scholarly journals Antibody-Mediated Rejection in Kidney Transplant Recipients

2013 ◽  
Vol 67 (1) ◽  
pp. 2-8
Author(s):  
Rafails Rozentâls ◽  
Ieva Ziediņa
Keyword(s):  
Kidney Transplantation ◽  
Transplant Recipients ◽  
Humoral Rejection ◽  
Kidney Transplant Recipients ◽  
Hla Antibodies ◽  
Antibody Mediated Rejection ◽  
Peritubular Capillaries ◽  
Before And After ◽  
The One ◽  
Clinical Changes

This paper provides a review of the significant problem of humoral, or antibody-mediated rejection, in kidney transplantation. The main cause of antibody-mediated rejection is donor-specific anti-HLA antibodies. Patients with anti-HLA antibodies are called sensitised patients. The outcome of humoral rejection is unfavourable: graft dysfunction and failure have been frequent from the early post-transplant period and are continuing. International laboratories and clinics offer sensitive and accurate methods to determine antibodies before and after kidney transplantation, but the methods are not always successful in recognition of sensitised patients. For diagnostics of humoral rejection the important issue is detecting complement breakdown deposition (C4d) in peritubular capillaries during immunohistological examination. On the one hand, their presence is characteristic for humoral rejection, but on the other hand, they can occur without any clinical changes or can remain undetected during severe humoral rejection. Current methods of prevention, diagnostics and treatment of humoral rejection are discussed. Difficulties of evaluation of chronic antibody-mediated injury are particularly highlighted.

scholarly journals The determinants, biomarkers, and consequences of microvascular injury in kidney transplant recipients

2019 ◽  
Vol 316 (1) ◽  
pp. F9-F19 ◽  
Author(s):  
Alice Doreille ◽  
Mélanie Dieudé ◽  
Heloise Cardinal
Keyword(s):  
Kidney Disease ◽  
Kidney Transplant ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Hla Antibodies ◽  
Microvascular Injury ◽  
Antibody Mediated Rejection ◽  
Peritubular Capillaries

Independent of the initial cause of kidney disease, microvascular injury to the peritubular capillary network appears to play a central role in the development of interstitial fibrosis in both native and transplanted kidney disease. This association is explained by mechanisms such as the upregulation of profibrotic genes and epigenetic changes induced by hypoxia, capillary leakage, endothelial and pericyte transition to interstitial fibroblasts, as well as modifications in the secretome of endothelial cells. Alloimmune injury due to antibody-mediated rejection and ischemia-reperfusion injury are the two main etiologies of microvascular damage in kidney transplant recipients. The presence of circulating donor-specific anti-human leukocyte antigen (HLA) antibodies, histological findings, such as diffuse C4d staining in peritubular capillaries, and the extent and severity of peritubular capillaritis, are commonly used clinically to provide both diagnostic and prognostic information. Complement-dependent assays, circulating non-HLA antibodies, or evaluation of the microvasculature with novel imaging techniques are the subject of ongoing studies.

scholarly journals Association of non-HLA antibodies against endothelial targets and donor-specific HLA antibodies with antibody-mediated rejection and graft function in pediatric kidney transplant recipients

2021 ◽  
Author(s):  
Alexander Fichtner ◽  
Caner Süsal ◽  
Britta Höcker ◽  
Susanne Rieger ◽  
Rüdiger Waldherr ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
Graft Function ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Hla Antibodies ◽  
Antibody Mediated Rejection ◽  
Peritubular Capillaries ◽  
Increased Risk ◽  
Antibody Positivity ◽  
Hla Antibody

