Transplant Glomerulopathy: Importance of Ultrastructural Examination

Morphologic Alteration ◽

Background: Transplant glomerulopathy (TG) is a morphologic alteration in glomeruli of renal allografts, characterized by glomerular basement membrane reduplications. Summary: TG is associated with progressive chronic allograft dysfunction and proteinuria and is a diagnostic feature of chronic antibody-mediated rejection (ABMR) in patients positive for donor-specific antibodies, according to the Banff schema for renal allograft pathology. It is a definitive endpoint in clinical trials and interventional studies for ABMR, but the lesion can also occur in the absence of definitive alloimmune injury, as a consequence of chronic thrombotic microangiopathy, and in some cases in association with hepatitis C infection. This review discusses the pathophysiology and clinical presentation of TG, the diagnostic features by light microscopy, and focuses on the sequential ultrastructural stages of the lesion. The differential diagnosis of TG, and Banff grading of the lesion, are reviewed. Clinicopathological indications for performing routine ultrastructural examination of renal allograft biopsies are discussed. Key Messages: TG can be diagnosed at an early stage by electron microscopy, before histological features are apparent, emphasizing the importance of ultrastructural examination of renal allograft biopsies for an early diagnosis, when therapeutic intervention may be beneficial.

Comparing transplant glomerulopathy in the absence of C4d deposition and donor-specific antibodies to chronic antibody-mediated rejection

Clinical Transplantation ◽

10.1111/ctr.12433 ◽

2014 ◽

Vol 28 (10) ◽

pp. 1148-1154 ◽

Cited By ~ 14

Author(s):

Irina B. Torres ◽

Maite Salcedo ◽

Francesc Moreso ◽

Joana Sellarés ◽

Eva Castellá ◽

...

Keyword(s):

Specific Antibodies ◽

Clinicopathologic Relevance of Vascular Changes Associated with Transplant Glomerulopathy Secondary to Chronic Antibody-mediated Rejection in the Renal Allograft

10.14232/phd.9718 ◽

2018 ◽

Author(s):

Deján Dobi

Keyword(s):

Renal Allograft ◽

Vascular Changes ◽

P1755EFFICACY AND SAFETY ECULIZUMAB FOR THE TREATMENT OF ANTIBODY MEDIATED REJECTION FOLLOWING RENAL TRANSPLANTATION

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1755 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Hark Rim ◽

Jisu Kim ◽

Haesu Jeon ◽

Ye Na Kim ◽

Ho Sik Shin ◽

...

Keyword(s):

Alternative Therapy ◽

Standard Of Care ◽

Ivig Therapy ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Open Label ◽

Potential Alternative ◽

Abstract Background and Aims : We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis (PP) and intravenous immunoglobulin (IVIG) therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR). Methods This was a multi-center, open-label, prospective, randomized analysis. The patients were randomized as to therapy type (eculizumab infusions or standard of care, SOC: PP/IVIG). The patients (eculizumab arm: 7 patients, SOC arm: 4 patient) were evaluated for the continuing presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histological evidence, using repeat renal biopsies after treatment. Results The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. Following AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm. Conclusion Eculizumab alone is not sufficient to treat AMR and does not prevent acute AMR from progressing to chronic AMR or to transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.

Donor-Specific Antibodies in Kidney Transplant Recipients

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.00700117 ◽

2017 ◽

Vol 13 (1) ◽

pp. 182-192 ◽

Cited By ~ 54

Author(s):

Rubin Zhang

Keyword(s):

Kidney Transplant ◽

De Novo ◽

Binding Capacity ◽

Graft Loss ◽

Igg Subclasses ◽

Kidney Transplant Recipients ◽

Specific Antibodies ◽

Donor-specific antibodies have become an established biomarker predicting antibody-mediated rejection. Antibody-mediated rejection is the leading cause of graft loss after kidney transplant. There are several phenotypes of antibody-mediated rejection along post-transplant course that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity. Preformed donor-specific antibodies in sensitized patients can trigger hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection. De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy. The pathogeneses of antibody-mediated rejection include not only complement-dependent cytotoxicity, but also complement-independent pathways of antibody-mediated cellular cytotoxicity and direct endothelial activation and proliferation. The novel assay for complement binding capacity has improved our ability to predict antibody-mediated rejection phenotypes. C1q binding donor-specific antibodies are closely associated with acute antibody-mediated rejection, more severe graft injuries, and early graft failure, whereas C1q nonbinding donor-specific antibodies correlate with subclinical or chronic antibody-mediated rejection and late graft loss. IgG subclasses have various abilities to activate complement and recruit effector cells through the Fc receptor. Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury, whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy. Our in-depth knowledge of complex characteristics of donor-specific antibodies can stratify the patient’s immunologic risk, can predict distinct phenotypes of antibody-mediated rejection, and hopefully, will guide our clinical practice to improve the transplant outcomes.

