Importancia diagnóstica del C4d en la nefropatía membranosa / Diagnostic significance of C4d in membranous ne phropathy

Resumen Introducción : La nefropatía membranosa (NM) es la causa más frecuente de síndrome nefrótico primario en adultos (20-30%). En la microscopia óptica se obser va engrosamiento de membrana basal glomerular con aparición de espigas. Estos hallazgos histológicos no son evidentes en formas tempranas, en cuyo caso el patrón de depósito granular de IgG y/o C3 en la membrana basal por inmunofluorescencia (IF) permite diferenciarla de enfermedad por cambios mínimos (ECM). El sistema del complemento juega un papel central en la fisiopatología de la NM. C4d es producto de degradación y un marcador de la activación del complemento. La marcación con C4d en muestras de biopsias re nales, por técnica de inmunohistoquímica (IH) puede colaborar en el diagnóstico diferencial entre ambas glomerulopatías. Nuestro objetivo fue explorar el poder de discriminación del C4d para diferenciar NM de ECM en material de biopsias renales. Métodos : Se recuperaron muestras en parafina de biopsias renales con diagnóstico de NM y ECM realizados entre 1/1/2008 y 1/4/2019. Se realizaron tinciones de IH por técnica de inmunoperoxidasa con C4d usando un anticuerpo policlonal antihumano de conejo. Resultados : En todos los casos con NM (n = 27, 15 hombres) con mediana de edad de 63 (rango: 18-86) años se detectaron depósitos de C4d. En los 21 casos con ECM (12 hombres) con mediana de edad de 51 (rango: 18-87) años la marcación de C4d fue negativa. Conclusión : Los resultados indican que la marcación de la biopsia renal con C4d es una herramienta útil para el diagnóstico diferencial entre NM y ECM.

Abstract Introduction : Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome in adults (20-30%). Light microscopy shows thickening of glomerular basement membrane with appearance of spikes. These histological findings are not evident in early forms, in which case the granular deposition pattern of IgG and/or C3 in the basement membrane by immunofluorescence (IF) constitutes the diagnostic tool that allows to differentiate it from minimal change disease (MCD). Complement system plays a key role in the pathophysiology of MN. C4d is a degradation prod uct and a marker of the complement system activation. C4d labelling by immunohistochemical (HI) technique can help in the differential diagnosis between both glomerulopathies NM and MCD when the material for IF is insufficient and light microscopy is normal. Our objective was to explore the discrimination power of C4d to differentiate between MN and MCD in renal biopsy material. Methods : Paraffin-embedded samples were recovered from renal biopsies with a diagnosis of MN and MCD performed between 1/1/2008 and 4/1/2019. IH staining was performed by immunoperoxidase technique using a rabbit anti-human C4d polyclonal antibody. Results : In all cases with MN (n = 27, 15 males) with a median age of 63 (range: 18-87) years, C4d deposits were detected. In 21 cases with MCD (12 males) with a median age of 51 (range: 18-87) years, the C4d marking was negative in every samples. Conclusion : The results indicate that the marking of the renal biopsy with C4d is a useful tool for the dif ferential diagnosis between NM and MCD.

Diagnostic criteria and research progress on Banff classification of allograft pathology in composite tissue allotransplantation / 器官移植

Composite tissue allotransplantation (CTA) is a novel transplantation discipline to treat functional tissue or limb defects. Since a majority of CTA grafts were vascularized grafts, it is also known as vascularized composite allotransplantation (VCA). The grafts of CTA/VCA consist of two or more types of allogeneic skin, subcutaneous tissue, bone, muscle, nerve and vessel, etc. Most of CTA/VCA grafts contain skin tissues, which possess the highest antigenicity. Acute rejection after transplantation is the primary obstacle leading to CTA/VCA graft failure and primary graft dysfunction. Hence, histopathological characteristics of skin rejection in CTA/VCA grafts have become the primary hotspot. In this article, pathological features of CTA/VCA rejection, Banff classification in 2007 and related research progress were reviewed, aiming to provide reference for the diagnosis and treatment of rejection and other complications of CTA/VCA.

Pathology of antibody-mediated rejection in renal allograft / 器官移植

Antibody-mediated rejection (AMR), also known as humoral rejection, is an immune injury caused by rejection involved with multiple humoral immune effectors, such as antibodies and complements, etc. AMR plays a pivotal role in hyperacute, acute and chronic rejection. In this article, the basic definition of AMR, the research progress and major achievements on AMR pathology according to Banff classification on allograft pathology (Banff classification), and main pathological characteristics of AMR in renal allograft were reviewed, aiming to provide reference for accurate diagnosis and timely treatment of AMR, and guarantee the long-term survival of renal graft and recipients.

