• ABO blood type-incompatible
• blood type A/B antibody
• complement-binding blood type antibody
• hyperacute rejection
• kidney transplantation

• complement
• immunology and pathology
• ischemia-reperfusion
• kidney transplantation
• renal transplantation
• transplant outcomes
• transplant pathology

• Humans
• Kidney Transplantation/adverse effects
• Kidney/pathology
• Transplantation, Homologous
• Complement Activation
• Complement System Proteins
• Isoantibodies
• Ischemia/pathology
• Graft Rejection/prevention & control

• kidney transplant
• rejection
• transplantation

• Immunosuppressant
• molecular biology
• rejection
• signaling pathways
• transplant pharmacist

• Atypical hemolytic uremic syndrome
• Eculizumab
• Hemolytic uremic syndrome
• Pediatric

One of the principal obstacles in transplantation from living donors is that approximately 30% are immunologically incompatible because of the presence in the recipient of antibodies directed against the human leukocyte antigen system of the donor or because of the incompatibility of the ABO system. The aim of this review is to describe the more recent data from the literature on the different protocols used and the clinical outcomes of ABO-incompatible kidney transplantation. Two different strategies are used to overcome these barriers: desensitization of the recipient to remove the antibodies and to prevent their rebound after transplantation and the exchange of organs between two or more pairs. The largest part of this review is dedicated to describing the techniques of desensitization. Even if the first reports of successful renal transplantation between ABO-incompatible pairs have been published by 1980, the number of ABO-incompatible transplants increased substantially in this century because of our improved knowledge of the immune system and the availability of new drugs. Rituximab has substantially replaced splenectomy. The technique of apheresis has improved and more recently a tailored desensitization proved to be the more efficient strategy avoiding an excess of immunosuppression with the related side effects. Recent reports document outcomes for such transplantation similar to the outcomes of standard transplantation.

• ABO-incompatible transplants
• Desensitization strategies
• Immunological aspects
• B cell depletion
• Immunomodulation
• Apheresis techniques
• Kidney paired donation

• C1 esterase inhibitor
• Complement
• Eculizumab
• Rejection
• Transplant

• Autoimmunity
• autoantibody
• glomerulonephritis
• immunotherapy
• kidney

For decades, kidney diseases related to inappropriate complement activity, such as atypical hemolytic uremic syndrome and C3 glomerulopathy (a subtype of membranoproliferative glomerulonephritis), have mostly been complicated by worsened prognoses and rapid progression to end-stage renal failure. Alternative complement pathway dysregulation, whether congenital or acquired, is well-recognized as the main driver of the disease process in these patients. The list of triggers include: surgery, infection, immunologic factors, pregnancy and medications. The advent of complement activation blockade, however, revolutionized the clinical course and outcome of these diseases, rendering transplantation a viable option for patients who were previously considered as non-transplantable cases. Several less-costly therapeutic lines and likely better efficacy and safety profiles are currently underway. In view of the challenging nature of diagnosing these diseases and the long-term cost implications, a multidisciplinary approach including the nephrologist, renal pathologist and the genetic laboratory is required to help improve overall care of these patients and draw the optimum therapeutic plan.

• Complement-related diseases
• Kidney transplantation
• De novo
• Recurrent diseases

ABO-incompatible living related kidney transplantation (ABO-iLKT) has increased the possibilities for kidney transplantation in patients with end stage renal disease. Due to advancements in immunosuppressive agents and the identification of immunological conditions following ABO-iLKT, this transplantation technique has achieved the same success rate as ABO-compatible LKT. However, some patients continue to generate anti-blood type antibodies, despite conventional immunosuppressant treatment.

