Correlation between post-transplant non-HLA antibodies and humoral rejection after kidney transplantation / 中华器官移植杂志

Objective:To explore the correlation between post-transplant non-HLA antibodies and humoral rejection(HR)after kidney transplantation(KT).Methods:A retrospective study was conducted for KT recipients with non-HLA antibody level detected from September 2019 to January 2021.The recipients with biopsy confirmed HR and donor-specific HLA antibodies negative or feeble positive at the time of HR were designated as HR group while recipients with stable renal allograft function from 2 weeks post-KT to the time of detecting non-HLA antibody as stable group.The levels of HLA antibody, MHC classⅠchain-related gene A(MICA)antibody and 32 non-HLA antibodies were tested by Luminex single antigen bead and the levels of angiotensin Ⅱ type 1 receptor(AT1R)antibody quantified by enzyme-linked immunosorbent assay (ELISA). Inter-group differences in positive rate of non-HLA antibodies and number of positive non-HLA antibodies were analyzed.Results:Twenty-four recipients had positive non-HLA antibodies while the remainders had no positive non-HLA antibodies.Three HR recipients were positive for actin antibody, collagen Ⅲ antibody, glutathione S-transferase theta-1 antibody or IFN-γ antibody respectively.However, all four non-HLA antibodies of stable recipients were negative.There was significant inter-group difference( P=0.017). Four HR recipients were positive for collagenⅡantibody while only 1 stable recipient was positive for collagenⅡantibody.The positive rate of collagenⅡ antibody was significantly higher in HR recipients than that in stable recipients( P=0.023). HR recipients had an average of 2.36 positive non-HLA antibodies while stable recipients had an average of 0.90.There was significant inter-group difference ( P=0.008). Conclusions:A high level of non-HLA antibodies may elevate the risk of HR after KT.

Effect of cold ischemia time on early graft function and acute rejection after liver transplantation / 器官移植

Objective To evaluate the effect of different cold ischemia time (CIT) on early graft function and acute rejection (AR) after liver transplantation. Methods Clinical data of 218 donors and recipients undergoing liver transplantation were collected and analyzed. All patients were divided into three groups according to the CIT of donor liver: group A (CIT≤6 h, n=60), group B (6 h < CIT≤10 h, n=89) and group C (CIT > 10 h, n=69). Blood samples were collected on the 1, 7 and 14 d after liver transplantation. The changes of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and adenosine triphosphate (ATP) in CD4+T cells were detected. The incidence of AR and the positive rate of C4d deposition were analyzed. Results The ALT, AST and LDH levels in each group reached the peak on the 1 d after operation, and then gradually decreased. The indexes in each group were almost equivalent on the 14 d. An interaction effect existed between postoperative time and group. After liver transplantation, ATP levels in CD4+T cells were gradually increased in each group, peaked at postoperative 7 d, and then decreased gradually. An interaction effect was noted between postoperative time and group. The incidence of AR in groups A, B and C was 10%, 12% and 28%. Compared with group C, the incidence of AR in groups A and B was decreased significantly (both P < 0.05/3). The positive rate of C4d deposition in AR recipients of groups A, B and C was 1/3, 45% and 89% respectively. Compared with group C, the positive rate of C4d deposition in group A was decreased significantly (P=0.015). Conclusions The prolongation of CIT may lead to aggravation of early-stage liver function injury after liver transplantation, which is more easily to induce humoral AR.

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.

Clinical and pathological correlations of C4d immunostaining and its infl uence on the outcome of kidney transplant recipients / Correlações clinico-patológicas da marcação de C4d e sua influência na evolução de receptores de transplante renal

