Journal of Clinical Apheresis 29:206–210 (2014)
Commentary Therapeutic Apheresis in Renal Transplantation; Current Practices Douglas S. Keith* Division of Nephrology, University of Virginia Medical Center, Charlottesville, Virginia Apheresis is an important treatment modality for the removal of pathologic antibodies and circulating proteins in kidney transplantation. The use of apheresis has been shown to be a necessary preconditioning component in ABO incompatible kidney transplant. Removal of pathologic anti-A and anti-B antibodies has been accomplished with a variety of apheresis modalities including plasma exchange, fractional plasma exchange, and immunoaborption techniques. Using these modalities in conjunction with potent modern immunosuppression, ABO incompatible kidney transplants have achieved graft and patient survivals similar to that seen in ABO compatible transplants. Apheresis has also been an important modality in the removal of anti-human leukocyte antigen (HLA) antibodies both for the purposes of desensitization and treatment of antibody mediated rejection of the kidney. Although good randomized controlled trials are lacking in the treatment of acute antibody mediated rejection, most treatment regimens include the use of apheresis as an essential component for reduction of antiHLA antibody titers. Similarly, a variety of desensitization protocols have been developed to allow highly sensitized kidney transplant candidates to be successfully transplanted in the presence of donor-specific HLA antibodies. Most of these protocols involve apheresis to improve the removal of pathologic antibodies. Finally, aphereis has been used with mixed success for the treatment of recurrent focal segmental glomerulosclerosis. Evidence indicates that in some cases a circulating factor exists which apheresis can remove and ameliorate the nephrotic C 2014 Wiley Periodicals, Inc. proteinuria. J. Clin. Apheresis 29:206–210, 2014. V Key words: renal transplant; allograft rejection; focal segmental glomerulosclerosis; desensitization; ABO incompatible; kidney transplantation
INTRODUCTION
Pathologic antibodies to both ABO and human leukocyte antigens (HLA) are significant impediments to successful kidney transplantation. Apheresis is an important treatment modality in the treatment of these pathologic antibodies. Apheresis has also been used to treat recurrent focal segmental glomerulosclerosis (FSGS) after transplant which in some cases appears to be mediated by a circulating factor in the plasma. Most of the data supporting the use of apheresis in the treatment of pathologic antibodies in kidney transplantation are based on case series. Well controlled randomized controlled trials are lacking. Despite this apheresis has emerged as an important treatment modality in kidney transplantation. APHERESIS IN ABO INCOMPATIBLE KIDNEY TRANSPLANTATION
Antibodies directed against the ABO antigen system have limited the potential donor pool for different blood type combinations. Without pretreatment, transplantation of these incompatible donor recipient pairs C 2014 Wiley Periodicals, Inc. V
led to rapid rejection due to ABO antibodies directed against ABO antigens expressed on the donor kidney endothelium. Over the last 25 years, great progress has been made in overcoming this barrier to successful transplantation. Apheresis modalities have proved to be an essential component in the pretreatment of these donor recipient combinations, and recent data indicate that in addition to potent modern immunosuppression, apheresis may be the only additional pretreatment necessary for successful transplantation of ABO incompatible pairs [1,2]. Removal of pathologic anti-A and antiB antibodies has been accomplished with a variety of apheresis modalities including plasma exchange, fractional plasma exchange, and immunoaborption techniques [3–8]. Using these modalities with modern potent immunosuppression has resulted in kidney transplant *Correspondence to: Douglas Scott Keith; Associate Professor of Medicine, Division of Nephrology, University of Virginia Medical Center, Charlottesville, VA. E-mail: [email protected]. Received 23 March 2014; Accepted 1 May 2014 Published online 27 May 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jca.21330
Therapeutic Apheresis in Renal Transplantation
outcomes equivalent to that seen with ABO compatible donor recipient pairs [2,9–11]. APHERESIS IN THE DESENSITIZATION OF HLA INCOMPATIBLE DONOR RECIPIENT PAIRS
Recipient HLA antibodies directed against the donor continues to be a vexing problem in kidney transplantation. Approximately 30% of kidney transplant candidates have detectable HLA antibodies. These antibodies are usually the result of exposures to foreign HLA antigens from blood transfusions, previous pregnancies, and prior transplants. Traditionally, these antibodies were detected using either cytotoxic or flow crossmatch techniques and were a contraindication to transplantation in those unfortunate candidates. About half of the sensitized candidates are “highly” sensitized with HLA antibody reactivity to over 80% of potential donors. These candidates often languish for years on the waiting list without potential offers due to their high reactivity. To overcome this barrier, among these transplant candidates various desensitization protocols have been devised to lower HLA antibody titers. Typically, the approach to desensitization requires multiple treatment modalities many of which include apheresis [12–34]. Apheresis has been used to acutely lower antibody titers, particularly in living donor kidney transplant where the recipient has known HLA antibodies directed against the donor. Typically, other treatments are also given to reduce the production of antibody including IVIg, rituximab, and oral immunosuppression. Using these techniques has allowed the transplantation of HLA incompatible pairs albeit with a higher risk of graft failure and acute antibody mediated rejection. In spite of the higher risks of rejection and graft failure, it appears that these candidates as a population fare better than if they remain on dialysis [35]. APHERESIS FOR THE TREATMENT OF ANTIBODY-MEDIATED KIDNEY REJECTION
