Defining the Canonical Form of T-Cell-Mediated Rejection in Human Kidney Transplants

Famulski, Konrad S.; Einecke, G.; Sis, B.; Mengel, Michael; Hidalgo, Luis; Kaplan, Bruce; Halloran, Philip F.

doi:10.1111/j.1600-6143.2009.03007.x

Cited by 65 publications

(62 citation statements)

References 39 publications

(121 reference statements)

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“…We previously described the Banff histopathologic diagnoses. 47 We thus analyzed two independent sets of 28 nonrejecting biopsies each with early injury (see Results), 35 biopsies with Banff TCMR, 23 biopsies with borderline rejection, and 148 remaining biopsies representing 46 with ABMR (including 17 C4d-positive and 29 suspicious for ABMR, aka C4d-negative ABMR), 10 with mixed (ABMR/TCMR) rejection, 24 with GN, and 68 late nonrejecting biopsies. All diagnoses reflect updated donor-specific antibody status.…”

Section: Human Biopsies For Clinical Indications Histopathology Andmentioning

confidence: 99%

“…47 Biopsies were obtained under ultrasound guidance by spring-loaded needles (ASAP Automatic Biopsy; Microvasive, Watertown, MA). This study was approved by the University of Alberta Health Research Ethics Board (Issue #5299), the University of Illinois Chicago Office for the Protection of Research Subjects (protocol #2006-0544), and the University of Minnesota (protocol HSR#0606 M87646).…”

Section: Human Biopsies For Clinical Indications Histopathology Andmentioning

confidence: 99%

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Molecular Phenotypes of Acute Kidney Injury in Kidney Transplants

Famulski

Freitas²,

Kreepala³

et al. 2012

Journal of the American Society of Nephrology

137

155

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Little is known regarding the molecular phenotype of kidneys with AKI because biopsies are performed infrequently. However, all kidney transplants experience acute injury, making early kidney transplants an excellent model of acute injury, provided the absence of rejection, because donor kidneys should not have CKD, post-transplant biopsies occur relatively frequently, and follow-up is excellent typically. Here, we used histopathology and microarrays to compare indication biopsies from 26 transplants with acute injury with 11 pristine protocol biopsies of stable transplants. Kidneys with acute injury showed increased expression of 394 transcripts associated with the repair response to injury, including many epithelium-like injury molecules tissue, remodeling molecules, and inflammation molecules. Many other genes also predicted the phenotype, including the acute injury biomarkers HAVCR1 and IL18. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score in kidneys with acute injury correlated with reduced graft function, future renal recovery, brain death, and need for dialysis, but not with future graft loss. In contrast, histologic features of acute tubular injury did not correlate with function or with the molecular changes. Thus, the transcripts associated with repair of injury suggest a massive coordinated response of the kidney parenchyma to acute injury, providing both an objective measure for assessing the severity of injury in kidney biopsies and validation for many biomarkers of AKI.

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Section: Human Biopsies For Clinical Indications Histopathology Andmentioning

confidence: 99%

Section: Human Biopsies For Clinical Indications Histopathology Andmentioning

confidence: 99%

Molecular Phenotypes of Acute Kidney Injury in Kidney Transplants

Famulski

Freitas²,

Kreepala³

et al. 2012

Journal of the American Society of Nephrology

137

155

View full text Add to dashboard Cite

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“…The molecular characteristics of implant biopsies used previously identified pathogenesis-based transcript sets (PBT) that reflect biological processes of known relevance for the pathogenesis of renal inflammation and injury in transplants. Here, we applied the following PBTs to assess these processes: interferon-gamma (IFNG) effects on the tissue (GRIT) (37), kidney parenchymal transcripts (KT1s) and kidney solute carriers (KT2) (38), natural killer cell transcript burden (NKtb) (39), T cell transcript burden (TCtb) (39) and macrophage transcripts (QCMAT) (40). The information about probe sets as well as the algorithms for PBT generation is available on our homepage (http:// www.atagc.med.ualberta.ca/Research/GeneLists/Pages/default.aspx).…”

