Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation

Biglarnia, Ali-Reza; Nilsson, Bo; Nilsson, Thomas; Zur‐Mühlen, Bengt von; Wagner, Michael; Berne, Christian; Wanders, Alkwin; Magnusson, Anders; Tufveson, Gunnar

doi:10.1111/j.1432-2277.2011.01290.x

Cited by 72 publications

(51 citation statements)

References 17 publications

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“…When this occurs acutely, most frequently seen in pre-sensitised or ABO incompatible transplants, it can lead to rapid graft loss. The most compelling evidence that complement is important in acute AMR is the reported experience of complement inhibition with monoclonal anti-C5 in the treatment [67,68] or prevention of AMR [69] . The role of complement in chronic AMR, increasingly recognised as a cause of graft failure, is less clear.…”

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confidence: 99%

Complement activation in progressive renal disease

Fearn

Sheerin

2015

WJN

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ritis, thrombotic microangiopathies and transplant reje ction. In this review we discuss current evidence that complement activation contributes to progression of CKD, how complement could cause renal inflammation and whether complement inhibition would slow progression of renal disease. Core tip: Complement activation occurs in progressive chronic kidney disease and may contribute to the chronic inflammation that is characteristically found in the kidney. It is therefore possible that inhibiting complement activation would reduce inflammation, lead to reduced fibrosis and preservation of renal function. INTRODUCTIONChronic kidney disease (CKD) is recognised worldwide as a major public health problem [1] . In 2007 the United Kingdom age-standardised prevalence of CKD stages 3-5 was 8.5% (10.6% in females and 5.8% in males) [2] and similar prevalences have been described in other countries. In 2012 in the United Kingdom, the number of new patients requiring renal replacement therapy was 6891, equating to 108 patients per million population, with diabetes and glomerulonephritis being the two most common diagnoses in incident dialysis patients. Although not all patients with CKD will progress to renal failure, all stages of CKD are associated with increased AbstractChronic kidney disease (CKD) is common and the cause of significant morbidity and mortality. The replacement of functioning nephrons by fibrosis is characteristic of progressive disease. The pathways that lead to fibrosis are not fully understood, although chronic nonresolving inflammation in the kidney is likely to drive the fibrotic response that occurs. In patients with progressive CKD there is histological evidence of inflammation in the interstitium and strategies that reduce inflammation reduce renal injury in preclinical models of CKD. The complement system is an integral part of the innate immune system but also augments adaptive immune responses. Complement activation is known to occur in many diverse renal diseases, including glomeruloneph morbidity and mortality [1] . Tubulointerstitial inflammation and fibrosis is a major factor in the progressive loss of renal function in most kidney diseases [3] . The process is complex due to the number of interacting pathways which ultimately result in the replacement of functioning nephrons with scar tissue. Cellular stress and injury induces an inflammatory and pro-fibrogenic response involving growth factors [4][5][6] and pro-inflammatory cytokines as well as activation of the renin-angiotensin system. This leads to a chronic inflammatory cell infiltrate, increasing numbers of activated fibroblasts (myofibroblasts) and excessive matrix deposition. There is evidence from preclinical models that the immune system is important in the development of renal fibrosis [7,8] . A component of the innate immune system that may be important in driving renal inflammation is the complement system, which can directly affect cell function and also influence the adaptive immune response. REVIEW COMPLEMENT SYSTEMTh...

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confidence: 99%

Complement activation in progressive renal disease

Fearn

Sheerin

2015

WJN

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“…However, there were little to no difference after day 14 [71]. Following transplantation of different organs, ABO AMRs have been reversed using intense Ab removal [72] in combination with complement inhibition [30,33,73,74].…”

Section: Anti-a and Anti-b Antibody-mediated Rejectionmentioning

confidence: 97%

Molecular Deciphering of the ABO System as a Basis for Novel Diagnostics and Therapeutics in ABO Incompatible Transplantation

Holgersson¹,

Rydberg²,

Breimer

2013

International Reviews of Immunology

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In recent years ABO incompatible kidney transplantation (KTx) has become a more or less clinical routine procedure with graft and patient survival similar to those of ABO compatible transplants. Antigen-specific immunoadsorption (IA) for anti-A and anti-B antibody removal constitutes in many centers an important part of the treatment protocol. ABO antibody titration by hemagglutination is guiding the treatment; both if the recipient can be transplanted as well as in cases of suspected rejections if antibody removal should be performed. Despite the overall success of ABO incompatible KTx, there is still room for improvements and an extension of the technology to include other solid organs. Based on an increased understanding of the structural complexity and tissue distribution of ABH antigens and the fine epitope specificity of the ABO antibody repertoire, improved IA matrices and ABO antibody diagnostics should be developed. Furthermore, understanding the molecular mechanisms behind accommodation of ABO incompatible renal allografts could make it possible to induce long-term allograft acceptance also in human leukocyte antigen (HLA) sensitized recipients and, perhaps, also make clinical xenotransplantation possible.

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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%

“…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.…”

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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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Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation

Cited by 72 publications

References 17 publications

Complement activation in progressive renal disease

Complement activation in progressive renal disease

Molecular Deciphering of the ABO System as a Basis for Novel Diagnostics and Therapeutics in ABO Incompatible Transplantation

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

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