Abstract Background Non-HLA antibodies against endothelial targets have been implicated in the pathogenesis of antibody-mediated rejection (ABMR), but data in pediatric patients are scarce. Methods We retrospectively analyzed a carefully phenotyped single-center (University Children’s Hospital Heidelberg, Germany) cohort of 62 pediatric kidney transplant recipients (mean age at transplantation, 8.6 ± 5.0 years) at increased risk of graft function deterioration. Patients had received their transplant between January 1, 1999, and January 31, 2010. We examined at time of late index biopsies (more than 1-year post-transplant, occurring after January 2004) the association of antibodies against the angiotensin II type 1 receptor (AT1R), the endothelin type A receptor (ETAR), the MHC class I chain-like gene A (MICA), and vimentin in conjunction with overall and complement-binding donor-specific HLA antibodies (HLA-DSA) with graft histology and function. Results We observed a high prevalence (62.9%) of non-HLA antibody positivity. Seventy-two percent of HLA-DSA positive patients showed additional positivity for at least one non-HLA antibody. Antibodies against AT1R, ETAR, and MICA were associated with the histological phenotype of ABMR. The cumulative load of HLA-DSA and non-HLA antibodies in circulation was related to the degree of microinflammation in peritubular capillaries. Non-HLA antibody positivity was an independent non-invasive risk factor for graft function deterioration (adjusted hazard ratio 6.38, 95% CI, 2.11–19.3). Conclusions Our data indicate that the combined detection of antibodies to HLA and non-HLA targets may allow a more comprehensive assessment of the patients’ immune responses against the kidney allograft and facilitates immunological risk stratification.

scholarly journals Non-HLA Antibodies and Epitope Mismatches in Kidney Transplant Recipients With Histological Antibody-Mediated Rejection

2021 ◽  
Vol 12 ◽  
Author(s):  
Marta Crespo ◽  
Laura Llinàs-Mallol ◽  
Dolores Redondo-Pachón ◽  
Carrie Butler ◽  
Javier Gimeno ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
De Novo ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Serum Samples ◽  
Hla Antibodies ◽  
Aortic Endothelial Cells ◽  
Antibody Mediated Rejection ◽  
Donor Specific Antibodies

BackgroundCorrelation between antibody-mediated rejection (ABMR) and circulating HLA donor-specific antibodies (HLA-DSA) is strong but imperfect in kidney transplant (KT) recipients, raising the possibility of undetected HLA-DSA or non-HLA antibodies contributing to ABMR. Detailed evaluation of the degree of HLA matching together with the identification of non-HLA antibodies in KT may help to decipher the antibody involved.MethodsWe retrospectively assessed patients with transplant biopsies scored following Banff’15 classification. Pre- and post-transplant serum samples were checked for HLA and non-HLA antibodies [MICA-Ab, angiotensin-II type-1-receptor (AT1R)-Ab, endothelin-1 type-A-receptor (ETAR)-Ab and crossmatches with primary aortic endothelial cells (EC-XM)]. We also analyzed HLA epitope mismatches (HLA-EM) between donors and recipients to explore their role in ABMR histology (ABMRh) with and without HLA-DSA.ResultsOne-hundred eighteen patients with normal histology (n = 19), ABMRh (n = 52) or IFTA (n = 47) were studied. ABMRh patients were HLA-DSApos (n = 38, 73%) or HLA-DSAneg (n = 14, 27%). Pre-transplant HLA-DSA and AT1R-Ab were more frequent in ABMRh compared with IFTA and normal histology cases (p = 0.006 and 0.003), without differences in other non-HLA antibodies. Only three ABMRhDSAneg cases showed non-HLA antibodies. ABMRhDSAneg and ABMRhDSApos cases showed similar biopsy changes and graft-survival. Both total class II and DRB1 HLA-EM were associated with ABMRhDSApos but not with ABMRhDSAneg. Multivariate analysis showed that pre-transplant HLA-DSA (OR: 3.69 [1.31–10.37], p = 0.013) and AT1R-Ab (OR: 5.47 [1.78–16.76], p = 0.003) were independent predictors of ABMRhDSApos.ConclusionsIn conclusion, pre-transplant AT1R-Ab is frequently found in ABMRhDSApos patients. However, AT1R-Ab, MICA-Ab, ETAR-Ab or EC-XM+ are rarely found among ABMRhDSAneg patients. Pre-transplant AT1R-Ab may act synergistically with preformed or de novo HLA-DSA to produce ABMRhDSApos but not ABMRhDSAneg. HLA epitope mismatch associates with ABMRhDSApos compared with ABMRhDSAneg, suggesting factors other than HLA are responsible for the damage.