A 60-year-old man was referred to our hospital for kidney transplantation. The proposed transplant was ABO incompatible, from a donor with blood-type A to a recipient with blood-type O. The recipient’s anti-A blood-type IgG antibody titer was measured at 4096-fold dilution. Following desensitization therapy, including mycophenolate mofetil (MMF) 750 mg/day for 3 months, intravenous Rituximab 200 mg, and two sessions of double filtration plasmapheresis, the anti-A blood-type IgG antibody titer decreased to only 516-fold dilution and did not meet our target of less than 128-fold dilution. MMF was thus continued for an additional 4 months and four additional sessions of plasmapheresis were undertaken. Following these interventions, antibody titers decreased to 128-fold dilution and ABO-iLKT was performed. Following transplant, antibody-mediated rejection was not observed and renal function was preserved. However, a post-operative renal biopsy 1.5 months later showed evidence of T-cell-mediated rejection IB. The patient was treated with steroids, with no increase in serum creatinine.

Our findings suggest that the long-term single MMF desensitization therapy could be a suitable option for ABO-iLKT with high refractory and rebound anti-blood type antibody. Further studies are required to establish the optimal immunosuppression regimen to control B cell- mediated immunity in ABO-iLKT.

• ABO-incompatible living related kidney transplantation
• Anti-blood type antibody
• B-cell immunity
• Mycophenolate mofetil

Thrombotic microangiopathy (TMA) is one of the most devastating sequalae of kidney transplantation. A number of published articles have covered either de novo or recurrent TMA in an isolated manner. We have, hereby, in this article endeavored to address both types of TMA in a comparative mode. We appreciate that de novo TMA is more common and its prognosis is poorer than recurrent TMA; the latter has a genetic background, with mutations that impact disease behavior and, consequently, allograft and patient survival. Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as de novo disease with no evidence of previous involvement before transplant. While atypical hemolytic uremic syndrome is a rare disease that results from complement dysregulation with alternative pathway overactivity, de novo TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases. Management of both diseases varies from simple maneuvers, e.g., plasmapheresis, drug withdrawal or dose modification, to lifelong complement blockade, which is rather costly. Careful donor selection and proper recipient preparation, including complete genetic screening, would be a pragmatic approach. Novel therapies, e.g., purified products of the deficient genes, though promising in theory, are not yet of proven value.

• Kidney transplantation
• De novo thrombotic microangiopathy
• Thrombotic microangiopathy
• Recurrent thrombotic microangiopathy
• Atypical hemolytic uremic syndrome

• Clinical trial
• Complement
• Drug
• Eculizumab
• Indication
• Therapeutic

Thrombotic microangiopathy is a form of antibody-mediated rejection (ABMR): it is the main complication of ABO-incompatible (ABOi) kidney transplantation (KT). Herein, we report on two cases of ABMR with biological and histological features of thrombotic microangiopathy (TMA) that were treated by eculizumab after ABOi KT. The first patient presented with features of TMA at postoperative day (POD) 13. Because of worsening biological parameters and no recovery of kidney function, despite seven sessions of immunoadsorption, a salvage therapy of eculizumab was started on POD 23. Kidney function slightly improved during the first 4 months after transplantation. Eculizumab was stopped at month 4. However, kidney function worsened progressively, leading to dialysis at month 13 after transplantation. The second patient presented with features of TMA at POD 1. In addition to immunoadsorption therapy, eculizumab was started on POD 6. Kidney function improved. Eculizumab was stopped on POD 64 and immunoadsorption sessions were stopped on POD 102. At the last follow-up (after 9 months), eGFR was at 43 mL/min/1.73 m². Our case reports show the beneficial effect of eculizumab to treat ABMR after ABOi KT. However, it should be given early after diagnosing TMA associated with ABMR.

