Complement Activation as a Cause of Transient Hypotension During Plasmapheresis

Hypotension is one of the most common adverse effect of plasmapheresis (PP) and often is attributed to hypovolemia due to extracorporeal circulation and the vasovagal reflex. Complements are activated during PP, and the activated complements are strong anaphylatoxins and potent vasodilators. Therefore, we studied the relationship between the transient hypotension and the plasma levels of activated complements during and after PP in 8 sessions of 7 patients using the Plasmafro OP-08 as a plasma separator. Five of the patients underwent immunoadsorption PP using the IM-TR 350 or IM-PH 350 as the adsorption column. The other underwent double filtration PP using the Evaflux 4A as a second filter. In 4 of 8 sessions, patients experienced transient hypotension with significantly elevated plasma levels of activated complements C3a and C5a. In contrast, patients without hypotension showed no increases in C3a and C5a values during PP. In this report, we emphasize the critical role of activated complements for hypotension during PP.     

First A2-to-O renal transplantation in the 21st Century: a step in the transplantation history of Turkey

Renal transplantation is the best treatment modality for patients with end-stage renal disease. Turkey is a country with limited cadaveric donor organ programs. Herein we have reported the first A2-to-O living donor kidney transplantation in Turkey. A 20-year-old female patient was admitted for a living related renal transplantation from her only potential donor her mother. She was blood group O and her mother was blood group A2. Three plasmapheresis sessions followed by intravenous immunoglobulin (IVIG) were performed every other day in the week prior to transplantation. Daclizumab was administered at the time of transplantation with an additional four doses every 2 weeks after the procedure. The immunsuppressive regimen included tacrolimus, mycophenolate mofetil, and prednisolone. Eight plasmapheresis sessions followed by IVIG were performed in the first 2 weeks posttransplant. Six months after transplantation, the serum creatinine was 1 mg/dL. Our experience showed that A2-to-O renal transplantation can be safely performed and may expand the pool of living kidney donors in Turkey.     

Blood group Lewis alloantibodies cause antibody-mediated rejection in renal transplant recipients

Three patients with negative Lewis phenotypes who displayed anti-Lewis antibodies suffered severe kidney allograft dysfunction. One woman and two men (22-44 years) received ABO compatible kidney transplants with negative donor-recipient cross-match tests. Two patients had the phenotype Le(a-b-) with anti-Le(a) and anti-Le(b) complement binding antibodies. The third patient of phenotype Le(a+b-) developed anti-Lewis(b) antibody a few months after transplantation. One patient presented recurrence of worsened graft function from the day 6 to 4 months after transplantation; despite treatment there was not full recovery. The second patient had recurrences of acute graft dysfunction at 4 and 6 months after transplantation with nephrotic range proteinuria. The third patient showed progressive graft dysfunction at 7 months after transplantation. Biopsy specimens showed histological changes of antibody-mediated rejection. In the third patient, we observed fibrinoid necrosis and thrombosis of arterioles and glomerular capillaries. Immunofluorescence studies showed immunoglobulin IgG and IgM in glomerular capillaries and C4d and C3 on endothelial cells of peritubular capillaries. Posttransplantation cross-match tests with donor lymphocytes were negative. Anti-Lewis antibodies were observed during follow-up. All patients were treated with methylprednisolone boluses. In addition, one subject received antithymocyte globulin (ATG) and 1 received plasmapheresis. Two patients had moderate renal dysfunction (creatinine levels 1.8 and 1.9 mg/dL) after 8-17 months follow-up. The third patient lost her graft at 11 months after transplantation. Lewis antibodies may injure a renal allograft. C4d deposition and failure to show donor-specific anti-HLA antibodies suggested the participation of other antibodies.     