The origin and development of Banff classification on allograft pathology and its effects in promoting organ transplantation / 器官移植

The Banff conference on allograft pathology (Banff conference) and the establishment of Banff classification on allograft pathology (Banff classification) are milestones in the development of international allograft pathology. At present, all organ transplantation centers around the world routinely perform pathological diagnosis by biopsy of the transplant kidney according to Banff classification. Subsequently, the consensus process and update mode of Banff classification for transplant kidney was quickly extended to transplant heart, lung, liver, pancreas, and small intestine, etc. The Banff conference has not only become a thematic meeting that includes the pathology study and discussion of various transplant organs, but also gradually developed unified diagnostic standard for the biopsy of each transplant organ, which better promoted the accurate diagnosis and treatment of complications after organ transplantation. This article summarized the history of international allograft pathology research, the Banff conference and Banff classification in promoting organ transplantation, which aimed to provide a reference for the smooth development of clinical organ transplantation.

Establishment and analysis of mouse model of acute antibody-mediated rejection in heart transplantation / 器官移植

Objective To establish a mouse model of acute antibody-mediated rejection (AMR) in heart transplantation and to analyze its characteristics. Methods Mouse models of heart transplantation and skin transplantation were established. According to different treatment methods, all animals were divided into the homologous control group, non-sensitized group, pre-sensitized group and pre-sensitized+ ciclosporin group (9 donors and 9 recipients in each group). The graft survival time, donor-specific antibody (DSA) level and pathological manifestations of each group were observed, and the characteristics of rejection were analyzed. Results In the homologous control group, the cardiac grafts of the mice survived for a long period of time during the 3-month observation period. The survival time of the cardiac grafts in the non-sensitized group, pre-sensitized group and pre-sensitized+ciclosporin group was (7.0±0.7) d, (2.6±0.5) d and (5.0±0.7) d, respectively. The differences among the groups were statistically significant (all P < 0.01). The DSA level in the pre-sensitized group was significantly elevated than the baseline level at 3 d after heart transplantation, and that in the pre-sensitized+ciclosporin group was remarkably up-regulated at 5 d after heart transplantation, the differences were statistically significant (P < 0.05, P < 0.01). The pathological manifestation of the non-sensitized group was the myocardial cell destruction, the formation of interstitial inflammation, mild C4d deposition and a large amount of CD3 cell infiltration. The pathological manifestations of the pre-sensitized group and the pre-sensitized+ciclosporin group showed myocardial cell destruction, capillary inflammation and a large amount of C4d deposition, whereas the amount of CD3 cell infiltration in the pre-sensitized group was more than that in the pre-sensitized+ciclosporin group. Conclusions The use of ciclosporin on the basis of heart transplantation and skin transplantation between different strains of mice can successfully establish a practical acute AMR model in mouse heart transplantation, which provides the basis for subsequent AMR pathogenesis and intervention research.

Value of cell-bound complement activation products in the diagnosis of systemic lupus erythematosus / 临床检验杂志

Objective@#To investigate the values of T lymphocyte-bound complement activation products such as T-C3d and T-C4d, B lymphocyte-bound complement activation products such as B-C3d and B-C4d and erythrocyte-bound complement activation products such as E-C3d and E-C4d in the diagnosis of systemic lupus erythematosus (SLE). @*Methods@#Peripheral blood samples from 68 SLE patients, 70 patients with non-SLE autoimmune diseases and 68 healthy controls were collected randomly, and the expression levels of T-C4d, B-C4d, E-C4d, T-C3d, B-C3d and E-C3d in these samples were detected by flow cytometry. Meanwhile, antinuclear antibodies (ANA), anti-double stranded DNA antibodies (anti-dsDNA), peripheral blood cell count and other markers were also detected. The differences of cell-bound complement activation products in three groups were analyzed with the area under the receiver operating characteristic curve (AUC), nonparametric test, sensitivity and specificity. @*Results@#The specific median fluorescence intensity (SMFI) of T-C4d, B-C4d, E-C4d, T-C3d, B-C3d and E-C3d in SLE patients were significantly higher than those in the patients with non-SLE autoimmune diseases and healthy controls (all P＜0.05). The SMFI (median \[P 25, P 75\]) of T-C4d, B-C4d and E-C4d in SLE patients were 3.8(1.2, 13.1), 22.1(6.2, 67.9) and 19.6(1.8, 52.4), respectively. The SMFI of T-C4d, B-C4d and E-C4d in SLE patients with reduced red blood cells and/or lymphocytes were significantly higher than that with normal red blood cell and lymphocyte count (all P＜0.05). The AUCs of T-C4d, B-C4d, E-C4d, T-C3d, B-C3d and E-C3d were 0.711, 0.763, 0.663, 0.631, 0.611 and 0.615, respectively (all P＜0.05). The sensitivity of the combination of T-C4d with B-C4d (73.5%) in the diagnosis of SLE was superior to that of anti-dsDNA (36.8%). @*Conclusion@#The cell-bound complement activation products (CB-CAPs) are specifically expressed in SLE patients, and their combination detection is helpful for the diagnosis of SLE.