• Belatacept
• Complement
• Eculizumab
• Hemolytic uremic syndrome
• Kidney transplantation
• Thrombotic microangiopathy

• Humans
• Kidney Failure, Chronic/surgery
• Kidney Transplantation/adverse effects
• Primary Graft Dysfunction/etiology
• Thrombotic Microangiopathies/complications

• complement
• kidney transplantation
• rejection
• transcriptional profiling

• atypical haemolytic uraemic syndrome
• complement
• eculizumab
• thrombotic microangiopathy

• MR/R000913/1 Medical Research Council

• Antibodies against complement components
• Antiphospholipid antibodies
• Biomarkers
• Biopharmaceuticals
• Complement

• antibody-mediated rejection
• anticomplement therapy
• complement
• ischemia/reperfusion injury
• kidney transplantation

• Antibody-mediated rejection
• C1 inhibitor
• Complement
• Eculizumab
• Kidney transplantation

• Acute cellular rejection
• TOL101
• Thymoglobulin
• alemtuzumab
• antibody mediated rejection
• antithymocyte globulin
• basiliximab
• belimumab
• eculizumab
• induction therapy
• monoclonal antibodies
• rATG
• rituximab
• tocilizumab
• transplant rejection
• transplantation

• Eculizumab
• Off-label use
• Organ rejection
• Orphan drugs
• Pharmaceutical spending
• Transplantation

A 46-year-old female with interstitial lung disease presented with proximal muscle weakness, worsening hypertension, microangiopathic hemolysis, thrombocytopenia and deteriorating renal function. She had no sclerodactyly, but had abnormal capillaroscopy. She tested positive for PM-Scl antibodies, and a renal biopsy showed an acute thrombotic microangiopathy consistent with scleroderma renal crisis (SRC). She failed to respond to corticosteroids, plasmapheresis and renin–angiotensin pathway inhibitors. She recovered quickly with the anti-C5 antibody, eculizumab. She had no genetic abnormalities associated with atypical hemolytic uremic syndrome except a DNA variant of unknown significance in C3. This case suggests that eculizumab may be effective for SRC.

• AKI
• autoantibodies
• complement
• plasmapheresis
• scleroderma renal crisis

ABO-incompatible kidney transplantation (ABOi KT) was introduced to expand the donor pool and minimize shortage of kidneys for transplantation. Because improved outcomes of ABOi KT were reported in Japan in the early 2000s, the number of ABOi KTs has been increasing worldwide. In addition, a better understanding of immune pathogenesis and subsequent aggressive immunosuppression has helped to make effective desensitization protocols. Current strategies of ABOi KT consist of pretransplant antibody removal using plasmapheresis or immunoadsorption to prevent hyperacute rejection and potent maintenance immunosuppression, such as tacrolimus and mycophenolate mofetil, to inhibit antibody-mediated rejection. Recent outcomes of ABOi KT are comparable with ABO-compatible KT. However, there are still many problems to be resolved. Very high anti-ABO antibody producers are difficult to desensitize. In addition, ABOi KT is associated with an increased risk of infection and possibly malignancy due to aggressive immunosuppression. Optimization of desensitization and patient-tailored immunosuppression protocols are needed to achieve better outcomes of ABOi KT. This review provides an overview of the history, immune mechanism, immunosuppressive protocol, outcomes, current obstacles, and future perspectives in ABOi KT.

• Blood group incompatibility
• Desensitization
• Kidney transplantation
• Outcomes

• acute humoral rejection
• case report
• eculizumab
• infant
• kidney transplant

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.

• ABO incompatibility
• AIHTR
• C1q
• MBL
• classical pathway
• complement
• inhibitor
• peptide

• GN
• renal transplantation
• transplant pathology

The major challenge in ABO-incompatible transplantation is to minimize antibody-mediated rejection. Effective reduction of the anti-ABO blood group antibodies at the time of transplantation has made ABO-incompatible kidney transplantation a growing practice in our hospital and in centers worldwide. ABO antibodies result from contact with A- and B-like antigens in the intestines via nutrients and bacteria. We demonstrate a patient with fulminant antibody-mediated rejection late after ABO-incompatible kidney transplantation, whose anti-A antibody titers rose dramatically following Serratia marcescens sepsis.