Studies on the removal of anti-pig xenoantibodies in the human by plasmapheresis/immunoadsorption

Abstract: Removal of human preformed natural anti-pig antibodies from the blood is a prerequisite before xenografting between pig and man can be performed. This work explores the effect of plasmapheresis and immunoadsorption (protein-A sepharose) on the reduction and recurrence of anti-pig antibodies in 14 patients. The anti-pig antibody changes were evaluated by lymphocy to toxic, hemagglutinating, and endothelial cell ELISA techniques. The changes induced showed a similar pattern with all three techniques used. In addition, plasma from plasmapheresis treatments were perfused through pig kidneys and the reduction of anti-pig antibodies was estimated by the mentioned in vitro techniques. The anti-pig antibody titers could be reduced to low levels, but not completely eliminated, by 3–4 plasmapheresis sessions. The titers gradually returned to pretreatment levels or higher in a period of 1–2 weeks. A few patients showed signs of a more rapid resynthesis reaching pretransplant levels in 3–4 days. Protein A immunoadsorption satisfactory removed IgG but not IgM antibodies. In vitro perfusion of pig kidneys at 37°C showed a rapid reduction of anti-pig antibody titers of 3–4 titer steps. The combination of 3–4 plasma exchanges followed by in vitro pig kidney perfusion completely removed all anti-pig antibodies. Reduction of the anti-pig lymphocyte and erythrocyte antibody titers by soluble oligosaccharides carrying terminal Galoc-epitopes was only partly successful. A 40–60% inhibition was achieved by 5–10 mg saccharide/ml serum and no clear inhibition difference between di- and trisaccharides was found. Inhibition of plasma obtained after 3–4 plasmapheresis treatments with soluble Galα1-di- and trisaccharides resulted in very low anti-pig titers. Therefore one feasible pretreatment procedure, before pig to human xenotransplantation could be plasmapheresis for major reduction of anti-pig antibody titer followed by neutralisation of the remaining antibodies by addition of soluble oligosaccharides or immunoadsorption with Galα-1-columns.     

Plasmapheresis in the treatment of the acute reaction of transplanted kidney rejection

A total of 14 patients with acute rejection of transplanted kidney were treated with plasmapheresis (in combination with prednisolone supporting therapy in a dose of 15 mg/kg). For the arrest of the rejection it was necessary to use 4 sessions of plasmapheresis on average for each person (from 3 to 8 sessions). The average volume of discharged plasma, 2,000 ml approximately, was compensated with frozen plasma. Plasmapheresis was exercised by plasma separation with an "Asahi" plasma filter with the surface of 0.5 m2. Plasmapheresis successfully arrested the rejection in 50 per cent of the patients. Pathogenetic reasonability of plasmapheresis for the treatment of the aforementioned patients (elimination of toxins, circulating immune complexes, elevation of C3 and C4 components of the complement) was substantiated. In patients who had undergone plasmapheresis for the arrest of acute rejection, lowered levels of proteinuria were considered as a favourable prognostic sign.     

不同血浆置换方式在免疫性疾病及肾移植急性排斥反应中的应用分析

目的探究不同血浆置换方式在免疫性疾病及肾移植急性排斥反应中的应用,为临床实践提供理论依据。方法本研究纳入2016年4月至2018年3月西安市中心医院收治的100例免疫性疾病及肾移植急性排斥反应患者,分为对照组和研究组,每组各50例,对照组给予单重滤过血浆净化,研究组给予双重滤过血浆置换,对比两组患者生化指标、治疗情况、不良反应、预后情况,进行统计学分析。结果研究组治疗后的血浆免疫球蛋白G和抗肾小球基底膜抗体水平低于对照组,差异具有统计学意义(P<0.05)。研究组不良反应发生率明显低于对照组,差异具有统计学意义(P<0.05)。研究组患者住院时间、治疗费用均优于对照组,差异具有统计学意义(P<0.05)。研究组患者肾功能恢复率明显高于对照组,差异具有统计学意义(P<0.05)。结论免疫性疾病及肾移植急性排斥反应患者实施选择性双重滤过血浆净化,有效改善血液免疫球蛋白G与抗肾小球基底膜抗体水平,缩短治疗时间,提高治疗有效率,降低不良反应,治疗效果显著。     