Faculty Opinions recommendation of De novo DQ donor-specific antibodies are associated with a significant risk of antibody-mediated rejection and transplant glomerulopathy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717948001.793453051 ◽

2012 ◽

Author(s):

David Kluth ◽

Neeraj Dhaun

Keyword(s):

De Novo ◽

Significant Risk ◽

Specific Antibodies ◽

Assessment of Tocilizumab (Anti-Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients

American Journal of Transplantation ◽

10.1111/ajt.14228 ◽

2017 ◽

Vol 17 (9) ◽

pp. 2381-2389 ◽

Cited By ~ 123

Author(s):

J. Choi ◽

O. Aubert ◽

A. Vo ◽

A. Loupy ◽

M. Haas ◽

...

Keyword(s):

Interleukin 6 ◽

Renal Allograft ◽

Potential Treatment ◽

Interleukin 6 Receptor ◽

Intimal Arteritis and Microvascular Inflammation Are Associated With Inferior Kidney Graft Outcome, Regardless of Donor-Specific Antibodies

Frontiers in Medicine ◽

10.3389/fmed.2021.781206 ◽

2021 ◽

Vol 8 ◽

Author(s):

Marek Novotny ◽

Petra Hruba ◽

Martin Kment ◽

Ludek Voska ◽

Katerina Kabrtova ◽

...

Keyword(s):

Graft Failure ◽

Significant Risk ◽

Kidney Graft ◽

Free Survival ◽

Graft Outcome ◽

Microvascular Inflammation ◽

Background: The prognostic role of intimal arteritis of kidney allografts in donor-specific antibody negative (DSA–) antibody-mediated rejection (ABMR) remains unclear.Methods: Seventy-two out of 881 patients who had undergone kidney transplantation from 2014 to 2017 exhibited intimal arteritis in biopsies performed during the first 12 months. In 26 DSA negative cases, the intimal arteritis was accompanied by tubulointerstitial inflammation as part of T cell-mediated vascular rejection (TCMRV, N = 26); intimal arteritis along with microvascular inflammation occurred in 29 DSA negative (ABMRV/DSA–) and 19 DSA positive cases (ABMRV, DSA+, N = 17). In 60 (83%) patients with intimal arteritis, the surveillance biopsies after antirejection therapy were performed. Hundred and two patients with non-vascular ABMR with DSA (ABMR/DSA+, N = 55) and without DSA (ABMR/DSA–, N = 47) served as controls. Time to transplant glomerulopathy (TG) and graft failure were the study endpoints.Results: Transplant glomerulopathy -free survival at 36 months was 100% in TCMRV, 85% in ABMR/DSA–, 65% in ABMRV/DSA-, 54% in ABMR/DSA+ and 31% in ABMRV/DSA+ (log rank p < 0.001). Death-censored graft survival at 36 months was 98% in ABMR/DSA-, 96% in TCMRV, 86% in ABMRV/DSA–, 79% in ABMR/DSA+, and 64% in ABMRV/DSA+ group (log rank p = 0.001). In surveillance biopsies, the resolution of rejection was found in 19 (90%) TCMRV, 14 (58%) ABMRV/DSA–, and only 4 (27%) ABMRV/DSA+ patients (p = 0.006). In the multivariable model, intimal arteritis as part of ABMR represented a significant risk for TG development (HR 2.1, 95% CI 1.2–3.8; p = 0.012) regardless of DSA status but not for graft failure at 36 months.Conclusions: Intimal arteritis as part of ABMR represented a risk for early development of TG regardless of the presence or absence of DSA. Intimal arteritis in DSA positive ABMR represented the high-risk phenotype.