Chronic Active T-Cell Mediated Kidney Rejection as a Clinically Significant Type of Allograft Loss?
Abstract
:1. Introduction
2. Materials and Methods
3. Characteristic Feature of Chronic Active T-Cell Mediated Rejection in Transplant Biopsy and Current Diagnostic Criteria
3.1. Overall View on Parameters Used in the Renal Histopathological Banff Classification
- The Banff lesion score t (tubulitis)—assesses the degree of inflammatory process within non-scaring cortical tubules’ epithelium. According to the definition of tubulitis, it is an inflammation located in the basolateral part of renal tubule epithelium caused by the presence of mononuclear cells. The score is measured in longitudinally cut tubules and defined by the quantity of mononuclear cells per 10 epithelial cells of the tubules. Tubulitis in CA TCMR refers to grades IA and IB. Lesions are considered in cortical tubules in non-scoring interstitial areas except ones with severe atrophy. Severely atrophic tubules are specified by the diameter lower than 25% of non-affected tubules.
- The Banff lesion score v (intimal arteritis)—this score refers to intimal arteritis, which is the presence of leukocytes, mainly lymphocytes, in the subendothelial space of at least one artery. Lesions penetrating the intima deeper are graded as stage II of CA TCMR.
- The Banff lesion score cv (vascular fibrous intimal thickening)—this term concerns the most severely affected artery in the specimen and assesses the thickening of arterial intima. These lesions are presented in grade II of CA TCMR.
- The Banff lesion score ti (total inflammation)—this score assesses the intensity of total cortical inflammation. If the score is at least 2 together with i-IFTA score the diagnosis of CA TCMR grade IA or IB can be considered [3].
- The Banff lesion score t-IFTA (tubulitis in areas of interstitial fibrosis)—this score has been introduced to differ the location of inflamed tubules. It refers to tubules located within scared cortex and does not include these ones present in preserved cortex. It has been proved that there is no effect of isolated t score on graft outcome—so the need of differentiation of location of inflamed tubules has been noticed. t-IFTA may be observed in CA TCMR as a moderate lesion in stage IA and as a severe lesion in stage IB [5].
- The Banff lesion score i-IFTA (inflammation in area of IFTA)—this criterion is important in recognition of CA TCMR. Without the presence of this type of lesions the diagnosis of CA TCMR cannot be made. This score refers to the inflammatory process in the scarred cortex. As it is mentioned above if the score is at least 2 together with ti score the diagnosis of CA TCMR grade IA or IB can be considered [3].
3.2. Current CA TCMR Diagnostic Criteria
- Grade IA: interstitial inflammation which involves >25% of the total cortex (ti2 or ti3) and >25% of scarred cortex (i-IFTA2 or i-IFTA3) with moderate tubulitis (t2 or t-IFTA2) involving at least one tubule but without including severely atrophic ones at the same time;
- Grade IB: interstitial inflammation which involves >25% of the total cortex (ti2 or ti3) and >25% of scarred cortex (i-IFTA2 or i-IFTA3) with severe tubulitis (t3 or t-IFTA3) involving at least one tubule but without including severely atrophic ones at the same time;
- Grade II: chronic allograft arteriopathy as in previous criteria.
3.3. Molecular Diagnostics of CA TCMR
- Reverse transcription polymerase chain reaction (RT-PCR) was the first molecular method ever used in studies regarding transplant rejection. It allows the evaluation of transcripts associated with cytokine burden or T-cell. Research based on this method enabled to establish associations of:
- Microarray technology enables large-scale analysis of transcriptomic data. Molecular tests for TCMR based on microarray analysis of mRNA expression provide a histologically independent measurement against which the relative validity of new algorithms for histologic diagnosis of TCMR can be determined. Molecular TCMR scores reflect the interaction of relevant effector T cells and antigen-presenting cells in the interstitium and are strongly correlated with histological lesions and diagnosis of TCMR. Studies showed the feasibility and utility of central microarray-based molecular measurements to assess disease states in transplant biopsies and demonstrate the possibility of molecular testing of biopsies combined with histology to improve our understanding of these diseases [13,14].
- Transcriptomic profiling of kidney graft biopsies which results demonstrate higher specificity in comparison to semi-quantitative histology assessment. Moreover, a smaller amount of tissue samples is required for adequate assessment [13].