INTRODUCTION: C4d is a marker of antibody-mediated rejection (ABMR) in kidney allografts, although cellular rejection also have C4d deposits. OBJECTIVE: To correlate C4d expression with clinico-pathological parameters and graft outcomes at three years. METHODS: One hundred forty six renal transplantation recipients with graft biopsies by indication were included. C4d staining was performed by paraffin-immunohistochemistry. Graft function and survival were measured, and predictive variables of the outcome were determined by multivariate Cox regression. RESULTS: C4d staining was detected in 48 (31 percent) biopsies, of which 23 (14.7 percent) had diffuse and 25 (16 percent) focal distribution. Pre-transplantation panel reactive antibodies ( percentPRA) class I and II were significantly higher in C4d positive patients as compared to those C4d negative. Both glomerulitis and pericapillaritis were associated to C4d (p = 0.002 and p < 0.001, respectively). The presence of C4d in biopsies diagnosed as no rejection (NR), acute cellular rejection (ACR) or interstitial fibrosis/ tubular atrophy (IF/TA) did not impact graft function or survival. Compared to NR, ACR and IF/TA C4d-, patients with ABMR C4d+ had the worst graft survival over 3 years (p = 0.034), but there was no difference between ABMR versus NR, ACR and IF/TA that were C4d positive (p = 0.10). In Cox regression, graft function at biopsy and high percentPRA levels were predictors of graft loss. CONCLUSIONS: This study confirmed that C4d staining in kidney graft biopsies is a clinically useful marker of ABMR, with well defined clinical and pathological correlations. The impact of C4d deposition in other histologic diagnoses deserves further investigation.

INTRODUÇÃO: A fração do complemento C4d é um marcador de rejeição mediada por anticorpos (RMA) em aloenxertos renais, embora na rejeição celular também se observem depósitos de C4d. OBJETIVOS: Correlacionar a expressão de C4d com parâmetros clínicopatológicos e a evolução do enxerto renal em três anos. MÉTODOS: Foram incluídos 146 receptores de transplante renal com biópsias por indicação. A marcação de C4d foi feita por imuno-histoquímica em parafina. Foram medidas a função e a sobrevida do enxerto e determinadas as variáveis preditivas de sua evolução por meio de modelo de regressão de Cox. RESULTADOS: A marcação positiva para C4d foi detectada em 48 (31 por cento) biópsias, das quais 23 (14,7 por cento) tinham marcação difusa e 25 (16 por cento), focal. A reatividade contra painel ( por centoPRA) de classe I e II pré-transplante foi significativamente maior nos pacientes C4d+ quando comparada aos C4d-. Tanto glomerulite quanto pericapilarite foram associadas com C4d (p = 0,002 e p < 0,001, respectivamente). A presença de C4d em biópsias sem rejeição (SR), rejeição celular aguda (RCA) ou fibrose intersticial/atrofia tubular (FI/AT) não teve impacto na função ou na sobrevida do enxerto. Comparados a indivíduos com SR, RCA e FI/AT C4d-, pacientes com RMA C4d+ tiveram pior sobrevida do enxerto em 3 anos (p = 0,034), mas não houve diferença entre RMA versus SR, RCA e FI/AT C4d+ (p = 0,10). Na regressão de Cox, função do enxerto no momento da biópsia e por centoPRA alto foram preditores de perda do enxerto. CONCLUSÕES: A pesquisa de C4d em biópsias do enxerto renal é útil para identificar RMA, com correlações clínicopatológicas bem definidas. O impacto do C4d em outros diagnósticos histológicos necessita de investigação adicional.

Inmunidad humoral y trasplante renal posibilidades terapéuticas / Humoral inmunity and renal trasplant: therapeutic possibilities

El trasplante renal es el tratamiento de elección para los pacientes con falla renal terminal. Las principales causas de pérdida de injertos son la muerte del paciente con injerto funcionante, especialmente de causa cardiovascular y la nefropatía crónica del injerto, con una pérdida crónica de injertos que resulta en un problema relevante. Dentro de las causas de nefropatía crónica destaca la causa inmunológica. Una de las causas de pérdida de injertos de origen inmunológico son los rechazos agudos, los que pueden ser de origen celular y humoral. Por otra parte, y a pesar de los avances en la comprensión de los mecanismos responsables de la inmunidad celular y el desarrollo de nuevas drogas inmunosupresoras (DIS), el rechazo mediado por anticuerpos o humoral aparece hoy como un peligro para la sobrevida del injertos a corto y a largo plazo. Afortunadamente el tratamiento del rechazo agudo humoral con drogas específicas ha resultado exitoso, sin embargo no ha ocurrido lo mismo con el rechazo mediado por anticuerpos de presentación más tardía, posiblemente por su comportamiento subclínico y un diagnóstico tardío, permaneciendo como un nuevo desafío recientemente reconocido. Por otra parte y basado en el exitoso tratamiento del RAH, se ha planteado mejorar las expectativas de llegar a realizar un trasplante a los pacientes sensibilizados. Esto es posible conseguir aplicando protocolos de desensibilización que se basan en la utilización de las mismas drogas para tratar RAH, consiguiendo ampliar las posibilidades de trasplante. El éxito de éstas es relativo al tipo de protocolos y a la intensidad de la sensibilización. La sobrevida del injerto en esta situación es plausible en la gran mayoría de los casos, sin embargo existe riesgo de presentar rechazo agudo humoral, y más complejo aún es el hecho que la sobrevida a largo plazo de los injertos sigue siendo todavía desconocida.

Renal Transplantation is the therapy of choice for patients with end-stage renal failure. The main causes for graft losses are patient death with functioning graft, mainly of cardiovascular etiology and chronic allograft nephropathy. Among the causes of chronic allograft nephropathy, the immunological ones are among the most important; one of them are the acute rejection episodes, which can be of cellular or humoral etiology; in addition, and despite the understanding of the mechanisms responsible for the cell immunity and the development of new immunosuppressive drugs (DIS) the antibody mediated rejection o humoral rejection has become today a danger for the short and long term allograft survival. Fortunately, the treatment of acute humoral rejection with specific drugs has become successful, however, the situation is different with late occurring antibody mediated rejection episodes, probably due to its subclinical behavior and a late diagnosis, remaining as a new challenge recently recognized. On the other hand based on the successful treatment of the RAH, expectations of performing a transplant in sensitized patients have been improved. This is possible to achieve using desensitizing protocols base don the same drugs used to treat RAH, thus increasing transplant possibilities. The success is related to the type of protocols and the intensity of the desensitizing. Graft survival in this situation is possible in the large majority of cases, however, the risk of acute humoral rejection is present, but even more complex is the fact thatlong-term survival is still unknown.

Diagnostic efficacy of C4d immunostaining in the detection of the humoral component of renal allograft rejection and therapeutic implications.

Context: In the current scenario of renal transplantation, the role of immunological methods in the detection of C4d has emerged as a useful adjunct in the recognition of acute humoral rejection (AHR). Few reports of this nature are available from the Indian context although there are several from the Western literature. Aims: To study the humoral component of renal allograft rejection in patients presenting clinically with graft dysfunction by histopathological detection of polymorphs in the peritubular capillaries and the expression of C4d using immunological techniques, as well as the response of patients to appropriate antirejection therapy. Settings and Design: This study from a tertiary care center reemphasizes the importance of recognition of AHR as a cause of renal allograft dysfunction. Materials and Methods: Percutaneous renal biopsies were obtained from 40 postrenal transplant patients and evaluated for C4d using immunofluorescence and immunohistochemical methods. Statistical a0 nalysis used: SPSS software. Results: Positive expression of C4d was seen in a total of 19/40 cases (44.4%) indicating immunological evidence of AHR. Diffusely positive cases were treated with IV immunoglobulin therapy, plasmapheresis and Rituximab following which graft function was restored. Patients with minimal to focal positive expression of C4d responded well to pulse steroids and change in immunosuppressive therapy. Conclusions: C4d staining is a useful adjunct to routine histopathological methods in evaluating the humoral component of acute renal allograft dysfunction and helps in planning appropriate antirejection therapy with the goal of achieving long-term graft survival.

A Case of C4d-Positive Acute Humoral Rejection Treated with Rituximab and Plasma Exchange / 대한신장학회잡지

Although acute humoral rejection is a major cause of renal allograft loss, the diagnosis and treatment of acute humoral rejection have been very difficult because of lack of proper diagnostic tools and effective therapeutic modalities. Recently C4d deposition in peritubular capillaries of renal allografts has been demonstrated to be a sensitive and diagnostic in-situ marker of humoral rejection that correlates strongly with the presence of circulating donor-specific antibodies. Whereas conventional immunosuppressive agents are effective for the treatment of cellular rejection, specific therapeutic strategies targeting the humoral limb of immunosuppression should be necessary for the treatment of humoral rejection. Here we report a case of acute humoral rejection diagnosed with C4d immunostaining from transplant kidney biopsy and treated successfully with combination of plasma exchange, polyclonal rabbit anti-thymocyte globulin, and rituximab.

A Case Report of Successful Treatment with Plasmapheresis and Intravenous Immunoglobulin in a Renal Transplant Recipient with Acute Humoral Rejection / 대한신장학회잡지

Acute humoral rejection after renal transplantation is associated with a higher frequency of allograft dysfunction and graft loss. We report a case of acute humoral rejection which was treated successfully with plasmapheresis and intravenous immunoglobulin. A 31- year-old man developed azotemia after kidney transplantation. Kidney biopsy finding was compatible with antibody-mediated rejection, demonstrated by the infiltration of monocytes and neutrophils and the deposition of C4d on glomerulus and peritubular capillaries. We performed five plasmapheresis with concomitant treatment of intravenous immunoglobulin after each session. With aggressive treatment, there was improvement of oliguric acute renal failure, accompanied by decrease in the percentage of PRA and the titer of donor specific antibodies. Repeated kidney biopsy revealed persistent C4d staining on peritubular capillaries despite disappearance of donor specific antibodies. In conclusion, plasmapheresis and intravenous immunoglobulin are effective in treating acute humoral rejection.

Eosinophil infiltration and peritubular capillary C4d deposition in acute renal allograft rejection / 中国免疫学杂志

Objective:To study the correlation between deposition of C4d along peritubular capillaries (PTC) and interstitial eosinophilic infiltration in renal allografts.Methods:Deposition of C4d in kidneys was assayed by indirect immunoflourescence of the renal allograft biopsies.Twenty-six patients were demonstrated strongly diffuse staining of PTC,who were defined as C4d+ group,while the biopsies of thirty patients with acute rejection exhibited negative for PTC C4d staining served as the controls,who were defined as C4d-group.Eosinophils were counted under microscope.Results:The C4d+group was demonstrated significantly greater interstitial eosinophilic infiltration than did the C4d-group(P

Diagnosis and treatment of humoral liver allograft rejection / 解放军医学杂志

Objective To explore the evidences of the humoral factor involved in the liver allograft rejection, and to explore better monitoring methods and therapy of the humoral liver rejection. Methods After the humoral liver rejection, liver puncture biopsies were performed. Immunohistochemical examinations of C4d, CD20+ B lymphocytes and CD138+ plasma cells were performed to judge whether humoral factor was involved in liver rejection. The dosage of tacrolimus was increased first when rejection was identified. The patients with severe liver function damage were treated with methyllprednisolone, and the steroid-insensitive cases were treated with antithymocyte globulins (ATG) and rapamycin. Results 25 biopsies were performed in 16 patients. Humoral rejection was diagnosed for 15 times in 10 patients, cellular rejection was diagnosed for 6 times in 4 patients, and the both kinds of rejection occurred in the last 2 patients. The effect of methylprednisolone was obviously lower in the humoral rejection cases (29.4%, 5/17) than that of the cellular rejection cases (7/8). Steroid-insensitive humoral rejections were diagnosed in 12 biopsies from 7 patients receiving liver transplantation. One patient was cured with ATG and 5 patients were cured with addition of rapamycin. The case whose blood type was AB receiving a liver transplant from the donor of O blood type died of liver function failure even after an extensive treatment. Conclusions Humoral immune factors maybe involved in some acute and chronic liver allograft rejection. ATG and rapamycin are more effective for the patients with humoral liver rejection.