In spite of the advances in immunosuppression, antibody-mediated rejection remains a difficult treatment problem and leads to high rates of graft injury and loss. In the majority of cases of antibody-mediated kidney rejection, the offending antibody is directed against HLA antigens in the donor. New technology has allowed us to identify these HLA antibodies using flow beads coated with different HLA antigens. As a result for the first time, antibody levels can be followed prospectively during treatment. The treatment of antibody-mediated rejection is largely based on case series and poorly controlled randomized trials that typically included multiple simultaneous treatments including apheresis [31,36–58]. Nevertheless, apheresis
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appears to be an important modality in the treatment of antibody-mediated rejection. In the best designed trial using immunoabsorption to remove HLA antibodies, the trial was halted due to very poor outcomes in the control arm suggesting that acute antibody removal is necessary for successful treatment [59]. APHERESIS AND THE TREATMENT OF RECURRENT FSGS
Recurrent idiopathic FSGS after renal transplantation can be a devastating complication leading to rapid failure of the allograft. Previous studies have suggested that in many cases a circulating, nonimmunoglobulin factor is important in the pathogenesis of this complication [60]. This hypothesis is supported by case series showing plasma protein absorption or plasmapheresis reduces proteinuria in these patients and that serum from patients with recurrent FSGS can increase glomerular permeability to albumin in in vitro and in vivo assays. As a result apheresis has been used to treat this complication seen in kidney transplantation. Although the literature suggests that up to 80% of cases respond to apheresis, this seemingly significant benefit may be inflated by publication bias [61–84]. CONCLUSIONS
Various forms of apheresis have been used to treat variety of antibody-mediated problems in kidney transplantation with mixed success. The most successful use of apheresis has been in the preconditioning of ABO incompatible donor recipient pairs. Apheresis has been shown to remove pathologic HLA antibodies both in the preconditioning of highly sensitized kidney transplant recipients and the treatment of antibody-mediated rejection. Finally, the treatment of recurrent FSGS after transplant in many cases responds to apheresis. Further study is necessary to determine both the best type of apheresis and intensity of treatment necessary to control these pathologic processes. ACKNOWLEDGMENT
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Commentary Therapeutic Apheresis in Renal Transplantation; Current Practices Douglas S. Keith* Division of Nephrology, University of Virginia Medical Center, Charlottesville, Virginia Apheresis is an important treatment modality for the removal of pathologic antibodies and circulating proteins in kidney transplantation. The use of apheresis has been shown to be a necessary preconditioning component in ABO incompatible kidney transplant. Removal of pathologic anti-A and anti-B antibodies has been accomplished with a variety of apheresis modalities including plasma exchange, fractional plasma exchange, and immunoaborption techniques. Using these modalities in conjunction with potent modern immunosuppression, ABO incompatible kidney transplants have achieved graft and patient survivals similar to that seen in ABO compatible transplants. Apheresis has also been an important modality in the removal of anti-human leukocyte antigen (HLA) antibodies both for the purposes of desensitization and treatment of antibody mediated rejection of the kidney. Although good randomized controlled trials are lacking in the treatment of acute antibody mediated rejection, most treatment regimens include the use of apheresis as an essential component for reduction of antiHLA antibody titers. Similarly, a variety of desensitization protocols have been developed to allow highly sensitized kidney transplant candidates to be successfully transplanted in the presence of donor-specific HLA antibodies. Most of these protocols involve apheresis to improve the removal of pathologic antibodies. Finally, aphereis has been used with mixed success for the treatment of recurrent focal segmental glomerulosclerosis. Evidence indicates that in some cases a circulating factor exists which apheresis can remove and ameliorate the nephrotic C 2014 Wiley Periodicals, Inc. proteinuria. J. Clin. Apheresis 29:206–210, 2014. V Key words: renal transplant; allograft rejection; focal segmental glomerulosclerosis; desensitization; ABO incompatible; kidney transplantation
INTRODUCTION
Pathologic antibodies to both ABO and human leukocyte antigens (HLA) are significant impediments to successful kidney transplantation. Apheresis is an important treatment modality in the treatment of these pathologic antibodies. Apheresis has also been used to treat recurrent focal segmental glomerulosclerosis (FSGS) after transplant which in some cases appears to be mediated by a circulating factor in the plasma. Most of the data supporting the use of apheresis in the treatment of pathologic antibodies in kidney transplantation are based on case series. Well controlled randomized controlled trials are lacking. Despite this apheresis has emerged as an important treatment modality in kidney transplantation. APHERESIS IN ABO INCOMPATIBLE KIDNEY TRANSPLANTATION