CRISPR/Cas9-Engineered HLA-Deleted Glomerular Endothelial Cells as a Tool to Predict Pathogenic Non-HLA Antibodies in Kidney Transplant Recipients

2021 ◽  
Vol 32 (12) ◽  
pp. 3231-3251
Author(s):  
Baptiste Lamarthée ◽  
Carole Burger ◽  
Charlotte Leclaire ◽  
Emilie Lebraud ◽  
Aniela Zablocki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Kidney Transplant ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Hla Antibodies ◽  
Specific Antibodies ◽  
Antibody Mediated Rejection ◽  
Biopsy Specimens ◽  
Glomerular Endothelial Cells ◽  
Donor Specific Antibodies

BackgroundAfter kidney transplantation, donor-specific antibodies against human leukocyte antigen donor-specific antibodies (HLA-DSAs) drive antibody-mediated rejection (ABMR) and are associated with poor transplant outcomes. However, ABMR histology (ABMRh) is increasingly reported in kidney transplant recipients (KTRs) without HLA-DSAs, highlighting the emerging role of non-HLA antibodies (Abs).MethodsW e designed a non-HLA Ab detection immunoassay (NHADIA) using HLA class I and II–deficient glomerular endothelial cells (CiGEnCΔHLA) that had been previously generated through CRISPR/Cas9-induced B2M and CIITA gene disruption. Flow cytometry assessed the reactivity to non-HLA antigens of pretransplantation serum samples from 389 consecutive KTRs. The intensity of the signal observed with the NHADIA was associated with post-transplant graft histology assessed in 951 adequate biopsy specimens.ResultsW e sequentially applied CRISPR/Cas9 to delete the B2M and CIITA genes to obtain a CiGEnCΔHLA clone. CiGEnCΔHLA cells remained indistinguishable from the parental cell line, CiGEnC, in terms of morphology and phenotype. Previous transplantation was the main determinant of the pretransplantation NHADIA result (P<0.001). Stratification of 3-month allograft biopsy specimens (n=298) according to pretransplantation NHADIA tertiles demonstrated that higher levels of non-HLA Abs positively correlated with increased glomerulitis (P=0.002), microvascular inflammation (P=0.003), and ABMRh (P=0.03). A pretransplantation NHADIA threshold of 1.87 strongly discriminated the KTRs with the highest risk of ABMRh (P=0.005, log-rank test). A multivariate Cox model confirmed that NHADIA status and HLA-DSAs were independent, yet synergistic, predictors of ABMRh.ConclusionThe NHADIA identifies non-HLA Abs and strongly predicts graft endothelial injury independent of HLA-DSAs.

All-cause and cancer-specific overall survival in kidney transplant recipients with pre-transplant malignancies in a German cohort

2020 ◽  
Vol 4 (3) ◽  
pp. 171-178
Author(s):  
Fabian Jacoby ◽  
Holland-Letz Tim ◽  
Martin Zeier ◽  
Susanne Delecluse
Keyword(s):  
Overall Survival ◽  
Kidney Transplantation ◽  
Tumor Recurrence ◽  
Tumor Development ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Before And After ◽  
Gynecologic Tumors ◽  
Kidney Insufficiency ◽  
And Gender

