Validation of a Peripheral Blood Gene Expression Profile for Subclinical Acute Rejection in Kidney Transplant Recipients – Findings from the CTOT 08 Study

May 4, 2015

J. Friedewald, S. Kurian, T. Gelbart, D. Salomon, M. Abecassis

We have discovered and clinically validated a gene expression profile in the peripheral blood of patients with subAR. This gene expression profile (subAR) differs from a previously validated peripheral blood signature for patients with clinical acute cellular rejection found on a “for cause” biopsy (cAR). We also developed a molecular scoring system to help determine clinical phenotypes based on peripheral blood gene expression profiles. Our study expands the repertoire of clinical phenotypes that can be identified through noninvasive genomic monitoring, and demonstrates the potential of integrating predictive molecular biomarkers into clinical practice to serially monitor and improve long-term outcomes for kidney transplant patients.

Gene Expression of Kidney Biopsies Reveals Common Mechanisms of Rejection and a Cluster of Co-Expressed Genes Predictive of Long-term Outcomes

May 3, 2015

B. Modena, S. Kurian, J. Friedewald, F. Harrison, T. Gelbart, S. Head, M. Abecassis, D. Salomon

We sought to show by differential gene expression that the arc of AR immune responses, injury and metabolic mechanisms could be identified in Interstitial fibrosis and tubular atrophy (IFTA) phenotypes. We then looked at correlation of these findings with long-term graft function and survival.

Validation of Blood and Biopsy Gene Expression-Based Molecular Diagnostics for Subclinical Acute Rejection: Comparing DNA Microarrays Vs. Next-Generation RNA Sequencing

May 3, 2015

S. Kurian, J. Friedewald, F. Harrison, T. Gelbart, S. Head, P. Ordoukhanian, M. Abecassis, D. Salomon

We compare gene expression signatures obtained from peripheral blood and biopsies using both global profiling platforms to evaluate their diagnostic capabilities to differentiate subclinical Acute Rejection (subAR) from clinical Acute rejection (cAR) and Transplant eXcellent subjects (TX). A second objective was to provide a validation of our array-based gene expression diagnostics using an orthogonal RNA expression technology.

Blood and Biopsy mRNA Expression Signatures Can Distinguish Major Causes of Graft Injury in Liver Transplant Recipients

July 31, 2014

J. Levitsky, D. Salomon, S. Kurian, J. Friedewald, S. Rao, A. Demetris, S. Rindt, J. Charette, 
M. Abecassis

In both the peripheral blood and graft tissue from liver transplant recipients, we have identified gene expression classifier sets that can distinguish between AR, HCV and HCV+AR with AUCs between 0.79-0.83 (blood) and 0.69-0.83 (biopsies). We have also discovered profiles in whole blood that can distinguish between AR, ADNRR and normal TX with AUCs ranging from 0.87-0.92. These signatures have the potential to enhance: decision-making in the need to perform liver biopsy, the specificity of diagnosis, particularly in managing patients with contrasting etiologies (e.g., AR vs. HCV-R vs. ADNRR), the understanding of mechanisms of graft injury in LT recipients, and the ability to minimize immunosuppression or need to augment. Prospective multicenter studies, including our NIAID funded CTOT-14 are underway to validate these diagnostic signatures, test their predictive value before graft injury occurs, and determine how they respond to therapy.

Molecular Signature in the Peripheral Blood Detects Sub-Clinical Acute Kidney Rejection

July 30, 2014

J. Friedewald, S. Kurian, J. Levitsky, S. Brietigam, J. Charette, M. Abecassis, D. Salomon

We have discovered a gene expression profile in the peripheral blood of patients with acute cellular rejection on a surveillance protocol biopsy (SCAR) that is different from that of patients with normal protocol surveillance biopsies (TX – normal creatinine). This gene expression profile (SCAR) differs from a previously validated peripheral blood profile/signature for patients with clinical acute cellular rejection (AR - elevated creatinine) found on a “for cause” biopsy. Peripheral blood gene expression profiling may prove to be a useful, minimally invasive method for monitoring kidney transplant recipients. We are currently validating this SCAR signature in the multi-center NIH-funded (CTOT-08) study.

Global Transcriptional Profiling Of Standard Criteria Donor (SCD) Kidneys from Donors with Acute Kidney Injury (AKI) Reveals Early Amelioration of Injury

July 29, 2014

S. Kurian, T. Gelbart, K. Reddy, M. Smith, D. Salomon, R. Heilman

In this study, we wanted to determine if we could use kidneys from donors with severe acute kidney injury (AKI) without compromising post-transplant outcomes. We reasoned that gene expression profiles of patient biopsies, 1 and 4 months post- transplant, would reveal the resolution of donor AKI-induced injury as well as signals of early graft dysfunction if present. In conclusion, 1-month biopsies of recipients of AKI kidneys show many differentially expressed genes associated with cell death/stress, inflammation and disrupted metabolic processes typical of kidney injury. By four months these injury/inflammation signals have resolved. These results support the routine use of properly selected AKI donors.

Molecular Phenotyping of Kidney Biopsies by Global Gene Expression Tightly Correlates with Histology Phenotypes and Long-term Outcomes

July 27, 2014

S. Kurian*, B. Modena, J. Friedewald, S. Brietigam, J. Charette, C. Ventura, E. David-Neto, M. Abecassis, D. Salomon

We report on the global gene expression profiles from ~400 kidney transplant patients encompassing four major phenotypes, well-functioning kidney grafts (TX), Acute Rejection (AR), Chronic Rejection(CR) and grafts that have acute dysfunction but due to causes other than rejection (ADNR). This study used the current “gold standard”, light histology, to test correlations of our molecular phenotypes to graft survival and function. We also mapped gene expression to reveal the biology of AR and CR.

Discovery Of Peripheral Blood And Biopsy-based Molecular Classifiers In Brazilian Kidney Transplant Patients

July 27, 2014

C. Ventura, S. Kurian*, T.Gelbart, D. David, F. Agena, M. Abecassis, J. Friedewald, E. David-Neto, D. Salomon.

In this study, we determined both the peripheral blood and biopsy gene expression profiles of Brazilian transplants with Acute Rejection (AR), Acute Dysfunction/No Rejection (ADNR), Chronic Allograft Nephropathy (CAN/IFTA), recurrent and de novo Transplant Glomerular Disease (TGDz) and Transplant Excellent (TX). This is the first discovery study of molecular phenotypes in Brazilian transplant patients.