Antibodies directed against the ABO antigen system have limited the potential donor pool for different blood type combinations. Without pretreatment, transplantation of these incompatible donor recipient pairs C 2014 Wiley Periodicals, Inc. V
led to rapid rejection due to ABO antibodies directed against ABO antigens expressed on the donor kidney endothelium. Over the last 25 years, great progress has been made in overcoming this barrier to successful transplantation. Apheresis modalities have proved to be an essential component in the pretreatment of these donor recipient combinations, and recent data indicate that in addition to potent modern immunosuppression, apheresis may be the only additional pretreatment necessary for successful transplantation of ABO incompatible pairs [1,2]. Removal of pathologic anti-A and antiB antibodies has been accomplished with a variety of apheresis modalities including plasma exchange, fractional plasma exchange, and immunoaborption techniques [3–8]. Using these modalities with modern potent immunosuppression has resulted in kidney transplant *Correspondence to: Douglas Scott Keith; Associate Professor of Medicine, Division of Nephrology, University of Virginia Medical Center, Charlottesville, VA. E-mail: [email protected]. Received 23 March 2014; Accepted 1 May 2014 Published online 27 May 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jca.21330
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outcomes equivalent to that seen with ABO compatible donor recipient pairs [2,9–11]. APHERESIS IN THE DESENSITIZATION OF HLA INCOMPATIBLE DONOR RECIPIENT PAIRS
Recipient HLA antibodies directed against the donor continues to be a vexing problem in kidney transplantation. Approximately 30% of kidney transplant candidates have detectable HLA antibodies. These antibodies are usually the result of exposures to foreign HLA antigens from blood transfusions, previous pregnancies, and prior transplants. Traditionally, these antibodies were detected using either cytotoxic or flow crossmatch techniques and were a contraindication to transplantation in those unfortunate candidates. About half of the sensitized candidates are “highly” sensitized with HLA antibody reactivity to over 80% of potential donors. These candidates often languish for years on the waiting list without potential offers due to their high reactivity. To overcome this barrier, among these transplant candidates various desensitization protocols have been devised to lower HLA antibody titers. Typically, the approach to desensitization requires multiple treatment modalities many of which include apheresis [12–34]. Apheresis has been used to acutely lower antibody titers, particularly in living donor kidney transplant where the recipient has known HLA antibodies directed against the donor. Typically, other treatments are also given to reduce the production of antibody including IVIg, rituximab, and oral immunosuppression. Using these techniques has allowed the transplantation of HLA incompatible pairs albeit with a higher risk of graft failure and acute antibody mediated rejection. In spite of the higher risks of rejection and graft failure, it appears that these candidates as a population fare better than if they remain on dialysis [35]. APHERESIS FOR THE TREATMENT OF ANTIBODY-MEDIATED KIDNEY REJECTION
In spite of the advances in immunosuppression, antibody-mediated rejection remains a difficult treatment problem and leads to high rates of graft injury and loss. In the majority of cases of antibody-mediated kidney rejection, the offending antibody is directed against HLA antigens in the donor. New technology has allowed us to identify these HLA antibodies using flow beads coated with different HLA antigens. As a result for the first time, antibody levels can be followed prospectively during treatment. The treatment of antibody-mediated rejection is largely based on case series and poorly controlled randomized trials that typically included multiple simultaneous treatments including apheresis [31,36–58]. Nevertheless, apheresis
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appears to be an important modality in the treatment of antibody-mediated rejection. In the best designed trial using immunoabsorption to remove HLA antibodies, the trial was halted due to very poor outcomes in the control arm suggesting that acute antibody removal is necessary for successful treatment [59]. APHERESIS AND THE TREATMENT OF RECURRENT FSGS
Recurrent idiopathic FSGS after renal transplantation can be a devastating complication leading to rapid failure of the allograft. Previous studies have suggested that in many cases a circulating, nonimmunoglobulin factor is important in the pathogenesis of this complication [60]. This hypothesis is supported by case series showing plasma protein absorption or plasmapheresis reduces proteinuria in these patients and that serum from patients with recurrent FSGS can increase glomerular permeability to albumin in in vitro and in vivo assays. As a result apheresis has been used to treat this complication seen in kidney transplantation. Although the literature suggests that up to 80% of cases respond to apheresis, this seemingly significant benefit may be inflated by publication bias [61–84]. CONCLUSIONS
Various forms of apheresis have been used to treat variety of antibody-mediated problems in kidney transplantation with mixed success. The most successful use of apheresis has been in the preconditioning of ABO incompatible donor recipient pairs. Apheresis has been shown to remove pathologic HLA antibodies both in the preconditioning of highly sensitized kidney transplant recipients and the treatment of antibody-mediated rejection. Finally, the treatment of recurrent FSGS after transplant in many cases responds to apheresis. Further study is necessary to determine both the best type of apheresis and intensity of treatment necessary to control these pathologic processes. ACKNOWLEDGMENT
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