A 58-year-old woman underwent an ABO-incompatible kidney transplantation for end-stage renal disease secondary to autosomal dominant polycystic kidney disease. It concerned a blood group A1 to O donation. Pre-desensitization titers were 64 for anti-blood group A IgM and 32 for anti-blood group A IgG titers. Desensitization treatment consisted of rituximab, tacrolimus, mycophenolate mofetil, corticosteroids, immunoadsorption and intravenous immunoglobulines. She was readmitted to our hospital 11 weeks after transplantation for S. marcescens urosepsis. Her anti-A IgM titer rose to >5000 and she developed a fulminant antibody-mediated rejection.

We hypothesized that the (overwhelming) presence in the blood of S. marcescens stimulated anti-A antibody formation, as S. marcescens might share epitopes with blood group A antigen. Unfortunately we could not demonstrate interaction between blood group A and S. marcescens in incubation experiments.

Two features of this post-transplant course are remarkably different from other reports of acute rejection in ABO-incompatible kidney transplantation: first, the late occurrence 12 weeks after kidney transplantation and second, the very high anti-A IgM titers (>5000), suggesting recent boosting of anti-A antibody formation by S. marcescens.

• Immunosuppression
• Investigational agents
• Renal/kidney transplant
• Review

Antibody-mediated rejection (AMR) is an important cause of graft loss after organ transplantation. It is caused by anti-donor-specific antibodies especially anti-HLA antibodies. C4d had been regarded as a diagnosis marker for AMR. Although most early AMR episodes can be successfully controlled or reversed, late and chronic AMR remains the leading cause of late graft loss. The strategies which work in early AMR have limited effect on late/chronic episodes. Here, we reviewed the lines of evidence that late/chronic AMR is the leading cause of late graft loss, characteristics of late AMR, and current strategies in managing late/chronic AMR. More effort should be put on the management of late/chronic AMR to make a better long term graft survival.

Serum complement cascade, a part of innate immunity required for host protection against invading pathogens, is also a mediator of various forms of disease and injury. It is activated by classical, lectin, and alternative pathways that lead to activation of C3 component by C3 convertases, release of C3b opsonin, C5 conversion and eventually membrane attack complex formation. The tightly regulated activation process yields also C3a and C5a anaphylatoxins, which target a broad spectrum of immune and non-immune cells. The review discusses the involvement of the complement cascade in kidney disease pathogenesis and injury. The role of the complement pathways in autoantibody-mediated forms of glomerulonephritis (lupus nephritis, anti-glomerular basement membrane disease, anti-neutrophil cytoplasmic autoantibody-induced or membranoproliferative glomerulonephritis, membranous nephropathy), C3 glomerulopathy, atypical forms of hemolytic uremic syndrome, ischemic-reperfusion injury of transplanted kidney, and antibody-mediated renal allograft rejection are discussed. The disturbances in complement activation and regulation with underlying genetics are presented and related to observed pathology. Also promising strategies targeting the complement system in complement-related disorders are mentioned.

Purpose. Acute antibody-mediated rejection, a complication of cross match positive and sensitized renal transplants, occurs despite the use of standard desensitization protocols. Rescue therapy consists of plasmapheresis and intravenous immunoglobulin (IVIg). In patients with preformed donor specific antibodies, rejection can be aggressive. We report here a case in which laparoscopic splenectomy was added to the standard rescue regimen. Case Report and Results. A 40-year-old Hispanic female with end stage renal disease had been receiving hemodialysis. The patient had numerous class 1 unacceptable antigens. She was scheduled to undergo an incompatible 1-1-1 mismatch living related donor kidney transplant. Preoperatively, the patient received plasmapheresis, IVIG, and thymoglobulin. There was good graft function until postoperative day 5. At that point, worsening renal function was noted. Renal biopsy was consistent with AMR. The patient became anuric and dialysis was initiated. To salvage the transplant, the patient underwent laparoscopic splenectomy. Postoperatively, renal function improved. Two years after transplant, the patient continues to have excellent graft function. Conclusion. In a small but significant number of renal transplants, antibody production occurs at a rate that traditional treatments are unable to reduce effectively. Based on our experience, the addition of splenectomy to standard rescue therapy can salvage renal transplants.