Validation of Noninvasive Tests for Post-Transplant Management of Kidney Graft Recipients

MedicalResearch.com Interviews with:
Dr. Sunil M. Kurian Ph.D.Lead- Biomarker Discovery at the Laboratory of Functional Genomics and Cell Therapy The Scripps Research Institute and Transplant Genomics Inc.Dr. Sunil M. Kurian Ph.D.
Lead- Biomarker Discovery at the Laboratory of Functional Genomics and Cell Therapy
The Scripps Research Institute and Transplant Genomics Inc. and

 

Dr. John J. Friedewald, MDAssociate Professor of Medicine and Surger Northwestern University’s Feinberg School of Medicine and a transplant nephrologist at Northwestern Memorial Hospital and the Kovler Organ Transplant CenterDr. John J. Friedewald, MD
Associate Professor of Medicine and Surgery
Northwestern University’s Feinberg School of Medicine and a transplant nephrologist at Northwestern Memorial Hospital and the Kovler Organ Transplant Center

Editor’s note: These interviews are based on two abstracts presented at the American Transplant Congress 2015.

MedicalResearch: What is the background for these studies?

Response: Previous studies by the scientific founders of Transplant Genomics Inc. helped lay the groundwork for the company’s development of genomic biomarker tests for kidney transplant graft status and demonstrated feasibility as noninvasive monitoring tools that could enable differential diagnosis of graft status in kidney transplant recipients.1-3

These included a study involving five transplant centers published in the American Journal of Transplantation.4 In that study, peripheral blood gene expression profiling was used to classify kidney graft recipients into three key categories of graft status based on gene expression signatures – clinical acute rejection, acute dysfunction no rejection, and stable graft performance – with very high predictive accuracy.

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

MedicalResearch: What are the main findings?

Response: The current study presented recently at the 2015 American Transplant Congress5 validated that gene expression signatures as indicators of kidney graft status can be detected as robustly with RNA sequencing as with microarrays, with implications for reduced cost of analysis, faster turnaround times and improved throughput for sample processing.

In this study, we substantiated RNA sequencing as an alternative data generation platform for analyzing gene expression profiles in peripheral blood and tissue from kidney transplant recipients. The data validated that gene expression signatures for subclinical acute rejection (a histological acute cellular rejection in the presence of a normal or stable serum creatinine that is associated with decreased graft survival), clinical acute rejection and stable graft performance can be detected as robustly with RNA sequencing as with microarrays.

MedicalResearch: What should clinicians and patients take away from your report?

Response: The key point of this study is that gene expression profiles generated and validated using microarray technology have been successfully translated to a technology platform based on RNA sequencing. Sequencing has the potential to offer advantages such as reduced cost of analysis, faster reporting back to the clinician and improved throughput for sample processing. In addition, it could facilitate development of kits enabling standardized assay performance on local lab-based sequencing systems and expansion of test use worldwide.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Response: We recommend that future studies focus on generating comparable data in less time, and further reducing the cost of data generation by sequencing.

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

MedicalResearch: What are the main findings?

Response: The current study presented recently at the 2015 American Transplant Congress6 validated the use of gene expression signatures for subclinical acute rejection, a histological acute cellular rejection in the presence of a normal or stable serum creatinine that is associated with decreased graft survival.

In this study, Dr. John Friedewald, colleagues and I analyzed gene expression profiles in blood samples from patients with protocol biopsy proven subclinical acute rejection, clinical acute rejection, or from stable patients. A distinct gene expression profile that classified patients with subclinical acute rejection was discovered in the peripheral blood. The expression profiles were then clinically validated in a separate cohort of samples, where the different phenotypes were distinguished with high accuracy.

MedicalResearch: What should clinicians and patients take away from your report?

Response: A noninvasive test for subclinical acute rejection could reduce the need for protocol biopsies, inform the need for a ‘for cause’ biopsy and help with monitoring and adjustment of immunosuppressive drug therapy. Our study shows the first validated blood-based signature for subclinical acute rejection and demonstrates the potential value of integrating molecular biomarkers into clinical practice to serially monitor kidney transplant patients.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Response: We recommend that future studies focus on the clinical utility of a test for subclinical acute rejection. For example, a test for subclinical acute rejection could be useful for monitoring transplant patients serially in a minimally invasive manner, and with greater frequency than is practical with protocol biopsies. Any indication of subclinical acute rejection could be treated early, minimizing the risk of further graft injury.

Such a test may also be useful for monitoring the success or failure of adjusting immunosuppression. The result could not only specify a diagnosis but also provide a molecular score that indicates the degree of acute rejection in a patient. Such information could help support the physician in making a decision to taper immunosuppression in a personalized and objective fashion.

References:

  1. Friedewald J, Kurian S, Levitsky J, et al. Molecular signature in the peripheral blood for sub-clinical acute kidney rejection. Presentation at World Transplant Congress, July 30, 2014.
  2. Kurian SM, Modena B, Friedewald J, et al. Molecular phenotyping of kidney biopsies by global gene expression tightly correlates with histology phenotypes and long-term outcomes. Poster presentation A495 at World Transplant Congress, July 27, 2014.
  3. Ventura C, Kurian SM, Gelbart T, David-Neto E, Salomon DR. Discovery of peripheral blood and biopsy-based molecular classifiers in Brazilian kidney transplant patients. Poster presentation A523 at World Transplant Congress, July 27, 2014.
  4. Kurian SM, Williams AN, Gelbart T, et al. Molecular classifiers for acute kidney transplant rejection in peripheral blood by whole genome gene expression profiling. Am J Transplant 2014;5(14):1164-1172.
  5. Kurian S, Friedewald J, Harrison F, et al. Validation of a blood and biopsy gene expression-based molecular diagnostics for subclinical acute rejection: comparing DNA microarrays vs. next-generation RNA sequencing. Presentation at American Transplant Congress, May 3, 2015.
  6. Friedewald J, Kurian S, et al. Validation of a Peripheral Blood Gene Expression Profile for SubClinical Acute Rejection in Kidney Transplant Recipients – Findings from the CTOT 08 Study. Presentation at American Transplant Congress, May 4, 2015.

Citation:

Abstracts Presented at American Transplant Congress 2015

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

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

This research was funded in large part by a grant from the National Institute of Allergy and Infectious Diseases (NIAID) – http://www.niaid.nih.gov/Pages/default.aspx, as part of the Clinical Trials in Organ Transplantation (CTOT) through a grant (U01 AI084146 – Proteogenomics for Organ Transplantation; Prediction, Diagnosis, Intervention; Principal Investigator: Michael M. Abecassis MD)

Link to Press Release

 

Dr. Sunil M. Kurian Ph.D.Lead- Biomarker Discovery at the Laboratory of Functional Genomics and Cell Therapy, Dr. John J. Friedewald, MDAssociate Professor of Medicine and Surgery, & Northwestern University’s Feinberg School of Medicin (2015). Validation of Noninvasive Tests for Post-Transplant Management of Kidney Graft Recipients