A novel approach to successful ABO-incompatible high-titer renal transplantation

BACKGROUND: Currently the long-term outcome among recipients of ABO-incompatible renal transplantations is excellent in Japan. However, previous reports have documented poor outcomes in patients with high (> 1:256) anti-A/B antibody titers pretreatment. The immunosuppressive protocol for ABO-incompatible high-titer renal transplantation has remained a medical challenge. METHODS: We treated 3 patients with high (> 1:512) anti-A/B antibody titers prior to ABO-incompatible renal transplantation. Our immunosuppressive protocol was initiated 1 month prior to surgery and included mycophenolate mofetil (1 g/d) and low-dose steroid (methylprednisolone [8 mg/d]). Two doses of the anti-CD20 antibody rituximab, (150 mg/m(2)) were administered 2 weeks before and on the day of transplantation. We performed antibody removal with 6 to 8 sessions of plasmapheresis (plasma exchange or double-filtration plasmapheresis) before transplantation. Splenectomy was also performed on the day of transplantation. Postoperative immunosuppression followed the same regimen as ABO-compatible cases, in which calcineurin inhibitors were initiated 3 days before transplantation combined with 2 doses of basiliximab. RESULT: With this protocol, the anti-A/B antibody was reduced to below 1:16 in all cases. All 3 patients underwent successful transplantation with a mean current serum creatinine of 1.32 mg/dL (range, 1.22-1.50 mg/dL). There were no episodes of antibody-mediated rejection. No serious complications or side effects were encountered. CONCLUSIONS: A preconditioning protocol consisting of rituximab infusions, splenectomy, plasmapheresis, and pharmacologic immunosuppression enabled ABO-incompatible renal transplantation in patients with high (> 1:512) anti-A/B antibody titer.     

The Use of Bortezomib as a Rescue Treatment for Acute Antibody-Mediated Rejection: Report of Three Cases and Review of Literature

Antibody-mediated rejection (AMR) typically occurs early after transplantation in approximately 5%–7% of recipients. The literature reports suggest that 12%–37% of kidney transplant recipients with acute AMR do not respond to treatment and eventually lose their grafts. The proteasome inhibitor bortezomib is currently approved by the Food and Drug Administration for the treatment of multiple myeloma. It has been demonstrated both in vitro and in vivo to possess apoptotic properties against mature plasma cells. Herein we have described a series of 3 patients with positive cross-matches who developed early AMR after kidney transplantation. Bortezomib rescue treatment was administered after the patients failed to respond to plasmapheresis/intravenous immunoglobulin and splenectomy. All 3 patients responded with full, durable recovery of renal function. In conclusion, bortezomib is useful to treat refractory AMR after kidney transplantation.     

Complement activation following multiple injuries

Complement activation was evaluated by assay of plasma C3dg and the terminal complement complex (TCC) in 19 patients with multiple injuries. In the nine patients with thoracic involvement, statistically significant increase of plasma TCC was found at first sampling (average 90 min post-trauma), and of C3dg after 24 hours. Such increase was not found in the ten patients without thoracic involvement. Heightened granulocyte elastase activity was found in bronchial lavage fluid 90 min after the trauma in three patients with thoracic injury. Pulmonary insufficiency (pO2/FiO2 less than 16 kPa on intermittent positive-pressure ventilation) arose in four patients. All four had raised plasma levels of TCC or C3dg on arrival at the hospital. Six patients with complement activation did not show pulmonary insufficiency. Although the series was relatively small, the results indicate that thoracic injury is particularly associated with complement activation, and that complement activation alone does not suffice to produce post-traumatic pulmonary insufficiency.     

Prolonged neuromuscular block due to cholinesterase depletion by plasmapheresis

Plasmapheresis is a well-known therapeutic procedure for several medical conditions in which removal of circulating antibodies or albumin-bound toxins is desired. Circulating plasma cholinesterase enzyme levels are also depleted with plasmapheresis. This action causes patients to be susceptible to prolonged neuromuscular blockade when neuromuscular blocking drugs that are metabolized by this enzyme are used. We describe a case of prolonged neuromuscular blockade following succinylcholine and mivacurium administration in a 24-year-old renal transplant patient undergoing repeated plasmapheresis for recurrence of focal segmental glomerulosclerosis and acute vascular rejection. Serum and plasma cholinesterase levels were less than 20% of normal at the time of the event. The patient had spontaneous recovery after 12 hours of conservative supportive care. She tolerated a similar procedure uneventfully two weeks later when she was not taking plasmapheresis. Anesthesiologists should be aware of plasmapheresis as a mechanism for plasma cholinesterase depletion when using neuromuscular blocking drugs that are metabolized by this enzyme.     