Kidney insufficiency and immunosuppression are well established contributors of tumor development, both before and after kidney transplantation. Patients with pre-transplant malignancies (PTM) are at risk of tumor recurrence and of the development of an unrelated tumor after transplantation. In this retrospective study of a German patient cohort, we analyzed 1089 patients that underwent kidney transplantation to determine the frequency, recurrence rate and overall survival of patients with pre-existing tumors across a 10-year period. PTM were found in 5.79% of the patients and appeared at a mean time of 7.39 (SD 6.8) years before transplantation. The tumors were most frequently of urologic (41.43%) origin, followed by malignancies of the skin (25.71%) and gynecologic tumors (10%). Tumor recurrence was observed in one case (1.6%) where the patient died of metastatic spinocellular carcinoma. Patients with pre-existing malignancies had a statistically significantly worse overall survival compared to transplant recipients without tumors (HR = 2.71, 95% CI 1.49–4.969). However, these differences could be entirely ascribed to the age (HR = 1.06, 95% CI 1.04–1.08) and gender (HR = 1.67, 95% CI 1.11–2.52) of the patients. We found that there was no difference in cancer-specific mortality or posttransplant cancer rate between patients with and without pre-existing malignancies (HR = 0.94, 95% CI 0.21–4.26).

scholarly journals Transcriptional Changes in Kidney Allografts with Histology of Antibody-Mediated Rejection without Anti-HLA Donor-Specific Antibodies

2020 ◽  
Vol 31 (9) ◽  
pp. 2168-2183 ◽  
Author(s):  
Jasper Callemeyn ◽  
Evelyne Lerut ◽  
Henriette de Loor ◽  
Ingrid Arijs ◽  
Olivier Thaunat ◽  
...  
Keyword(s):  
Etiologic Factor ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Multicenter Cohort Study ◽  
Hla Antibodies ◽  
Transcriptional Signature ◽  
Antibody Mediated Rejection ◽  
Biopsy Specimens ◽  
Transcriptional Changes ◽  
Donor Specific Antibodies

BackgroundCirculating donor-specific anti-HLA antibodies (HLA-DSAs) are often absent in serum of kidney allograft recipients whose biopsy specimens demonstrate histology of antibody-mediated rejection (ABMR). It is unclear whether cases involving ABMR histology without detectable HLA-DSAs represent a distinct clinical and molecular phenotype.MethodsIn this multicenter cohort study, we integrated allograft microarray analysis with extensive clinical and histologic phenotyping from 224 kidney transplant recipients between 2011 and 2017. We used the term ABMR histology for biopsy specimens that fulfill the first two Banff 2017 criteria for ABMR, irrespective of HLA-DSA status.ResultsOf 224 biopsy specimens, 56 had ABMR histology; 26 of these (46.4%) lacked detectable serum HLA-DSAs. Biopsy specimens with ABMR histology showed overexpression of transcripts mostly related to IFNγ-induced pathways and activation of natural killer cells and endothelial cells. HLA-DSA–positive and HLA-DSA–negative biopsy specimens with ABMR histology displayed similar upregulation of pathways and enrichment of infiltrating leukocytes. Transcriptional heterogeneity observed in biopsy specimens with ABMR histology was not associated with HLA-DSA status but was caused by concomitant T cell–mediated rejection. Compared with cases lacking ABMR histology, those with ABMR histology and HLA-DSA had higher allograft failure risk (hazard ratio [HR], 7.24; 95% confidence interval [95% CI], 3.04 to 17.20) than cases without HLA-DSA (HR, 2.33; 95% CI, 0.85 to 6.33), despite the absence of transcriptional differences.ConclusionsABMR histology corresponds to a robust intragraft transcriptional signature, irrespective of HLA-DSA status. Outcome after ABMR histology is not solely determined by the histomolecular presentation but is predicted by the underlying etiologic factor. It is important to consider this heterogeneity in further research and in treatment decisions for patients with ABMR histology.