- The NanoString nCounter system based on Formalin-Fixed Paraffin-Embedded (FFPE) biopsy is a modern, practical technology. It identifies similar associations of transcript with the histologic and molecular phenotypes as those reported in microarray studies. The NanoString system provide comparable results between fresh frozen samples and FFPE, with a higher sensitivity than that of microarrays and almost equal to reverse transcription polymerase chain reaction (RT-PCR) without a need of enzymes and requires only a single reaction per one sample despite the level of multiplexing. The system is approved for clinical use and introduced in pathology laboratories, equipped with analytical software and an automated platform being easily operated by lab technicians.
- NGS (next generation sequencing) is a relatively new technology based on DNA sequencing that has revolutionized genomic research [17]. It could be possibly useful to analyze transplant failure resulting from organ rejection, which may originate from an exaggerated or/and aberrant immune response. Basing on a subset of studies [18], Tsai-Hung et al. presumed that sequencing the expressed genes of B- and T-cells in the immune repertoire (iR) could provide clinical implications in the management and prediction of renal transplant rejection caused by immune diversity. Using NGS, they conducted the analysis in which they monitored the sequence change of CDR3 (complementary determining region 3) in BCR (B-cell receptors) IGH (immunoglobulin heavy-chain) iR in patients after kidney transplantation. The results of this research led to the conclusion that immune diversity is closely related to graft loss. However, they underlined the issue of an insufficient number of samples. Hence, interpreting an individual’s immune response regarding the iR information undoubtedly deserves further investigation [18].
3.4. Evaluation of Current Diagnostic Criteria Based on Recent Clinical Experience
3.5. The Future Prospect for Changes in Diagnostic Criteria
4. Treatment Approach
4.1. Assessment of Efficiency of Current and Previous Treatment Methods
4.2. Immunosuppression in Treatment of CA TCMR
4.3. The Revision of the Need of CA TCMR Treatment
5. The Impact of ABMR Coincidence on the CA TCMR Prognosis
5.1. Significance of Non-HLA Antibodies in Patients with TCMR
5.2. The Influence of ABMR on Treatment Methods
6. Significance of CA TCMR for Transplant Survival
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
CA | chronic active |
TCMR | T-cell mediated rejection |
ABMR | antibody mediated rejection |
i-IFTA | inflammation of the area with interstitial fibrosis |
KT | kidney transplantation |
t-IFTA | tubulitis in areas of interstitial fibrosis and tubular atrophy |
MDWG | Molecular Diagnostic Working Group |
B-HOT | Human Organ Transplant Panel |
RT-PCR | reverse transcription polymerase chain reaction |
PBT | pathogenesis-based transcript set |
FFPE | formalin-fixed paraffin-embedded |
DeaKAF | deterioration of kidney allograft function |
DC-GS | death-censored graft survival |
DSA | donor specific antibody |
KRT | kidney replacement therapy |
QoL | quality of life |
MP | methyloprednisolone |
Tac | tacrolimus |
MMF | mycophenolate mofetil |
EVR | everolimus |
ATG | anti-thymocyte globulin |
CNI | calcineurin inhibitors |
VGCV | valganciclovir |
dnDSA | de novo donor specific antibody |
CKTR | chronic kidney transplant rejection |
NGS | next generation sequencing |
iR | immune repertoire |
BCR | B-cell receptor |
IGH | immunoglobulin heavy chain |
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Banff Lesion Score | Abbreviation | 0 | 1 | 2 | 3 |
---|---|---|---|---|---|
Inflammation in non-scarred cortex | i | Absent/minimal (Less than 10% of non-scarred cortex inflamed) | Mild, (10–25% of non-scarred cortex inflamed) | Moderate, (26–50% of non-scarred cortex inflamed) | Severe, (more than 50% of non-scarred cortex inflamed) |
Tubulitis | t | None | Mild, (1–4 mononuclear leukocytes per tubular cross-section or 10 tubular epithelial cells in most severely involved tubule) | Moderate, (5–10 mononuclear leukocytes per tubular cross-section) | Severe, (more than 10 mononuclear leucocytes per tubular cross-section) |