Correlation between nephropathy score and hormone threapy in minimal change disease / 临床与实验病理学杂志

Purpose To observe the clinical characteristics, expression of C4d and the morphology of podocyte lesions in steroid-sensitive minimal change disease (SS-MCD) ,steroidresistant minimal change disease (SR-MCD) and early focal segmental glomerulosclerosis (E-FSGS) ,as well as to analyze their differences among the three groups,and provide a novel method for effective evaluation the therapeutic effects of steroid and diagnosis of SR-MCD. Methods To study the clinical data from 24 cases of SS-MCD,30 cases of SR-MCD and 25 cases of E-FSGS as control,and all the biopsies were examined by light microscopy,immunohistochemistry and transmission electron microscopy. Meanwhile,the clinical characteristics,the morphology of podocyte lesion and the expression of C4d were observed. Results The average score of podocyte lesion of SR-MCD was higher than that of SS-MCD,but lower than that of E-FSGS (P< 0. 05) . C4d positive average score of SS-MCD was lower than that of both SR-MCD and E-FSGS (P < 0. 05) ,but there was no significant difference between SR-MCD and E-FSGS (P > 0. 05) . The sum of the average score of podocyte lesion and C4d positive average score of SS-MCD was lower than that of SRMCD and E-FSGS (P < 0. 01) ,however,there was also no significant difference between SR-MCD and E-FSGS(P > 0. 05) . The scores of IgM,C3d and C1q were not significantly different among the three groups. The area under the receiver operating curve (ROC) of the C4d positive score,podocyte lesion score and the sum of the two were 0. 753,0. 658 and 0. 803,respectively, and there was no significant difference between them and the optimal cutoff values were 3,1. 5,and 4. 5 points,respectively. Conclusions The C4d positive score,podocyte lesion score and the sum of the two scores of MCD (the last one is named for MCD nephropathy score in our study) can be used for evaluating the therapeutic effects of steroid and identification of SR-MCD,most especially MCD nephropathy score. The optimal cut-off values of the three kinds of scores are 3,1. 5,and 4. 5 points,respectively. When the values are exceeded,the clinicians should be reminded to follow-up and take appropriate treatment measures to patients.

Primary Glomerulonephritis with Unique C4d Deposition and Concurrent Non-infectious Intermediate Uveitis: a Case Report and Literature Review

C4 glomerulopathy is a recently introduced entity that presents with bright C4d staining and minimal or absent immunoglobulin and C3 staining. We report a case of a 62-year-old man with C4 glomerulonephritis (GN) and uveitis. He presented to the nephrology department with proteinuria and hematuria. The patient also had intermediate uveitis along with proteinuria and hematuria. A kidney biopsy that was performed in light of continuing proteinuria and hematuria showed a focal proliferative, focal sclerotic glomerulopathy pattern on light microscopy, absent staining for immunoglobulin or C3 by immunofluorescence microscopy, with bright staining for C4d on immunohistochemistry, and electron-dense deposits on electron microscopy. Consequently, C4 GN was suggested as the pathologic diagnosis. Although laser microdissection and mass spectrometry for glomerular deposit and pathologic evaluation of the retinal tissue were not performed, this is the first report of C4 GN in Korea and the first case of coexisting C4 GN and uveitis in the English literature.

The clinical research of donor specific antibody in liver transplantation / 中华器官移植杂志

Objective To analyze the donor specific antibody (DSA) in liver transplantation,and discuss the therapeutic schemes.Methods We retrospectively analyzed prospectively collected samples from 139 cases of liver transplantation from September 1,2013 to July 1,2015.Luminex assays were applied to determine human leukocyte antigen,panel reactive antibody (PRA).For PRA positive cases,DSA,C1q and C4d were detected,and liver biopsy was done.Results Of 139 cases enrolled,there were 12 cases positive for DSAs,including 2 cases of PreDSA:1 case of Ⅰ DSA (HLA-A mismatch),and 1 case of Ⅱ DSA (HLA-DQ mismatch).Ten cases of de novo DSA (including 1 case of PreDSA) all were HLA-DQ mismatch.The liver biopsy on 5 cases showed hepatic fibrosis,early rejection and intrahepatic cholestasis,and only 2 cases showed positive C4d.Of 6 cases of DSA,5 cases showed positive C1q.In the patients positive for DSA,tacrolimus dose was adjusted postoperatively,adding mycophenolatemofetil or increasing its dose,or methylprednisolone and immunoglobulin given.Conclusion DSAs are important indicators of sensitized recipients in liver transplantation,associated with trends toward worse outcomes in patients or allografts.The monitoring of DSA is requisite in order to adjust the immunosuppressant.

Glomerular C4d Deposition Is a Prognostic Factor for IgA Nephropathy / 中国医科大学学报

Objective To investigate the significance of glomerular deposition of C4d in accessing the severity and prognosis of IgA nephropathy. Methods A total of 131 patients were recruited for the study. Immunofluorescence was used to detect the deposition of C4d in renal tissue of pa?tients with IgA nephropathy,and the relationship between C4d deposition and clinical and pathological parameters and renal remission was ana?lyzed. Results Totally 30 patients had glomerular deposition of C4d. Compared with the patients without C4d deposition,the patients with C4d deposition had significantly higher levels of serum creatinine,urinary protein excretion and C4d and higher prevalence of hypertension,but had sig?nificantly decreased levels of glomerular filtration rates. With the histopathological phenotypes segregated by Lee 's classification,the ratios of C4d deposition presented an increase(P=0.005). The patients with C4d deposition had more severe mesangial proliferation,endocapillary hypercellu?larity,segmental glomerulosclerosis and tubular?interstitial injury. The rates of renal remission were significantly lower in IgA nephropathy patients with C4d deposition than those without C4d deposition(P<0.001). Conclusion IgA nephropathy patients with C4d deposition have more se?vere clinical and pathological manifestations and lower rate of renal remission. Glomerular C4d deposition is expected to be an important pathologi?cal prognostic factor for predicting the prognosis of IgA nephropathy.

Biopsia hepática en la patología del trasplante, período postrasplante temprano, enfoque dirigido al diagnóstico histopatológico y su correlación clínico-patológica: Histopathological Diagnosis and Clinicopathological Correlation in the Early Post-Transplant Period / Liver Biopsies in Transplant Pathology

La biopsia hepática de los aloinjertos sigue siendo considerada el estándar de oro y juega un papel importante e integral en la interpretación y explicación de los cambios que puedan ocurrir en respuesta a alteraciones en las pruebas de la función o bioquímica hepática, anomalías funcionales o alteración en las imágenes diagnósticas, las cuales pueden, o no, ir acompañadas de síntomas. También es útil en el seguimiento o biopsias por protocolo (1-3). La evaluación de biopsias, después del trasplante, puede ser difícil debido a que es muy amplio el espectro de las complicaciones que pueden presentarse en el período postrasplante; más aún, cuando muchas de ellas necesitan un diagnóstico y tratamiento inmediato. La patología más frecuente es el rechazo agudo. Sin embargo, también pueden observarse cambios de perfusión/reperfusión, alteraciones funcionales, recidiva de enfermedad de base, lesión de la vía biliar, lesiones vasculares, infecciones oportunistas, patologías de novo, como la hepatitis autoinmune, hepatitis crónica idiopática postrasplante, toxicidad farmacológica o tumores, entre otras patologías (4). En este artículo relacionado con la patología del trasplante hepático se tratarán las patologías más frecuentes, no quirúrgicas, en el período postrasplante temprano, con un enfoque histopatológico dirigido a las dificultades y controversias para una adecuada correlación clínico-patológica.

Biopsies of liver allografts are still considered to be the gold standard. They play an important and integral role in the interpretation and explanation of changes that may occur in response to alterations in function tests, in the interpretation and explanation of liver biochemistry, in the interpretation and explanation of functional abnormalities, and in the interpretation and explanation of diagnostic images (whether or not accompanied by symptoms). Biopsies are also useful for monitoring and are often part of the protocol (1-3). The evaluation of biopsy samples after transplantation can be difficult especially because of the very broad spectrum of complications that may arise in the post-transplant period. Many of them require immediate diagnosis and treatment despite this difficulty. Although the most common condition is acute rejection, many other conditions and disorders can be observed. They include perfusion/reperfusion alterations, functional impairment, recurrence of underlying diseases, injury to the bile duct, vascular lesions, opportunistic infections, de novo pathologies such as autoimmune hepatitis, post-transplant idiopathic chronic hepatitis, drug toxicity, and tumors (4). This is the second article about the pathology of liver transplantation. It discusses the most common pathologies in the early post-transplant period and provides a histopathological approach towards difficulties and controversies for adequate clinicopathological correlation.

Prevalence of Erythrocytopenia & Thrombocytopenia in Eastern Indian Population & its Correlation with Acute Antibody Mediated Renal Transplant Rejection & Cytomegaloviral Nephropathy.

Objective: Our objective was to study the prevalence of thrombocytopenia & erythrocytopenia post renal transplantation in Eastern Indian population. Thrombocytopenia & erythrocytopenia are common phenomena prevailing post transplant rejection. It is found to occur in patients developing HCMV (human cytomegaloviral nephropathy), post transplantation. Whereas in the case of none rejected patients thrombocytopenia is unlikely to occur. Methods: Several methodologies such as the serological cross match, HLA-cross match DSA luminex, renal biopsy including C4d staining, hematological RBC & platelet count monitoring were adopted in the study, along with these the serum creatinine levels of the rejected patients were tested by making use of several biochemical approaches. Statistical analysis of the data obtained from the laboratories, were also done by the software prism 4.1. Results: Out of total population of 30 patients selected randomly, 24 were found to have successful transplants as for them a significant increase in both platelet & RBC count were noticed post transplantation where as for the other 6 patients a significant decrease in the RBC & platelet count was observed post transplantation along with a significant increase in the serum creatinine levels. There was also a significant decrease in the GFR (glomerular filtration rate) which was an indication of some sort of graft dysfunctioning. All the patients were checked for viral nephropathy & the above 6 patients were found to develop HCMV nephropathy. For the above mentioned 6 patients, the presence of C4d marker in their renal peritubular capillaries after performing the immunehistochemical C4d staining was a key indicator of acute antibody mediated rejection. Conclusion: Our study clearly reveals that Thrombocytopenia & erythrocytopenia was quite common in the patients with acute antibody mediated renal transplant rejection. A low RBC & platelet count persisted in them even after transplantation owing to allograft rejection, & HCMV nephropathy. Whereas for the patients with successful transplants events such as thrombocytopenia & erythrocytopenia were nevertheless unlikely.

El papel de los anticuerpos anti-cromatina, antiC1qy las fracciones del complemento unidas a célulasen el diagnóstico precoz de actividad lúpica / Role of Anti-chromatin, anti-C1q and cell bound complement activation products in the early diagnosis of Systemic Lupus Erythematosus disease activity

Actualmente se percibe una necesidad apremiante en la identificación y validación debiomarcadores que reflejen tempranamente el inicio de actividad lúpica o que se conviertanen predictores de la misma. La actividad clínica del lupus eritematoso sistémico (LES) esondulante a lo largo del tiempo y la actividad subyacente persistente lleva a daño tisular.Este daño es reflejo de cambios irreversibles en la función y estructura orgánica, por loque la prevención, más que el tratamiento, debería ser la meta de cualquier terapia enLES y así lograr disminuir la morbimortalidad y los costos directos e indirectos causadospor la enfermedad. Es necesario encontrar biomarcadores no invasivos de actividadlúpica que no solo permitan tomar de forma oportuna decisiones terapéuticas, sino quetambién se correlacionen con los desenlaces clínicos y sean útiles en los ensayos clínicos,permitiendo acortar el tiempo del desarrollo de estos estudios. Este artículo pretendebuscar la evidencia que se tiene con respecto a los nuevos biomarcadores existentes paraactividad de la enfermedad en LES y su utilidad actual y futura, enfatizando en la necesidadde buscar nuevas moléculas que permitan un diagnóstico más precoz de la actividad de laenfermedad.