Acute antibody-mediated rejection in paediatric renal transplant recipients

Acute antibody-mediated rejections (aAMR) after renal transplantation are defined by rapidly deteriorating graft function, detection of donor-specific antibodies (DSA) and characteristic histological features. In adults, anti-rejection strategies comprise intravenous immunoglobulin (IVIG), steroid pulses, plasmapheresis and rituximab. Data of children with aAMR are scarce. We report four episodes of aAMR in three children (aged 10, 10 and 11 years respectively) occurring early after renal transplantation. Pre-transplant complement-dependent cytotoxicity crossmatches were negative; in the case of re-transplantation repeated antigens were excluded. Basic immunosuppression comprised cyclosporine A, MMF and steroids. All four rejection episodes were histologically proven and associated with acute renal failure. De novo DSAs were detected in two aAMRs; one patient was additionally tested positive for AT1-receptor antibodies. All aAMRs were treated with steroid pulses, tacrolimus, MMF, IVIG, plasmapheresis and one single dose of rituximab. Despite therapy one graft was lost; in the remaining three cases kidney function re-established within 1–8 weeks. At follow-up, 14, 15 and 22 months’ post-rejection their GFRs were 65, 88 and 105 ml/min/1.73 m² respectively. A combined therapy of steroid pulses, IVIG, plasmapheresis and rituximab is potentially effective in the treatment of aAMR in children.     

Clearance of C4d deposition after successful treatment of acute humoral rejection in follow-up biopsies: a report of three cases

Acute humoral rejection (AHR) is currently perceived as an immunological reaction against donor antigens mediated by complement-binding antibodies. C4d, a split product of complement activation and bound to endothelial cells of the peritubular capillaries, is used as a diagnostic marker for AHR. We report on three patients with biopsy-proven acute humoral rejection who were treated initially with plasmapheresis (PS). As two of the patients did not recover renal function, and biopsy showed persistent C4d staining after PS, immunoadsorption (IAS) was additionally performed on them. In all patients, renal function recovered, and follow-up biopsies in two patients showed complete disappearance of C4d, 29 days and 58 days after transplantation and only minimal residual C4d deposits in one patient 48 days after transplantation. We conclude that successful treatment of AHR is followed by complete resolution of serological and histological markers of AHR, displayed by the disappearance of C4d.     

Successful treatment of crescentic glomerulonephritis associated with adult-onset Henoch-Schoenlein purpura by double-filtration plasmapheresis

Henoch-Schoenlein purpura (HSP) crescentic glomerulonephritis with acute renal failure in adults is extremely rare. The condition carries a grave renal outcome if it is not appropriately managed. Oral corticosteroids, intravenous methylprednisolone pulse therapy and plasmapheresis with concomitant plasma replacement have been used alone or in various combinations to treat patients with HSP nephritis, yet the effects are uncertain. We describe a 33-year-old man with oliguric acute renal failure in the setting of HSP crescentic glomerulonephritis that is refractory to intravenous methylprednisolone pulse therapy (1,000 mg/day for 3 days) with maintained oral prednisolone (1 mg/kg/day) and oral cyclophosphamide (2 mg/kg/day) for 3 weeks, resulting in successful recovery of renal function after 9 sessions of simple double-filtration plasmapheresis treatment without concomitant plasma replacement. There was no recurrence of vasculitic events within 18 months. In this case, we emphasize that simple double-filtration plasmapheresis without concomitant plasma replacement is an effective and safe modality therapy for adult patients with HSP crescentic glomerulonephritis and acute renal failure, especially when conventional therapy has failed.     

Urinary C3dg and C5b-9 indicate active immune disease in human membranous nephropathy.

