Finding Could Lead to Earlier Detection, Treatment and Organ Survival
Researchers at UC San Francisco have developed a potential test for diagnosing and predicting acute rejection in kidney transplants, a finding that eventually could replace the need for biopsies and lead to earlier detection and treatment.
The study is in the Nov. 11 issue of PLOS Medicine.
“We have found a set of genes in blood that pick up inflammation and acute rejection in different solid organ transplants and thus can replace the need for an invasive biopsy in the future,” said senior author Minnie Sarwal, MD, PhD, professor of transplant surgery at UCSF. “This assay also predicts the onset of histological rejection by three to four months, meaning graft inflammation can be treated early and proactively, even reversed.”
“This is the first assay of its kind that can provide a sensitive readout of very early rejection and inflammation in the organ, which cannot be picked up by any other blood test on the market,” Sarwal continued. “The result is improved graft function and survival.”
All organ transplant recipients have some amount of acute rejection (AR). In extreme cases, the donated organ can be injured or even fail, resulting in costly treatments and diminished quality of life.
Occurring in 15-20 percent of kidney transplant recipients, AR is detected by an invasive biopsy after a drift in the patient’s serum creatinine, then treated with immunosuppressive medications. However, this drift is not specific for AR and occurs only after substantial organ damage, and some patients can contract AR without a drift.
To improve disease diagnosis and patient monitoring, scientists are working on noninvasive molecular assays in several clinical areas. In this PLOS Medicine study, Sarwal and her international study team sought to create a “kidney solid organ response test” (kSORT) using a simple blood gene expression assay that would detect patients at risk for AR.
The researchers developed an algorithm after analyzing gene expression data in 558 blood samples from 436 adult and pediatric renal transplant patients. These samples were collected from UCSF and seven other transplant centers in the United States, Mexico and Spain from 2005-2012 through the multicenter AART (Assessment of Acute Rejection in Renal Transplantation) Study.
A kSORT comprised of 17 genes was selected in 143 samples for AR classification, then validated in 124 independent samples and evaluated for AR prediction in 191 samples. The kSORT predicted AR up to three months earlier than detection by biopsy, independent of age, time after transplant and sample source.
In addition, the researchers created an algorithm in 100 independent samples to provide a numerical AR risk score toward classifying patients as either high or low risk.
“The kSORT assay could be a potential breakthrough in transplant medicine,” said contributing author Elaine Reed, PhD, director of the University of California Los Angeles Immunogenetics Center. “This multicenter study reflects a wide cohort of patients nationally and internationally, and the results hold real promise in identifying future patients at risk for rejection."
The next step is to confirm the effectiveness of kSORT through clinical observational and interventional trials, Sarwal said. Two prospective trials in the European Union and Mexico already are under way whereby kidney transplant patients are having immune monitoring by serial blood testing for kSORT.
“This report validates the kSORT assay to detect risk of acute rejection in renal transplant patients, giving it the potential to become a simple, robust and clinically applicable blood test that will provide each patient with an immune risk ‘window’ for optimal immunosuppression delivery,” Sarwal said.
While this PLOS Medicine paper focuses on the discovery and validation of these genes in blood in adults and children with kidney transplant rejection, Sarwal and her colleagues already have published on a similar gene set for diagnosis of heart transplant rejection in adults, and the same genes also predict kidney transplant rejection in pediatric kidney transplant recipients. The genes have been independently validated for rejection monitoring in children ages 1-21 in a National Institutes of Health multicenter trial.
Other contributors to the PLOS Medicine study were Silke Roedder, Pharm.D., PhD, Tara Sigdel, PhD, Sue Hsieh, MS, Flavio Vincenti, MD, and Nancy Ascher, MD, PhD, in the UCSF Department of Surgery; Nathan Salomonis, PhD, University of Cincinnati/Cincinnati Children’s Hospital Medical Center; Hong Dai, PhD, and Oscar Salvatierra, MD, Stanford University; Oriol Bestard, MD, PhD, Bellvitge University Hospital Renal Transplant Unit in Barcelona, Spain; Diana Metes, MD, Adriana Zeevi, PhD, and Camila Macedo, MD, University of Pittsburgh Thomas E. Starzl Transplantation Institute; Jennifer Cheeseman, MS, and Allan Kirk, MD, PhD, Emory University Department of Surgery; Hans Albin Gritsch, MD, UCLA David Geffen School of Medicine Department of Urology; Ram Peddy, MD, California Pacific Medical Center; and Mara Medeiros, MD, PhD, Hospital Infantil de México Laboratorio de Investigacion en Nefrologia. Roedder, Sigdel and Salomonis are joint first authors.
Funding was provided by the National Institute of Allergy and Infectious Diseases (NIAID), Mexican Federal Funds for Research, a Spanish national public grant and a European Commission grant within the BIODrIM (BIOmarker-Driven personalized IMmunosuppression) Consortium.
UCSF is the nation's leading university exclusively focused on health. Now celebrating the 150th anniversary of its founding as a medical college, UCSF is dedicated to transforming health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with world-renowned programs in the biological sciences, a preeminent biomedical research enterprise and top-tier hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals.