The multifaceted role of complement in kidney transplantation

Biglarnia, Ali-Reza; Huber‐Lang, Markus; Mohlin, Camilla; Ekdahl, Kristina Nilsson; Nilsson, Bo

doi:10.1038/s41581-018-0071-x

Cited by 65 publications

(63 citation statements)

References 175 publications

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“…Interestingly, complement blockade has recently emerged as an interesting therapeutic option for acute AMR in kidney allotransplantation 17 . Eculizumab is a humanized monoclonal antibody that binds to the human C5 complement protein, resulting in terminal pathway complement inhibition and blockade of C5a, a crucial anaphylatoxin that promotes neutrophil attraction and acute inflammation.…”

Section: Discussionmentioning

confidence: 99%

Upfront use of eculizumab to treat early acute antibody‐mediated rejection after kidney allotransplantation and relevance for xenotransplantation

Schwotzer

Paganetti

Barchi

et al. 2020

Xenotransplantation

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Acute antibody‐mediated rejection (AMR) early after transplant remains a challenge, both in allotransplantation and in xenotransplantation. We report the case of an early and severe acute AMR episode in a kidney transplant recipient that was successfully treated with upfront eculizumab. A 58‐year‐old woman had been on dialysis since 2014. She underwent a first kidney transplant in 2018 with primary non‐function and received several blood transfusions. Postoperatively, she developed anti‐HLA antibodies. One year later, she received a second allograft from a deceased donor. At day 0, there was only one preformed low‐level donor‐specific antibody (DSA) anti‐DQ7. After initial excellent allograft function, serum creatinine increased on days 7‐9, and this was associated with oligo‐anuria. On day 7, there was an increase in her DSA anti‐DQ7 and 4 de novo DSA had developed at high MFI values. Allograft biopsy showed severe active AMR with diffuse C4d deposits in peritubular capillaries. The early acute AMR episode was treated with upfront eculizumab administration (2 doses) with efficient CH50 blockade (< 10% CH50). Rituximab was also administered on day 12, and intravenous immunoglobulin (IVIG) was given over the following days. There was an excellent clinical response to eculizumab administration. Eculizumab administration rapidly reversed the acute AMR episode without the need for plasmapheresis. Rituximab and IVIG were also used as B‐cell immunomodulators to decrease DSA. Blocking efficiently the terminal complement pathway may become a useful strategy to treat acute AMR in sensitized recipients of allografts, and possibly in recipients of discordant xenografts.

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Section: Discussionmentioning

confidence: 99%

Upfront use of eculizumab to treat early acute antibody‐mediated rejection after kidney allotransplantation and relevance for xenotransplantation

Schwotzer

Paganetti

Barchi

et al. 2020

Xenotransplantation

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“…It is increasingly appreciated that solid organ transplantation triggers several pathogenic pathways that are tightly intertwined with various effectors of complement activation, both in the vasculature and on the allograft surface 55,56 . In addition to its cardinal role in triggering donor organ inflammatory damage via CP/LP-mediated neoepitope recognition during I/R, complement activation is also considered a major pathogenic driver in acute antibody-mediated rejection (ABMR) following allogeneic organ transplantation 32,57,58 (FIG.…”

Section: Organ Transplantationmentioning

confidence: 99%

“…Moreover, its multifaceted role in driving adaptive immune stimulation and humoral responses is growingly appreciated as a factor further affecting long-term graft function 32 . Sensitization of transplant recipients by donor-specific human leukocyte antigen (HLA)-directed or ABO-directed alloantibodies marks a key initial trigger for both acute transplant rejection and for fuelling chronic cell-mediated organ injury and rejection (that is, across HLA and ABO transplantation barriers) 56,58 . Given the pervasive nature of complement's involvement in the transplant process, it is hardly surprising that pharmaceutical companies are devoting attention to targeted therapeutics for organ transplantation.…”

Section: Organ Transplantationmentioning

confidence: 99%

Clinical promise of next-generation complement therapeutics

Mastellos

Ricklin

Lambris

2019

Nat Rev Drug Discov

257

283

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Author contributions All authors researched the data for the article, contributed to discussions of the content, wrote the text, and reviewed or edited the article before submission. Competing interests J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors for therapeutic purposes. J.D.L. and D.R. are inventors of patents or patent applications that describe the use of complement inhibitors for therapeutic purposes, some of which are developed by Amyndas Pharmaceuticals. J.D.L. is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals (that is, 4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives). D.C.M. declares no competing interests.

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“…To reduce the level of anti-HLA antibodies, many therapeutical regimens can be used. Usually they are combination of plasmapheresis (PP), immunoadsorption (IA), intravenous immunoglobulin (IVIg), rituximab, proteasome inhibitors such as bortezomib, complement inhibitors (69,70). Applications of these stratagems prior to kidney (69,71,72), heart (73)(74)(75) and lung (57) transplantation, or treatment of AMR (4,76), have been reviewed extensively in published literatures.…”

Section: False Positivity Due To Antigen Configuration or Other Unknomentioning

confidence: 99%

Detecting donor-specific antibodies: the importance of sorting the wheat from the chaff

McCaughan

Tinckam

2019

Hepatobiliary Surg. Nutr

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Human leukocyte antigen (HLA) compatibility is very important for successful transplantation of solid organs. In this paper, we focused on the humoral arm of immunity in the clinical setting of organ transplantation: how HLA antibodies develop, how they can be detected, and what they can do to injure organ transplants. Specifically, we explore the technical perspectives of detecting donor-specific antibodies (DSA) in HLA laboratories, and use real-life clinical cases to explain the principles. Currently there are many tools in our HLA antibody detection toolbox: conventional cytotoxicity cross match, flow cross match, and solid phase assays using beads conjugated with single or multiple HLA antigens. Single antigen bead (SAB) assay is the most sensitive tool available for detecting HLA antibodies and assessing the immunological risk for organ transplant. However, there are intrinsic limitations to solid-phase assays and they are prone to both false negativity and importantly, false positivity. Denatured antigens on single antigen beads might be the most prominent source of false positive reactivity, and may have been underestimated by many HLA experts. No single assay is perfect and therefore multiple methods, including the less sensitive assays, should be employed to determine the clinical relevance of detected HLA antibodies. Thoughtful process, including knowledge of HLA systems, cross reactivity, epitopes, and the patient's clinical history should be employed to correctly interpret data. The clinical team should work closely with HLA laboratories to ensure accurate interpretation of information and optimal management of patients before and after organ transplantation.

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The multifaceted role of complement in kidney transplantation

Cited by 65 publications

References 175 publications

Upfront use of eculizumab to treat early acute antibody‐mediated rejection after kidney allotransplantation and relevance for xenotransplantation

Upfront use of eculizumab to treat early acute antibody‐mediated rejection after kidney allotransplantation and relevance for xenotransplantation

Clinical promise of next-generation complement therapeutics

Detecting donor-specific antibodies: the importance of sorting the wheat from the chaff

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