explain this hemodynamic change. Indeed, the decrease in oncotic pressure secondary to albumin loss may enhance a shift of fluid into the extravascular space. The second filter used (Cascadeflo TM EC-20W) had a sieving coefficient for albumin of 0.61. Higgins et al evaluated the DFPP in the antibody-incompatible kidney transplant patients using a second filter that had a similar albumin-sieving coefficient. [7] They encountered a significant proportion of patients who had to be prematurely terminated from the DFPP because of the low blood pressure that did not respond to the administered human albumin. The use of a second filter with a higher sieving coefficient of albumin in this setting could improve tolerability, but removal of plasma immunoglobulin IgG would then be less effective.

In addition to hypotension, we observed two cases of fistula thrombosis (used as an access for the DFPP) a few hours after the first session. This clotting complication was presumably caused by the hemodynamic instability and hemoconcentration that occurred during the therapy. Indeed, the DFPP sessions were associated with high removal of clotting factors. Fibrinogen, which is characterized by a molecular weight of 340 kDa, is known to be partially removed during the DFPP sessions. [7],[8],[9] Factor XIII, which has a key role in the formation of stabilized fibrin clots, was also partially removed by the DFPP. [10] We observed that fibrinogen was the clotting factor with the highest removal rate, but there was also a significant loss of factors II and V. Moreover, for the first time, we have reported a loss of antithrombin-III activity during the DFPP. Despite significant removal of clotting factors during therapy, there were no bleeding complications in the four cases.

Three of four patients experienced gastrointestinal symptoms during the DFPP sessions. In two cases, these were abdominal pain (patients 2 and 4), whereas in the other patients, these were nausea and vomiting (patient 3). These symptoms might have been related to the decrease in oncotic pressure, which might have resulted in mesenteric edema; alternatively, the decreases in both systemic blood pressure as well as oncotic pressure during the DFPP session might have resulted in decreased blood flow in the mesenteric arteries, leading to transient mesenteric ischemia.

In conclusion, our experience was negative for the use of DFPP to desensitize patients prior to antibody-incompatible kidney transplantation. The use of this plasmapheresis method is associated with hemodynamic instability and clotting complications in chronic hemodialysis patients, which limits its extensive use. However, other studies that include protocols for the administration of human albumin during the DFPP session to improve tolerability are needed in order to further assess the efficacy of DFPP for the modified desensitization protocols.

 
   References Top

1.
Flint SM, Walker RG, Hogan C, et al. Successful ABO-Incompatible Kidney Transplantation with Antibody Removal and Standard Immunosuppression. Am J Transplant 2011;11:1016-24.  Back to cited text no. 1
    
2.
Genberg H, Kumlien G, Wennberg L, Berg U, Tydén G. ABO-incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: A 3-year follow-up. Transplantation 2008;85:1745-54.  Back to cited text no. 2
    
3.
Higgins RM, Bevan DJ, Carey BS, et al. Prevention of hyperacute rejection by removal of antibodies to HLA immediately before renal transplantation. Lancet 1996;348:1208-11.  Back to cited text no. 3
    
4.
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.  Back to cited text no. 4
    
5.
Tanabe K. Double-filtration plasmapheresis. Transplantation 2007;84(12 Suppl):S30-2.  Back to cited text no. 5
    
6.
Otsubo S, Tanabe K, Shinmura H, et al. Effect of post-transplant double filtration plasmapheresis on recurrent focal and segmental glomerulosclerosis in renal transplant recipients. Ther Apher Dial 2004;8:299-304.  Back to cited text no. 6
    
7.
Higgins R, Lowe D, Hathaway M, et al. Double filtration plasmapheresis in antibody-incompatible kidney transplantation. Ther Apher Dial 2010;14:392-9.  Back to cited text no. 7
    
8.
Yeh JH, Chiu HC. Coagulation abnormalities in serial double-filtration plasmapheresis. J Clin Apher 2001;16:139-42.  Back to cited text no. 8
    
9.
Taniguchi M, Furukawa H, Shimamura T, et al. Impact of double-filtration plasmapheresis in combination with interferon and ribavirin in living donor liver transplant recipients with hepatitis C. Transplantation 2006;81:1747-9.  Back to cited text no. 9
    
10.
Hanafusa N, Satonaka H, Doi K, Noiri E, Fujita T. Virus removal and eradication by modified double filtration plasmapheresis decreases factor XIII levels. Ther Apher Dial 2010;14:287-91.  Back to cited text no. 10
    

Top
Correspondence Address:
Prof. Nassim Kamar
Department of Nephrology, Dialysis, and Organ Transplantation, CHU Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9
France
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DOI: 10.4103/1319-2442.152435

PMID: 25758878

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