There is a need for the identification and validation of biomarkers that reflect the early onset of lupus activity or may be predictors of this. The clinical activity of systemic lupus erythematosus (SLE) fluctuates over time and the underlying activity leads to persistent tissue damage. This damage is a reflection of irreversible changes in the function and organic structure, so prevention, rather than treatment, should be the goal of any therapy in SLE.This will reduce morbidity, mortality, direct and indirect costs caused by the disease. It is necessary to find biomarkers of lupus activity that not only allow making treatment decisions in the short term, but also to correlate with clinical outcomes. These could also be useful in clinical trials and may shorten the duration of these studies. This article aims to find evidence on new biomarkers for SLE disease activity, and their current and future use. Emphasis will be made on the need to find new molecules for an early diagnosis of disease activity.

Pathologic Updates on Antibody Mediated Rejection in Renal Transplantation / 대한이식학회지

Progress in the field of antibody mediated rejection (ABMR) in kidney transplantation has shown a rapid increase during the past two decades. New pathologic entities have emerged and replace old concepts and diagnostic terms. According to newly acknowledged facts discovered by clinicians, researchers, and pathologists all over the world, an updated classification, rather than Banff 07, is needed. In order to improve the diagnostic accuracy for ABMR in clinicians as well as pathologists, recognition and awareness of various conditions such as C4d-negative ABMR, subclinical ABMR, de novo donor specific antibody, microcirculation inflammation, isolated vascular lesion, antibody-mediated transplant arteriopathy, etc. are essentially important.

Influence of immunosuppressants on C4d deposition in renal allografts of rats with chronic allograft nephropathy / 第二军医大学学报

Objective To observe C4d deposition in renal allografts of rats undergoing chronic allograft nephropathy (CAN), and to analyze the effects of immunosuppressants on deposition of C4d in peritubular capillaries. Methods The renal grafts of Fisher 344 rats were ortho topically transplanted into Lewis rats to create CAN models, and all the recipients were given cyclosporine A (CsA) 10 mg/(kg �� d) X10d after operation. The models were then divided into 5 groups (each n=9): Group A was normal saline control group, only receiving vehicle orally; Group B, C, D, and E received CsA 6 mg/(kg �� d), RAPA0. 8 mg/(kg �� d), FK506 0. 15 mg/(kg �� d), and MMF 20 mg/(kg �� d), respectively. The renal allografts were harvested after three rats were sacrificed at the 4th, 8th and 12th weeks post-transplantation. The histological changes were assessed according to Banff 97 standard. The deposition of C4d was detected by immunofluorescence method. Results C4d deposition in peritubular capillary (PTC) was found in all the allografts at the 4th week after transplantation, while there were no obvious clinical pathological changes of CAN in all groups, and the Banff scores were not significantly different among different groups (P > 0. 05). CAN manifestations of different degrees were observed 8 weeks after operation, with increased C4d deposition in the PTC. Severest CAN was observed at the 12th week after operation, accompanied by the most C4d deposition in the PTC. C4d deposition was positively correlated with the severity of CAN (r=0. 894, P = 0. 000). Compared with the control group, CsA and FK506 showed no significant effect on C4d deposition (P>0. 05); however, MMF and RAPA significantly decreasedC4d deposition (P<0. 05). Conclusion Deposition of C4d in PTC may appear in allografts earlier than the pathological changes of CAN, and the deposition is associated with the progression of CAN. MMF and RAPA can inhibit the progression of CAN, while CsA and FK506 can not.

The Significance and Limitation of C4d as a Biomarker in the Transplanted Kidney / 대한이식학회지

C4d is produced from the direct interaction between antibodies and tissue injury at an antibody binding site in a graft. C4d deposition along peritubular capillaries (PTCs) in a renal allograft is a characteristic finding of antibody-mediated rejection (AMR), and is a useful diagnostic tool of AMR. The C4d along PTCs is associated with poor graft survival. Therefore C4d is regarded as a biomarker of AMR and was included in the diagnosis criteria of AMR at 2007 Banff conference. However, although C4d assay is widely used, it has several limitations. ABO-incompatible transplantations develop C4d along the PTCs in the majority of grafts but this seems to be graft accommodation rather than AMR. Recent studies reported that more than half of renal allograft biopsies with chronic AMR were C4d-negative. Without treatment, the C4d-negative AMR can cause scarring within the graft, transplant glomerulopathy (TG) or even graft loss. C4d is not a certain indicator of antibody-mediated rejection and C4d staining is not always highly sensitive for detecting AMR. Measuring endothelial gene expression in kidney graft biopsies with alloantibody can be another sensitive and specific method to diagnose AMR and predict graft outcomes. Because of these complexities, at the 2011 Banff meeting, criteria for diagnosis of chronic AMR in the kidney were refined, and the need for inclusion of C4d-negative AMR in the Banff classification was investigated.

