Predictors of Graft Success in Patients with Antibody-Mediated Rejection Following Kidney Transplantation

Vural Yilmaz^*
*Correspondence: Vural Yilmaz, Department of Internal Medicine, Division of Nephrology, Akdeniz University Medical School, Antalya, Turkey, Email:

Keywords

Renal transplantation • Antibody-mediated rejection • Graft survival

Introduction

A common cause of graft failure is active and persistent antibody-mediated rejection, or AMR. An earlier study suggested that the prevalence of AMR could range anywhere from 5.6% to 23%. AMR is frequently brought on by donor HLA antigens and rarely by non-HLA antigens. Conditions related to donor-specific antibodies (DSA) to human leukocyte (HLA) or non-HLA antigens, active and chronic active AMR, histological evidence of acute and chronic damage, recent antibody interaction with the vascular endothelium, and other factors are included in the updated Banff 2017 classification of the ABMR. DSAs bind to HLA or non- HLA molecules expressed on renal allograft endothelial cells and are produced by activation of B and plasma cells. Active AMR is responsible for peritubular capillaritis, glomerulitis, and a rapid decrease in allograft function [1].

Histologically, transplant glomerulopathy is the manifestation of chronic AMR, which leads to a steady decline in kidney function. The presence of circulating DSAs, histological evidence of acute-chronic tissue damage, and evidence of antibody interaction with vascular endothelium (peritubular capillary C4d accumulation) are the three primary diagnostic criteria for AMR. Peritubular C4d staining, DSA, and pathological findings in patients with AMR have all been linked in a number of studies. The treatment for AMR is based on two fundamental mechanisms after the diagnosis: the suppression of B cells or plasma cells as well as the removal of antibodies that are specific to a donor. We wanted to find out what demographic, histological, and clinical characteristics transplant recipients with AMR had, and how these characteristics affected graft survival in relation to antirejection therapy options.

Literature Review

Late-onset AMR is characterized by de novo DSA caused by inadequate immunosuppression, glomerulitis and/or peritubular capillary (PTC) inflammation (MVI), C4d deposition, and persistent morphologic changes like transplant TG and multilamination of PTC basement membranes. Silver staining reveals that activated glomerular capillary endothelial cells have expanded the subendothelial area with fibrillary and neomembrane material, resulting in "double contours." There must be a pathologic diagnosis of chronic AMR that is both accurate and reliable. Due to aberrant endothelial transcript expression in "C4d-negative" rejection (using the diffuse C4dptc3 threshold), AMR was underdiagnosed and misdiagnosed in the initial Banff schema [2]. Histologic AMR without DSA or C4dptc still presents diagnostic issues, but iteratively lowering the C4dptc thresholds to "focal" C4d2 (10%–50% for immunofluorescence) and "minimum" C4d1 (1%–9% for immunoperoxidase) and adding MVI8 increased sensitivity and decreased false-negative findings.

When target PTC are lost due to humoral damage, a major flaw in the diagnosis of chronic active-AMR (CA-AMR) is the overreliance on C4dptc and MVI lesions. Capillary endothelial cells undergo apoptosis and detachment in acute AMR, resulting in interstitial microcirculation collapse and luminal blockage. As interstitial fibrosis progresses in chronic rejection, this interstitial microcirculation gradually disappears. Weighted average of 12 investigations and 656 biopsies, 49.4% of TG samples tested positive for C4dptc [3]. Early subclinical AMR accounts for 37.0 percent of the C4dptc variation, which is unaffected by predictions of graft failure or parenchymal disease. One possible solution is to investigate C4dglom, a larger antigenic target for DSA deposition. Cleaved C4b forms covalent bonds with nearby amino acid and carbohydrate moieties on basement membrane collagen and glomerular endothelial cells by means of reactive sulfhydryl groups. Stable C4d remains detectable after proteolytic deactivation as the local "footprint" of the classical complement system activation by DSA binding within the glomerular capillaries [4].

Discussion

Due to the variable positivity of C4d immunofluorescence in mesangium, sporadic capillary loops, and collagen autofluorescence from sclerosed glomeruli in normal glomeruli, the initial Banff AMR diagnostic paradigm of 2001 excluded glomeruli. Since healthy glomeruli lack background C4dglom, chromogenic C4d immunohistochemical labeling of formalin-fixed, paraffinembedded tissue eliminates this issue, despite being less sensitive. In complement-activating native glomerular disorders (such as membranous, lupus, and immune-complex glomerulonephritis [GN]), mesangial and glomerular capillary C4d immunoperoxidase of formalin-fixed, paraffin-embedded tissue is utilized for salvaging when immunofluorescence tissue is lacking. Although immunoperoxidase-based C4dglom staining in active AMR and chronic TG was found in a number of transplant studies, its use as a diagnostic biomarker is not generally accepted. Three hypotheses were made by us: In transplanted kidneys, C4dglom represents endothelial interaction with antibody; (ii) There is a correlation between C4dglom's immunoperoxidase staining level and its clinical, immunologic, and pathologic humoral activities; (iii) incorporating late chronic AMR expressed as TG into the Banff chronic AMR schema would improve diagnostic sensitivity and etiologic classification. A well-defined cohort of 3524 consecutive adequate samples from ABO-compatible kidney transplant recipients was used to calculate the prevalence of C4dglom, epidemiologic risk factors, and correlations with authenticated AMR markers like circulating DSA, histologic MVI, Banff cg scores, and C4dptc. None of the donor tissues for the preimplantation procedure displayed any background C4dglom staining. The subpar diagnostic performance of the Banff 2019 CA-AMR definition for diagnosis verified TG (using only C4dptc) was significantly improved by including C4dglom and enhancing graft failure discrimination [5,6].

Using GRAfT, a multicenter prospective cohort study of heart transplant recipients, we sequenced the circulating plasma miR transcriptome to identify miRs that are differently regulated during acute allograft rejection. The development of various miR panels with superior test performance characteristics that can be used to screen for and noninvasively diagnose ACR and AMR from a peripheral blood sample is one of the main findings of this investigation.

Conclusion

The clinical parameters of the study indicate that ABMR has a poor prognosis; As a result, the course of treatment ought to be adapted to the individual pathological findings and graft functions of the patient at the time of diagnosis. Although PP, rituximab, and ATG should be utilized in some instances, pulse methylprednisolone and intravenous immunoglobulin (IVIG) should be administered to all ABMR patients. ABMR has a poor prognosis, so treatment should be tailored.

Acknowledgement

None.

Conflict of Interest

The author shows no conflict of interest towards this manuscript.

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