Immunoadsorption Combined with Membrane Filtration to Counteract Early Treatment-Refractory Antibody-Mediated Rejection

2020 ◽  
Vol 49 (5) ◽  
pp. 576-585 ◽  
Author(s):  
Konstantin Doberer ◽  
Gregor Bond ◽  
Johannes Kläger ◽  
Heinz Regele ◽  
Robert Strassl ◽  
...  
Keyword(s):  
Membrane Filtration ◽  
Therapeutic Option ◽  
High Grade ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Antibody Mediated Rejection ◽  
Peritubular Capillaries ◽  
Allograft Function ◽  
Treatment Refractory

Introduction: Immunoadsorption (IA) represents a therapeutic option for acute antibody-mediated rejection (ABMR) after kidney transplantation. The addition of membrane filtration (MF) to enhance elimination of macromolecular components that potentially contribute to rejection, such as key complement component C1q and alloreactive IgM, may be an effective strategy to further improve its therapeutic efficiency. Results: Here we present 4 consecutive patients with episodes of HLA donor-specific antibody-positive ABMR nonresponsive to cycles of 6–16 sessions of IA treatment. Rejection episodes were characterized by severe microvascular injury (high-grade microcirculation inflammation and/or signs of thrombotic microangiopathy) and evidence of intense complement activation in peritubular capillaries (diffuse C4d-positivity). IA combined with MF led to substantial morphologic improvement (follow-up biopsies: g + ptc and C4d scores ≤1) and stabilization of allograft function. Conclusions: Our findings provide evidence for an effect of combination of IA + MF in refractory early acute/active ABMR in kidney transplant recipients.

scholarly journals Orosomucoid 1 is involved in the development of chronic allograft rejection after kidney transplantation

2020 ◽  
Vol 32 (5) ◽  
pp. 335-346 ◽  
Author(s):  
Haruka Higuchi ◽  
Daisuke Kamimura ◽  
Jing-Jing Jiang ◽  
Toru Atsumi ◽  
Daiki Iwami ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Kidney Transplant ◽  
Therapeutic Target ◽  
Allograft Rejection ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Kidney Allograft ◽  
Tubular Cells ◽  
Chronic Allograft Rejection ◽  
Antibody Mediated Rejection

Abstract Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NFκB and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NFκB and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NFκB activation, respectively. Finally, ORM1-enhanced NFκB-mediated inflammation development in vivo. These results suggest that an enhanced NFκB-dependent pathway following NFκB and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection.

scholarly journals Measurements of Serum Pituitary-Gonadal Hormones and Investigation of Sexual and Reproductive Functions in Kidney Transplant Recipients

2010 ◽  
Vol 2010 ◽  
pp. 1-6 ◽  
Author(s):  
Guang-chun Wang ◽  
Jun-hua Zheng ◽  
Long-gen Xu ◽  
Zhi-lian Min ◽  
You-hua Zhu ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Kidney Transplant ◽  
Gonadal Hormones ◽  
Gonadal Hormone ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Sperm Density ◽  
Normal Ranges ◽  
Before And After ◽  
Stage Renal Disease

Objective. To investigate changes in serum pituitary-gonadal hormones and restoration of sexual and reproductive functions after successful kidney transplantation.Patients and Methods. Serum pituitary-gonadal hormones before and after kidney transplantation were measured in 78 patients with end-stage renal disease (ESRD) and in 30 healthy adults. Pre- and postoperative semen specimens of 46 male recipients and 15 male controls were collected and compared. Additional 100 married kidney transplant recipients without children were followed up for 3 years to observe their sexual function and fertility.Results. Serum PRL, LH, and T orE2levels gradually restored to the normal ranges in all kidney transplant recipients, and sperm density, motility, viability, and morphology significantly improved in the male recipients 4 months after successful kidney transplantation (P<.05). Thirty-three male recipients (55.93%) reobtained normal erectile function, and 49 kidney transplant recipients (61.25%) had children within the 3-year follow-up period.Conclusion. Successful kidney transplantation could effectively improve pituitary-gonadal hormone disturbance and sexual and reproductive dysfunctions of ESRD patients.

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