Intimal arteritis | v | None | Mild (at least 1 leukocyte directly under the endothelium of at least 1 artery) | Moderate, (as grade 1, but with ≥25% luminal occlusion) | Severe, (with arterial fibrinoid necrosis or transmural inflammation) |
Glomerulitis | g | None | Mild, (with at least 1 leukocyte AND associated endothelial swelling occluding more than 50% of at least 1 capillary lumina in at least 1 but less than 25% of glomeruli) | Moderate, (as grade 1 but involving 25–75% of glomeruli) | Severe, (as grade 1 but involving more than 75% of glomeruli) |
Peritubular capillaritis | ptc | Minimal, (with less than 3 leukocytes in the most severely involved cortical PTC and/or leukocytes in less than 10% of cortical PTCs) | Mild, (with at least 1 leukocyte in at least 10% of cortical PTCs AND 3–4 leukocytes in the most severely involved PTC) | Moderate, (as grade 1 but with 5–10 leukocytes in most severely involved PTC) | Severe, (as grades 1–2 but with more than 10 leukocytes in most severely involved cortical PTC) |
Interstitial fibrosis in cortex | ci | Minimal, (not more than 5% of fibrosis) | Mild, (6–25%) | Moderate, (26–50%) | Severe, (more tahn 50%) |
Tubular atrophy in cortex | ct | None | Mild, (1–25% of atrophy) | Moderate, (26–50%) | Severe, (more than 50%) |
Arterial intimal fibrosis | cv | None | Mild, (present but with not more than 25% narrowing of luminal area in the most involved artery) | Moderate, (26–50% luminal narrowing) | Severe, (more than 50% luminal narrowing) |
Chronic glomerulopathy | cg | None | 1a (early mild, no GBM double contours by LM but subendothelial neo-densa in at least 3 glomerular capillaries by EM with associated endothelial cell enlargement and/or subendothelial electron-lucent widening, 1b (mild, GBM double contours by LM in 1–25% of glomerular capillaries by LM in the most severely involved glomerulus) | Moderate, (double contours by LM in 26–50% of capillaries) | Severe, (double contours by LM in more than 50% of capillaries) |
Total cortical inflammation | ti | Absent/Minimal, (less than 10% of inflamed cortex) | Mild, (10–25%) | Moderate, (26–50%) | Severe, (more than 50%) |
Inflammation in scarred cortex | i-IFTA | Absent/Minimal, (less than 10% of non-scarred cortex inflamed OR if the extent of cortical IFTA is less than 10%) | Mild, (10–25% of scarred cortex inflamed) | Moderate (26–50% of scarred cortex inflamed) | Severe, (more than 50% of scarred cortex inflamed) |
Tubulitis in tubules within scarred cortex | t-IFTA | None | Mild, (1–4 mononuclear leukocytes per tubular cross-section or 10 tubular epithelial cells in most severely involved tubule) | Moderate, (5–10 mononuclear leukocytes), | Severe, (more than 10 mononuclear leukocytes) |
Intrarenal polyomavirus load level | pvl | None | Mild, (virus positive cells in not more than 1% of tubules) | Moderate, (more than 1% and less than 10%) | Severe, (at least 10%) |
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Mizera, J.; Pilch, J.; Kamińska, D.; Krajewska, M.; Donizy, P.; Banasik, M. Chronic Active T-Cell Mediated Kidney Rejection as a Clinically Significant Type of Allograft Loss? Diagnostics 2022, 12, 3220. https://doi.org/10.3390/diagnostics12123220
Mizera J, Pilch J, Kamińska D, Krajewska M, Donizy P, Banasik M. Chronic Active T-Cell Mediated Kidney Rejection as a Clinically Significant Type of Allograft Loss? Diagnostics. 2022; 12(12):3220. https://doi.org/10.3390/diagnostics12123220
Chicago/Turabian StyleMizera, Jakub, Justyna Pilch, Dorota Kamińska, Magdalena Krajewska, Piotr Donizy, and Mirosław Banasik. 2022. "Chronic Active T-Cell Mediated Kidney Rejection as a Clinically Significant Type of Allograft Loss?" Diagnostics 12, no. 12: 3220. https://doi.org/10.3390/diagnostics12123220
APA StyleMizera, J., Pilch, J., Kamińska, D., Krajewska, M., Donizy, P., & Banasik, M. (2022). Chronic Active T-Cell Mediated Kidney Rejection as a Clinically Significant Type of Allograft Loss? Diagnostics, 12(12), 3220. https://doi.org/10.3390/diagnostics12123220