The Diagnosis of Acute Antibody-Mediated Rejection in ABO-Incompatible Liver Transplants / 대한이식학회지

Liver transplantation (LT) across the ABO-blood type barrier is prone to antibody-mediated rejection (AMR), which often leads to a deleterious clinical outcome. While it is of paramount importance to make an early diagnosis of AMR, the morphologic features of AMR in the liver are not specific, and the differential diagnosis is often difficult or even impossible on a morphologic basis alone. The clinical utility of C4d immunostaining is limited in the liver, unlike other organs, further complicating the situation. Therefore, the diagnosis of AMR in the liver requires integration of clinical, morphologic, immunopathologic, and serological evidence.

Antibody-mediated rejection in human cardiac allografts: histopathological and immunohistochemical study / 中华器官移植杂志

Objective To observe the pathologic features on cardiac allograft and to test archived endomyocardial biopsy specimens for antibody-mediated rejection specific marker-C4d deposition and its characteristics by using immunoperoxidase (IP) techniques. Methods From January 2003 to December 2007,10 recipients underwent orthotopic cardiac transplantation and 17 specimens of endomyocardial biopsy were obtained either for a protocol basis (generally at 1 st month,3rd month,1st year and 2nd year post-transplant) and on immediate clinical indications.All specimens of endomyocardial biopsy were collected for histopathological examination and C4d immunohistochemical staining,simultaneously. All pathological diagnoses were done according to 2004 International Society for Heart and Lung Transplantation (ISHLT) recommendation working formulation and AMR Schema,and C4d staining intensity were graded and recorded as 0 to 3 +.Results Except 1 specimen unqualified,all 16 consecutive specimens of endomyocardial biopsy were qualified.There were 4 cases of acute T cell-mediated rejection (all graded 1 ),2 cases of Quilty lesion,and 7 cases of antibody-mediated rejection,who were documented according to ISHLT Schema and C4d deposition.Meanwhile,there were 6 cases showing evidence of antibody-mediated rejection without concurrent acute cellular rejection and only one case concordant with acute T cell-mediated rejection.One case of antibody-mediated rejection died 20 months posttransplantation due to combined transplant coronary artery disease (TCAD). The C4d in the cardiac allograft was deposited in microvasculature diffusively.Conclusion Antibody-mediated rejection is an important clinical entity following orthotopic heart transplantation and is difficult to diagnosis except to perform endomyoeardial biopsy.Immunoperoxidase staining for C4d is a sensitive and specific technique for detecting one marker of antibody-mediated rejection.

Proteasome-Inhibitor-Based Primary Therapy for Antibody-Mediated Rejection in a Renal Transplant Recipient / 대한내과학회지

Donor-specific anti-human leukocyte antigen antibodies (DSA) following kidney transplantation predict the evolution of humoral rejection and reduced graft survival. Rapid, complete elimination of DSA during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. We report the case of a 39-year-old female who was admitted for increasing azotemia and diagnosed with AMR based on diffusely positive histological changes on C4d immunostaining. In this case, bortezomib reversed the histological changes and induced a reduction in DSA. Proteasome-inhibitor-based combination therapy is a potential means for rapid DSA elimination in antibody-mediated rejection in renal transplant recipients.

Proteasome-Inhibitor-Based Primary Therapy for Antibody-Mediated Rejection in a Renal Transplant Recipient / 대한내과학회지

Donor-specific anti-human leukocyte antigen antibodies (DSA) following kidney transplantation predict the evolution of humoral rejection and reduced graft survival. Rapid, complete elimination of DSA during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. We report the case of a 39-year-old female who was admitted for increasing azotemia and diagnosed with AMR based on diffusely positive histological changes on C4d immunostaining. In this case, bortezomib reversed the histological changes and induced a reduction in DSA. Proteasome-inhibitor-based combination therapy is a potential means for rapid DSA elimination in antibody-mediated rejection in renal transplant recipients.