Section: Microarray Data Analysismentioning

confidence: 99%

Comparing Molecular Assessment of Implantation Biopsies With Histologic and Demographic Risk Assessment

Kreepala

Famulski

Chang

et al. 2013

American Journal of Transplantation

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We hypothesized that measurement of previously defined acute kidney injury-induced transcripts at the time of implantation would add a new dimension to existing methods based on donor factors, histology and recipient factors. We analyzed microarray results from implantation biopsies taken after reperfusion from 70 kidneys from 53 deceased donors. We used two definitions of early dysfunction: serum creatinine > 265 umol/L at day 7 posttransplant; and dialysis in the first week. The strongest correlate with early dysfunction was the mean expression of 30 injury transcripts. Older donor and recipient age were associated with early dysfunction, but histologic lesions were not. Prediction was best when the injury transcript expression was combined with donor or recipient age, particularly in standard criteria donors. In contrast, although extended criteria donor kidneys had a high risk of early dysfunction, no variables tested, including injury transcripts, predicted risk significantly, probably because these kidneys were allocated preferentially to old, high risk recipients. The injury transcripts did not predict late function, which was mainly associated with donor age. Thus, measurement of injury-induced transcripts at the time of implantation improves the prediction of early kidney dysfunction, but risk prediction may fail when old kidneys are transplanted into old recipients.

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“…The inflamed kidney tissue is a highly immunogenic microenvironment that activates professional and nonprofessional APCs and triggers recipient T cell activation and proliferation, ultimately leading to rejection, epithelium dedifferentiation, and fibrosis (6)(7)(8)(9). IFN-g is a master regulator of the homeostasis of the kidney transplant during rejection (8,10). IFN-g is a cytokine that is produced mostly by activated T cells and NK cells and has complex effects on immune and nonimmune cells.…”

mentioning

confidence: 99%

Tryptophan Depletion and the Kinase GCN2 Mediate IFN-γ–Induced Autophagy

Fougeray

Mami

Bertho

et al. 2012

The Journal of Immunology

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IFN-γ is a master regulator of the immune responses that occur in the transplanted kidney, acting both on the immune system and on the graft itself. The cellular responses to IFN-γ are complex, and emerging evidence suggests that IFN-γ may regulate autophagic functions. Conversely, autophagy modulates innate and adaptive immune functions in various contexts. In this study, we identify a novel mechanism by which IFN-γ activates autophagy in human kidney epithelial cells and provide new insights into how autophagy regulates immune functions in response to IFN-γ. Our results indicate that IFN-γ promotes tryptophan depletion, activates the eIF2α kinase general control nonderepressible-2 (GCN2), and leads to an increase in the autophagic flux. Further, tryptophan supplementation and RNA interference directed against GCN2 inhibited IFN-γ–induced autophagy. This process is of functional relevance because autophagy regulates the secretion of inflammatory cytokines and growth factors by human kidney epithelial cells in response to IFN-γ. These findings assign to IFN-γ a novel function in the regulation of autophagy, which, in turn, modulates IFN-γ–induced secretion of inflammatory cytokines.

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Defining the Canonical Form of T-Cell-Mediated Rejection in Human Kidney Transplants

Abstract: Banff defines T-cell-mediated rejection (TCMR) using nonspecific lesions and arbitrary cutoffs

Cited by 65 publications

References 39 publications

Molecular Phenotypes of Acute Kidney Injury in Kidney Transplants

Molecular Phenotypes of Acute Kidney Injury in Kidney Transplants

Comparing Molecular Assessment of Implantation Biopsies With Histologic and Demographic Risk Assessment

Tryptophan Depletion and the Kinase GCN2 Mediate IFN-γ–Induced Autophagy

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