Case Report: Eculizumab Rescue of Severe Accelerated Antibody-Mediated Rejection After ABO-Incompatible Kidney Transplant

Stewart, Zoe A.; Collins, Thomas E.; Schlueter, Annette J.; Raife, Thomas; Holanda, Danniele G.; Nair, Ranjith K; Reed, Alan; Thomas, Christie P.

doi:10.1016/j.transproceed.2012.03.053

Cited by 57 publications

(38 citation statements)

References 18 publications

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“…Plasma exchange in addition to CNI withdrawal can contribute to graft salvage (71,73,84). Recently, cases of remission with eculizumab in post-transplant de novo TMA in transplant have been reported (85)(86)(87).…”

Section: Thrombotic Microangiopathymentioning

confidence: 99%

De Novo Glomerular Diseases after Renal Transplantation

Ponticelli

Moroni

Glassock

2014

Clinical Journal of the American Society of Nephrology

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Glomerular diseases developing in the kidney allograft are more often recurrences of the original disease affecting the native kidneys. However, in an undefined number of cases de novo, glomerular diseases unrelated to the original disease in the native kidneys can develop in the transplanted kidney. The clinical presentation and histologic features of de novo diseases are often similar to those features observed in patients with primary or secondary GN in the native kidneys. However, in transplanted kidneys, the glomerular, vascular, and tubulointerstitial changes are often intertwined with structural abnormalities already present at the time of transplant or caused by antibody-or cell-mediated allograft rejection, immunosuppressive drugs, or superimposed infection (most often of a viral nature). The pathophysiology of de novo glomerular diseases is quite variable. In rare cases of de novo minimal change disease, circulating factors increasing the glomerular permeability likely participate. Maladaptive hemodynamic changes and tissue fibrosis caused by calcineurin inhibitors or other factors may be involved in the pathogenesis of de novo FSGS. The exposure of cryptic podocyte antigens may favor the development of de novo membranous nephropathy. Many cases of de novo membranoproliferative GN are related to hepatitis C virus infection. Patients with Alport syndrome lacking antigenic epitopes in their glomerular basement membrane may develop antibodies against these glomerular basement membrane antigens expressed in the transplanted kidney. Infection may cause acute GN to have a heterogeneous clinical presentation and outcome. De novo pauci-immune GN in renal transplant is rare. Preexisting or acquired intolerance to glucose may, in the long term, cause diabetic nephropathy. The prognosis of de novo diseases depends on the type of GN, the severity of lesions caused by the alloimmune response, or the efficacy of immunosuppressive therapy. In most cases, the management of de novo glomerular diseases is empirical or elusive.

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Section: Thrombotic Microangiopathymentioning

confidence: 99%

De Novo Glomerular Diseases after Renal Transplantation

Ponticelli

Moroni

Glassock

2014

Clinical Journal of the American Society of Nephrology

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“…Eculizumab is also marketed for atypical hemolytic uremic syndrome (aHUS) (48) and is currently in clinical trials for other indications (44). Eculizumab has also been reported to reverse antibody-mediated complement activation in a case of ABO incompatible kidney and pancreas transplantation (49), and kidney-alone transplantation (50) as well as other off-label uses. Eculizumab is very effective for individuals for PNH; however, it is currently one of the most expensive drugs on the market as a result of its high cost of production and its orphan status.…”

Section: Complement Inhibitors For Transfusion Medicine Applicationsmentioning

confidence: 99%

Peptide Inhibitor of Complement C1, a Novel Suppressor of Classical Pathway Activation: Mechanistic Studies and Clinical Potential

et al. 2014

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The classical pathway of complement plays multiple physiological roles including modulating immunological effectors initiated by adaptive immune responses and an essential homeostatic role in the clearance of damaged self-antigens. However, dysregulated classical pathway activation is associated with antibody-initiated, inflammatory diseases processes like cold agglutinin disease, acute intravascular hemolytic transfusion reaction (AIHTR), and acute/hyperacute transplantation rejection. To date, only one putative classical pathway inhibitor, C1 esterase inhibitor (C1-INH), is currently commercially available and its only approved indication is for replacement treatment in hereditary angioedema, which is predominantly a kinin pathway disease. Given the variety of disease conditions in which the classical pathway is implicated, development of therapeutics that specifically inhibits complement initiation represents a major unmet medical need. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement. In vitro studies have demonstrated that these peptide inhibitors of complement C1 (PIC1) bind to the collagen-like region of the initiator molecule of the classical pathway, C1q. PIC1 binding to C1q blocks activation of the associated serine proteases (C1s–C1r–C1r–C1s) and subsequent downstream complement activation. Rational design optimization of PIC1 has resulted in the generation of a highly potent derivative of 15 amino acids. PIC1 inhibits classical pathway mediated complement activation in ABO incompatibility in vitro and inhibiting classical pathway activation in vivo in rats. This review will focus on the pre-clinical development of PIC1 and discuss its potential as a therapeutic in antibody-mediated classical pathway disease, specifically AIHTR.

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“…15 A limitation of this observation was that multiple therapeutic agents were given before or simultaneously with eculizumab. Other cases [16][17][18][19] of acute ABMR in which eculizumab was used as salvage treatment have been published recently. The main drawbacks of these case reports is that multiple therapeutic agents were used before or simultaneously with eculizumab treatment, making it difficult to draw solid conclusions about the efficacy of eculizumab in ABMR improvement.…”

Section: Discussionmentioning

confidence: 99%

Eculizumab to Treat Antibody-Mediated Rejection in a 7-Year-Old Kidney Transplant Recipient

et al. 2015

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We report on successful early eculizumab administration to treat acute antibody-mediated rejection (ABMR) in a highly sensitized kidney transplant recipient. The recipient is a 7-year-old boy who received, 6 months after a desensitization protocol with monthly intravenous immunoglobulin infusion, a second kidney transplant in the presence of low donor-specific antibodies (DSAs). Both pretransplant lymphocytotoxic and flow cytometric crossmatch were negative. Allograft function recovered promptly, with excellent initial function. On postoperative day (POD) 4, the child developed significant proteinuria with an acute rise in serum creatinine. Allograft biopsy showed severe acute ABMR. Intravenous eculizumab (600 mg), preceded by a single session of plasmapheresis, was administered on POD 5 and 12 along with a 4-day thymoglobulin course. After the first dose of eculizumab, a strikingly rapid normalization of allograft function with a decrease in proteinuria occurred. However, because circulating DSA levels remained elevated, the child received 3 doses of intravenous immunoglobulin (POD 15,16,and 17), with a significant subsequent decrease in DSA levels. At 9 months after transplant, the child continues to maintain excellent allograft function with undetectable circulating DSA levels. This unique case highlights the potential efficacy of using early eculizumab to rapidly reverse severe ABMR in pediatric transplantation, and therefore it suggests a novel therapeutic approach to treat acute ABMR.

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Case Report: Eculizumab Rescue of Severe Accelerated Antibody-Mediated Rejection After ABO-Incompatible Kidney Transplant

Cited by 57 publications

References 18 publications

De Novo Glomerular Diseases after Renal Transplantation

De Novo Glomerular Diseases after Renal Transplantation

Peptide Inhibitor of Complement C1, a Novel Suppressor of Classical Pathway Activation: Mechanistic Studies and Clinical Potential

Eculizumab to Treat Antibody-Mediated Rejection in a 7-Year-Old Kidney Transplant Recipient

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