Transitional B cell cytokines may offer a way to predict kidney transplant rejection and alter treatment plans, according to investigators at the University of Pittsburgh Medical Center (UPMC) in Pittsburgh, Pennsylvania.
In a study of patients who received kidney transplants at their institution, the investigators demonstrated that the ratio of interleukin-10 (IL-10) to tumor necrosis factor-alpha (TNF-alpha) produced by transitional-1 B cells is a strong predictive biomarker of renal allograft outcomes and this might be used as a rationale for preemptive therapeutic intervention with TNF blockade. The IL-10/TNF-alpha ratio can predict allograft rejection with a lead time of about 8 months.
“I think this will have a big impact,” senior author David Rothstein, MD, a professor of surgery, medicine, and immunology at UPMC, told Renal & Urology News. “If we know which patients are at higher risk for rejection and reduced graft survival, then we know which patients may need more immunosuppression. Currently, there is an urgent need to better tailor immunosuppression therapy to individual patient risk.”
He and his colleagues published their findings in Science Translational Medicine.
Dr. Rothstein’s team examined the IL-10/TNF-alpha ratio produced by transitional-1 B cells at 3 months after transplantation. They analyzed blood samples from 244 patients who received kidney transplants at UPMC from 2013 to 2015. They categorized 162 patients who received a transplant during 2013 and 2014 as a training set and 82 patients who received a transplant in 2015 as an internal validation set. The investigators performed 327 biopsies in the training set (84 for cause and 243 for surveillance) and performed 168 biopsies in the internal validation set (55 for cause and 113 for surveillance). In the training set, 121 patients (77%) completed paired early and late biopsies. In the internal validation set, 53 patients (64%) completed paired early and late biopsies.
Results showed that the IL-10/TNF-alpha ratio at 3 months after transplantation predicted both clinical and subclinical rejection anytime in the first 12 months. Among biomarker high-risk patients, 60% had early rejection, and despite treatment, in 48% of these patients, rejection recurred later in the first post-transplant year. In patients considered to be high-risk without early rejection, 74% had later rejection. Only 5% of the patients considered low-risk had early rejection and only 5% experienced late rejection in the first post-transplant year. Overall, 91% of the biomarker high-risk group rejected their kidney within the first year, compared with only 10% in the biomarker low-risk group.
The investigators confirmed the predictive ability of the IL-10 to TNF-alpha ratio using an external validation set that included 95 patients who received a transplant from May 2011 to October 2014 at the Royal Free Hospital in London, UK. The biomarker was equally predictive of rejection in this patient cohort. Importantly, in both the Pittsburgh and London cohorts, the biomarker at 3 months identified patients at lower versus increased risk of allograft loss within 5 years, according to the investigators.
The authors pointed out that up to one-third of kidney transplant recipients lose their allograft within 10 years. Adopting the new biomarker could significantly lower that percentage, they noted.
‘Immune Set Point’
Dr. Rothstein said the balance between IL-10 and TNF-alpha seems to indicate a patient’s “immune set point” and whether the immune system is going to be quiescent or revved up and reject the transplant. It is hoped that the imbalance observed in high-risk patients can be restored with anti-TNF drugs. In the current study, treatment of B cells with anti-TNF alpha in vitro augmented the IL-10/ TNF alpha ratio and helped restore regulatory activity, as well as inhibiting secretion of complement-fixing antibodies by plasma cells.
First author Aravind Cherukuri, MD, an assistant professor of medicine (nephrology) and surgery at the Thomas E Starzl Transplantation Institute at UPMC, said the new findings are clinically relevant because of the size of the study and external validation of the biomarker in the UK patient population.
Dr. Rothstein said he and his collaborators are initiating steps to obtain biomarker approval through the US Food and Drug Administration.
Anatoli Horuzsko, MD, Ph.D., a professor of medicine at Augusta University in Georgia, said this type of biomarker can further advance personalized medicine for kidney transplant recipients. Currently, clinicians use a one-size-fits-all approach for most patients, but now it may be possible to significantly reduce immunosuppression in select patients.