We have measured complement activation markers, C3dg and C5b-9 in plasma and urine from patients with idiopathic membranous nephropathy and IgA nephropathy. There was no significant difference in levels of plasma C5b-9 between the patient groups. However, high plasma concentrations of C3dg were associated significantly with IgA nephropathy with 45% of patients having levels over 25 U/ml (P less than 0.001). High concentrations of urinary C3dg and C5b-9 were associated significantly with membranous nephropathy (43% and 43% of the patient group, respectively) compared to patients with IgA nephropathy (10% and 0%, respectively, P less than 0.001). In a retrospective analysis of 31 patients with membranous nephropathy, 66% of patients with high initial urinary C5b-9 showed an unstable clinical course compared to 18% of patients with initially absent or low C5b-9 (P less than 0.001). We suggest that high urinary C5b-9 identifies those patients with a membranous lesion which retains an active immunological component contributing to the pathology of progressive glomerular damage.     

Plasmapheresis treatment for recurrent focal sclerosis in pediatric renal allografts

Recurrence of focal segmental glomerulosclerosis (FSGS) in pediatric renal allografts is associated with a poor graft survival. This study reports on plasmapheresis for the treatment of recurrent FSGS in pediatric renal transplant recipients. The records of 100 consecutive pediatric (age <21 years) renal transplants were reviewed. Twenty patients had FSGS as the cause of renal failure. Eight of these (40%) had a recurrence (protein-uria >1 g/m² per day) within 1 month of transplantation. Five of six patients treated with plasmapheresis went into remission (<0.2 g/m² per day), receiving a total of 42±26 (12–73) sessions, with the mean number of sessions required to achieve a remission being 24±17 (8–51). One patient had a second recurrence 1 year following cessation of plasmapheresis and responded to another course of plasmapheresis. The 1 patient who did not respond to plasmapheresis had a delay in initiation of therapy of 42 days. Plasmapheresis initiated within 48 h of recurrence resulted in earlier remissions and improved graft survival among our patients. Plasmapheresis appears to be effective in treating recurrent FSGS following kidney transplantation and should be started as soon as possible. The number of plasmapheresis sessions used to achieve remission should be adjusted according to response rather than adhering to a fixed protocol. Received: 22 November 1999 / Revised: 2 March 2000 / Accepted: 6 March 2000     

Treatment of acute antibody-mediated rejection: a single-center experience

Introduction

Acute antibody-mediated rejection (AMR) leads to graft loss. The combination of plasmapheresis (PP), intravenous immunoglobulin (IVIG), and rituximab (RTX) has been reported to be effective therapy.

Patients and methods

Between October 2005 and September 2009, 8 (4.7%) kidney transplant recipients developed AMR, diagnosed by severe acute rejection and extensive C4d staining in peritubular capillaries.

Results

All patients were treated with two to six sessions of PP with IVIG added after the last PP. In two patients, RTX was prescribed after PP and IVIG. Baseline immunosuppression was based on steroids, mycophenolate mofetil or azathioprine, and tacrolimus or cyclosporine or everolimus. The presence of subsequent significant decrease in anti-HLA class I antibodies was demonstrated in a highly sensitized patient before and after transplantation with PP treatment. An increase was observed before the diagnosis of AMR. After a mean follow-up of 10 months (range = 1-23), patient and graft survivals were 100% and 50%, respectively. Three patients lost their transplants to AMR refractory to treatment and one patient, due to interstitial fibrosis and tubular atrophy at 23 months after AMR. Finally, four patients recovered renal function, showing a mean serum creatinine of 2.2 ± 0.45 mg/dL.

Conclusions

Early diagnosis and treatment with PP, IVIG, and RTX may resolve AMR. PP before and after transplantation in high-risk patients may result in anti-HLA class I and class II antibody removal from plasma and prevention of AMR.     

Plasmapheresis in the combined treatment of the kidney transplant rejection crisis

A total of 15 recipients of renal allotransplant were subjected to 41 sessions of gravitation plasmapheresis after immunosuppressive treatment with sandimmun, methypred, and azathioprine performed for prevention of acute steroid-resistant rejections. The efficacy of plasmapheresis was proved in 6 patients with early and 4 patients with advanced stages of the rejection crises. The authors developed the criteria for the assessment of plasmapheresis efficacy which should be considered for defining the optimal treatment regimens: the time-course of diuresis, the number of leukocytes, the plasma levels of creatinine and circulating immune complexes, the blood levels of IgG, IgA, IgM and the number of active rosette-forming cells, the blood serum complement activity (measured at least 24 hrs after the session).     

