Antibody-mediated rejection (ABMR) is a major obstacle to the long-term success in kidney transplantation. Diagnosis of ABMR is determined according to the internationally recognized Banff criteria. However, a significant proportion of patients does not meet all the defined criteria, and the outcome of such cases remains poorly understood. The histology of ABMR frequently lacks sensitivity and specificity. More importantly, mixed forms of ABMR and T cell-mediated rejection as well as findings of nonspecific injury are common in clinical settings. Donor-specific anti-HLA antibodies (DSA) are detectable only in half of the ABMR cases by histology. Prognostic role of non-HLA antibodies against various endothelial proteins has been discussed. Antibody independent NK cell activation reflecting killer-cells' inhibitory receptor incompatibility is suggested in microvascular inflammation in DSA negative patients. Molecular assessment of ABMR has been prioritized to overcome high interobserver variability and improve diagnostics in mixed forms of rejections and in DSA negative cases. Finally, donor-derived cell-free DNA detected in a recipient's peripheral blood sample has been proposed as a noninvasive marker for diagnosis of graft rejection, and thus might serve as a liquid biopsy in the near future. Despite all achievements, diagnosing ABMR in kidney allografts remains to be a challenge in a significant number of cases.
- MeSH
- alografty MeSH
- isoprotilátky MeSH
- ledviny patologie MeSH
- lidé MeSH
- rejekce štěpu diagnóza MeSH
- transplantace ledvin * škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
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.
- Publikační typ
- časopisecké články MeSH
Molecular assessment of renal allografts has already been suggested in antibody-mediated rejection (ABMR), but little is known about the gene transcript patterns in particular renal compartments. We used laser capture microdissection coupled with quantitative RT-PCR to distinguish the transcript patterns in the glomeruli and tubulointerstitium of kidney allografts in sensitized retransplant recipients at high risk of ABMR. The expressions of 13 genes were quantified in biopsies with acute active ABMR, chronic active ABMR, acute tubular necrosis (ATN), and normal findings. The transcripts were either compartment specific (TGFB1 in the glomeruli and HAVCR1 and IGHG1 in the tubulointerstitium), ABMR specific (GNLY), or follow-up specific (CXCL10 and CX3CR1). The transcriptional profiles of early acute ABMR shared similarities with ATN. The transcripts of CXCL10 and TGFB1 increased in the glomeruli in both acute ABMR and chronic active ABMR. Chronic active ABMR was associated with the upregulation of most genes (SH2D1B, CX3CR1, IGHG1, MS4A1, C5, CD46, and TGFB1) in the tubulointerstitium. In this study, we show distinct gene expression patterns in specific renal compartments reflecting cellular infiltration observed by conventional histology. In comparison with active ABMR, chronic active ABMR is associated with increased transcripts of tubulointerstitial origin.
- MeSH
- biopsie MeSH
- chronická nemoc MeSH
- dospělí MeSH
- glomerulus imunologie metabolismus patologie MeSH
- HLA antigeny imunologie MeSH
- isoprotilátky imunologie MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- laserová záchytná mikrodisekce MeSH
- ledviny imunologie metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- rejekce štěpu genetika imunologie metabolismus patologie MeSH
- senioři MeSH
- stanovení celkové genové exprese MeSH
- studie případů a kontrol MeSH
- transkriptom * MeSH
- transplantace ledvin škodlivé účinky MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Peripheral blood monocytes, which serve as precursors for tissue macrophages and dendritic cells (DC), play a key role in the immune response to kidney allograft, reparation processes and homeostasis regulation. In this prospective study, we used multicolor flow cytometry to monitor the phenotypic patterns of peripheral monocytes in subjects with uncomplicated outcomes and those with acute rejection. We found a reciprocal increase in the proportion of "classical monocytes" (CD14+CD16-) along with a decline in pro-inflammatory "intermediary" (CD14+CD16+) and "non-classical" (CD14lowCD16+) monocytes in subjects with normal outcomes. In subjects with acute rejection, we observed no reduction in "intermediary" monocytes and no increase in "classical" monocytes. Patients with uncomplicated outcomes exhibited downregulated HLA-DR in all three monocyte subpopulations. However, non-classical monocytes were unaffected in subjects with acute rejection. Expression of CD47 was downregulated after transplantation, while patients with antibody-mediated rejection and donor-specific antibodies showed higher pre-transplant values. In monocytes isolated at the time of biopsy, CD47 expression was higher in individuals with acute rejection compared to patients with normal outcomes one year post-transplant. Expression of CD209 (DC-SIGN) and the proportion of CD163+CD206+ subpopulations were upregulated during the first week after kidney transplantation. CD209 was also upregulated in samples taken on the day of biopsy confirming acute rejection. Our data demonstrate that kidney allograft transplantation is associated with phenotypic changes in peripheral blood monocytes during acute rejection.
- MeSH
- dospělí MeSH
- fenotyp MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- monocyty patologie MeSH
- prospektivní studie MeSH
- rejekce štěpu etiologie patologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- transplantace ledvin škodlivé účinky MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Kidney allograft transplantation improved the prognosis and quality of life of patients with end-stage renal diseases but the occurrence of acute rejection represents a limitation of the final outcome. Noninvasive biomarkers are needed as well as further advancements in the understanding of immune mechanisms of reaction to the allograft. Our study of 138 patients focused on one-year monitoring of serum concentrations of 12 chemokines regulating the recruitment of different immune cells into transplanted allograft and on in vitro regulation of the same chemokines release by interactions of renal proximal epithelial cells with monocyte/macrophage cell line stimulated with TNF alpha. In a group of 44 patients with acute rejection, higher serum pretransplant levels of CXCL1, CXCL5, CXCL6, CCL2, CCL21, and particularly CXCL10 and CX3CL1(both p < 0.001) were found suggesting their higher proinflammatory status as compared to subjects with the uncomplicated outcome. In samples collected at the day of biopsy positive for acute rejection, chemokines CXCL9 and CXCL11 attracting preferentially Th1 lymphocytes were found to be upregulated. In our in vitro model with TNF alpha induction, renal proximal epithelial cells seemed to be a more potent source of chemokines attracting neutrophils as compared to monocyte/macrophage cell line but the coculture of these cells potentiated release of neutrophilic chemokines CXCL5 and CXCL6. Similar augmentation of chemokine production was found also in the case of CCL2. On the other hand, adding of monocytes/macrophages to a culture of renal epithelial cells suppressed the release of CXCL10 and CXCL11 attracting T lymphocytes. We assume from our data that in kidney allograft transplantation, chemokines attracting neutrophils, T lymphocytes, and monocytes are induced simultaneously and measurement some of them in combination might be used as biomarkers of acute rejection. Mutual cell-cell interactions of immune cells with renal parenchyma seem to be important for fine regulation of chemokine release.
- MeSH
- alografty MeSH
- chemokin CCL2 krev MeSH
- chemokin CCL21 krev MeSH
- chemokin CX3CL1 krev MeSH
- chemokin CXCL1 krev MeSH
- chemokin CXCL10 krev MeSH
- chemokin CXCL11 krev MeSH
- chemokin CXCL5 krev MeSH
- chemokin CXCL6 krev MeSH
- chemokin CXCL9 krev MeSH
- chemokiny krev MeSH
- kvalita života MeSH
- lidé MeSH
- rejekce štěpu krev imunologie MeSH
- Th1 buňky metabolismus MeSH
- transplantace ledvin škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
