Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes
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PROVIDER: PRJNA631023 | ENA |
REPOSITORIES: ENA
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Project description:Previous studies of rejection-associated transcript expression in heart transplant biopsies identified not only rejection but a group of early biopsies with injury but no rejection. The present analysis used an expanded population of biopsies to explore parenchymal injury in all biopsies, with or without rejection, and its relationship to function, and outcome. Archetypal analysis defined five injury clusters: no-injury (N=376); mild (N=526); moderate (N=110); severe (N=87); and late (N=221). The late group, 62% of which had no rejection, had molecular characteristics associated with atrophy-fibrosis, depressed LVEF, and increased graft loss independent of rejection status. In random forest analysis, low LVEF was more strongly associated with injury scores than with rejection scores. Three-year graft failure was best predicted using a combination of injury and rejection scores. In heart transplant biopsies, injury-related molecular scores correlate with dysfunction and risk of failure and identify an important new group of late heart transplants, many with no rejection, that have impaired function and a high risk of graft loss. (ClinicalTrials.gov #NCT02670408).
2021-12-28 | GSE150059 | GEO
Project description:Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower eGFR, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR respectively diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.
2024-09-04 | GSE275126 | GEO
Project description:This retrospective, single-center study included 124 pancreas allograft biopsies obtained between April 2019 and May 2025. Biopsies were analyzed using a kidney-derived Molecular Microscope® Diagnostic System (MMDx) classifier, and molecular classifications were compared with histology and related to pancreas graft survival. MMDx classified 93 biopsies (75%) as no rejection, 13 (10%) as subthreshold rejection, and 18 (15%) as rejection, whereas histology identified rejection in 65 of 112 biopsies (58%) and 25 (22%) as indeterminate cases. Concordance between histology and MMDx was low (Cohen’s κ = 0.14, p<0.001). Acute cellular histologic grading correlated strongly with multiple molecular scores, including interstitial inflammation (ρ=0.60, p=3.4×10⁻12), TCMR (ρ=0.55, p<3.2×10⁻10), acute kidney injury (ρ=0.48, p=7.4×10⁻8), and overall inflammation (ρ=0.46, p=4.4×10⁻7). Both subthreshold rejection (HR=4.41, 95% CI 1.29–15.1, p=0.018) and MMDx-defined rejection (HR=6.52, 95% CI 2.36–18.03, p=0.0003) were associated with significantly worse three-year graft survival compared to no rejection, whereas histologic classification showed no significant prognostic impact. Molecular assessment using a kidney-derived MMDx classifier provides complementary prognostic information beyond histology in pancreas transplantation.
2026-06-30 | GSE327889 | GEO
Project description:In lung transplantation, antibody-mediated rejection (AMR) diagnosed by ISHLT criteria is uncommon compared to other organs, and previous studies failed to find molecular AMR (ABMR) in lung biopsies. However, understanding of ABMR has changed with the recognition that ABMR in kidney transplants is often DSA-negative and associated with NK cell transcripts. After optimizing rejection-selective transcript sets (RSTS) in a training set (n = 488), the resulting algorithms separated an NK cell-enriched rejection-like state (NKRL) from TCMR/Mixed in a test set (n = 488). Applying this approach to all 896 TBBs distinguished three groups - No rejection; TCMR/Mixed; and NKRL. Like TCMR/Mixed, NKRL had increased expression of all-rejection transcripts, but NKRL had increased expression of NK cell transcripts, whereas TCMR/Mixed had increased effector T cell and activated macrophage transcripts. NKRL was usually DSA-negative and not recognized as AMR clinically. TCMR/Mixed was associated with CLAD, reduced FEV1, and short-term graft failure, but NKRL was not. Thus, some lung transplants manifest a molecular state similar to DSA-negative ABMR in kidney and heart transplants, but its clinical significance must be established.
2025-07-24 | GSE303535 | GEO
Project description:Subthreshold rejection activity in many kidney transplants currently classified as having no rejection.
| PRJNA1149617 | ENA
Project description:Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. Groups differed in median time post-transplant e.g. R3injury 99 days vs. R4late 3117 days. R2TCMR biopsies expressed typical TCMR-related transcripts e.g. intense IFNG-induced effects. R3injury displayed increased expression of parenchymal injury transcripts (e.g. hypoxia-inducible factor EGLN1). R4late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2TCMR correlated with histologic rejection although with many discrepancies, and R4late with fibrosis. R2TCMR, R3injury, and R4late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2TCMR scores. No confirmed cases of clinical ABMR were present in the population, and strategies that previously revealed antibody-mediated rejection (ABMR) in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, molecular analysis of liver transplant biopsies detects rejection, has the potential to resolve ambiguities, and could assist with immunosuppressive management.
2020-05-06 | GSE145780 | GEO
Project description:Histologic assessment of kidney transplant biopsies relies on cortex rather than medulla, but for microarray studies, the proportion cortex in a biopsy is typically unknown and could affect the molecular readings. The present study aimed to develop a molecular estimate of proportion cortex in biopsies and examine its effect on molecular diagnoses. Microarrays from 26 kidney transplant biopsies divided into cortex and medulla components and processed separately showed that many of the most significant differences were in glomerular genes e.g. NPHS2, NPHS1, CLIC5, PTPRO, PLA2R1, PLCE1, PODXL and REN. Using NPHS2 (podocin) to estimate proportion cortex, we examined whether proportion cortex influenced molecular assessment in the Molecular Microscope Diagnostic System. In 1190 unselected kidney transplant indication biopsies (Clinicaltrials.govNCT01299168), only 11% had <50% cortex. Molecular scores for ABMR, TCMR, and injury were independent of proportion cortex. Rejection was diagnosed in many biopsies that were mostly or all medulla. Agreement in molecular diagnoses in paired cortex/medulla samples (23/26) was similar to biological replicates (32/37). We conclude that NPHS2 expression can estimate proportion cortex; that proportion cortex has little influence on molecular diagnosis of rejection, and that, although histology cannot assess medulla, rejection does occur in medulla as well as cortex.
2017-04-27 | GSE95611 | GEO
Project description:Molecular Rejection Signatures in Pancreas Transplant Biopsies
| PRJNA1452951 | ENA
Project description:Histologic assessment of kidney transplant biopsies relies on cortex rather than medulla, but for microarray studies, the proportion cortex in a biopsy is typically unknown and could affect the molecular readings. The present study aimed to develop a molecular estimate of proportion cortex in biopsies and examine its effect on molecular diagnoses. Microarrays from 26 kidney transplant biopsies divided into cortex and medulla components and processed separately showed that many of the most significant differences were in glomerular genes e.g. NPHS2, NPHS1, CLIC5, PTPRO, PLA2R1, PLCE1, PODXL and REN. Using NPHS2 (podocin) to estimate proportion cortex, we examined whether proportion cortex influenced molecular assessment in the Molecular Microscope Diagnostic System. In 1190 unselected kidney transplant indication biopsies (Clinicaltrials.govNCT01299168), only 11% had <50% cortex. Molecular scores for ABMR, TCMR, and injury were independent of proportion cortex. Rejection was diagnosed in many biopsies that were mostly or all medulla. Agreement in molecular diagnoses in paired cortex/medulla samples (23/26) was similar to biological replicates (32/37). We conclude that NPHS2 expression can estimate proportion cortex; that proportion cortex has little influence on molecular diagnosis of rejection, and that, although histology cannot assess medulla, rejection does occur in medulla as well as cortex. We studied 26 pairs of cortex/medulla biopsies from 26 patients (4 unpaired), characterizing the clinical and histological features, and defined the mRNA phenotype with Affymetrix expression microarrays. We also studied 37 pairs of biopsies from biological replicates and 12 pairs from technical replicates. This dataset is part of the TransQST collection.
2017-04-27 | E-GEOD-95611 | biostudies-arrayexpress
Project description:Improved understanding of lung transplant disease states is essential because failure rates are high, often due to chronic lung allograft dysfunction. However, histologic assessment of lung transplant transbronchial biopsies (TBBs) is difficult and often uninterpretable even with 10 pieces. All 242 single-piece TBBs produced reliable transcript measurements. Paired TBB pieces available from 12 patients showed significant similarity but also showed some sampling variance. Alveolar content, as estimated by surfactant transcript expression, was a source of sampling variance. To offset sampling variation, for analysis we selected 152 single-piece TBBs with high surfactant transcripts. Unsupervised archetypal analysis identified four idealized phenotypes (archetypes) and scored biopsies for their similarity to each: normal, T cell-mediated rejection (TCMR; T cell transcripts), antibody-mediated rejection (ABMR)-like (endothelial transcripts), and injury (macrophage transcripts). Molecular TCMR correlated with histologic TCMR. The relationship of molecular scores to histologic ABMR could not be assessed because of the paucity of ABMR in this population. Molecular assessment of single-piece TBBs can be used to classify lung transplant biopsies and correlated with rejection histology. Two or three pieces for each TBB will probably be needed to offset sampling variance.
2019-08-16 | GSE125478 | GEO