Serum immunoglobulin levels in relation to levels of specific antibodies in allogeneic and autologous bone marrow transplant recipients

BACKGROUND: The aim of this study was to investigate the correlation of total levels of immunoglobulins to levels of specific antibodies after allogeneic and autologous bone marrow transplantation. Autologous transplant patients had normal levels of IgA and IgG antibodies already at 6 months after transplantation. In allogeneic transplanted patients without chronic graft versus host disease the immunological recovery was slower. The IgA and IgG levels were at the limit for deficiency at 6 months after transplantation. In allogeneic transplant patients with chronic chronic graft versus host disease the immunological recovery was delayed further. The total IgG levels were low at 12 months after transplantation and the IgG subclass pattern did not normalize until 24 months after transplantation. IgA levels remained low at 24 months after transplantation in all allogeneic transplanted patients with chronic chronic graft versus host disease. Protective levels of specific antibodies against tetanus and pneumococci decreased during the first year after transplantation regardless of the total immunoglobulin levels, regardless of the donors immunity. Pneumococcal antibodies decreased only in allogeneic transplanted patients, although autologous transplant patients retained pretransplant immunity against pneumococci. There was no difference in levels of specific antibodies between patients with and without chronic chronic graft versus host disease at 12 months after transplantation. There was no correlation between total immunoglobulin levels to levels of specific antibodies against tetanus and pneumococci after transplantation in our study. Taken together, normalized immunoglobulin levels do not predict normalization of levels of specific antibodies against tetanus and pneumococci after transplantation.     

Tailored Eculizumab Therapy in the Management of Complement Factor H–Mediated Atypical Hemolytic Uremic Syndrome in an Adult Kidney Transplant Recipient: A Case Report

Atypical hemolytic uremic syndrome (aHUS) is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury (AKI) which frequently progresses to end-stage renal disease (ESRD). In 50% of affected patients, mutations in complement regulatory proteins cause inappropriate complement activation with endothelial injury. Complement factor H (CFH) mutations cause 25% of aHUS cases; these patients have an 80% recurrence risk after kidney transplantation. Eculizumab, an anti-C5 antibody, is effective in limiting hemolysis episodes in patients with aHUS, but less is known about preventing recurrence after kidney transplantation. Herein we report the use of prophylactic eculizumab in an adult with aHUS who underwent kidney transplantation. A 31-year-old female presented with aHUS and progressive AKI associated with low complement 3 level leading to ESRD despite plasmapheresis and corticosteroids. She had a heterozygous nonsense mutation in CFH and reduced plasma CFH levels. She was given preoperative plasmapheresis and eculizumab and underwent living unrelated renal transplantation. Postoperatively, eculizumab was dosed to achieve low functional complement 5 levels and low soluble membrane attack complex levels and she has maintained excellent graft function without aHUS recurrence. We propose that eculizumab with titrated dosing should be used in CFH-mediated aHUS patients who are at a high risk of recurrence.     

Desensitization strategies enabling successful renal transplantation in highly sensitized patients

Abstract:  Currently, the number of highly sensitized patients awaiting a renal transplant is increasing on the waiting lists of different organ exchange organizations. Due to the presence of antibodies against a broad variety of human leukocyte antigen (HLA) specificities, highly sensitized patients have a markedly reduced chance of receiving a crossmatch-negative organ. It has long been recognized that hyperacute rejection is associated with the presence of donor-specific anti-HLA antibodies at the time of transplantation. Meanwhile treatment protocols have been developed to achieve successful transplantation across antibody barriers. Therefore, the presence of donor-specific anti-HLA antibodies and a positive serological crossmatch are no longer considered as an absolute contraindication to renal transplantation. Mainly, two desensitization protocols have been established in order to overcome a positive crossmatch or to enhance the chance of highly sensitized patients to receive a crossmatch-negative organ: high-dose intravenous immunoglobulin (IVIg) or low-dose IVIg in combination with plasmapheresis. Herein, we summarize the characteristics of these two treatment regimes along with other alternative approaches that are currently used for the management of kidney graft recipients with broad alloantibody reactivity against potential kidney donors.