A functional immunologic assay that could easily be incorporated into routine laboratory work can predict which patients are at high risk for rejection of their newly transplanted kidney early enough in the process that it would give physicians time to treat them and possibly prevent rejection, new research shows.
“People have been trying to find a biomarker that identifies rejection without having to do a biopsy,” said senior author David Rothstein, MD, the Pittsburgh Steelers Chair in Transplantation and professor of surgery, medicine, and immunology at the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, told Medscape Medical News.
“Our biomarker allows us to predict rejection ahead of time, so this truly gives us a chance to preemptively increase immunosuppression and try and prevent damage before rejection occurs, because once the immune system is unleashed, it’s a lot harder to control,” he added.
“It’s an exciting study — the culmination of years of work — and I think it will allow us to take steps towards personalized medicine in our field of transplantation,” lead author Aravind Cherukuri, MD, also of the University of Pittsburgh, told Medscape Medical News. He noted that thus far, transplantation is behind other fields, such as oncology, with regard to personalized approaches to medicine.
“This biomarker could be used to guide surveillance biopsies and personalize immunosuppression in attempts to alter clinical course,” he and coauthors write.
“I think studies like these and others taking a similar path will help us achieve this goal for transplantation,” Cherukuri added.
The study was published online in Science Translational Medicine.
IL-10 to TNFα Ratio: Strong Predictor of Rejection Found in the Blood
About a third of patients lose their transplanted kidney within 10 years, and at that point, a new transplant isn’t easy. The patient’s immune system is sensitized to the foreign organ, and it’s harder to find a match.
A total of 244 kidney transplant recipients from the University of Pittsburgh School of Medicine participated in the study, 162 in the training set, and 82 in the internal validation set.
The investigators determined the ratio of interleukin-10 (IL-10) to tumor necrosis factor–α (TNFα) produced by transitional-1 B cells (T1B) in peripheral blood 3 months after transplant.
Their main goal was to see whether that ratio could serve as an early predictor of T-cell-mediated rejection (TCMR) in the kidney transplant recipients. As the authors explain, B cells secrete IL-10 and TNFα. The ratio of these two molecules is a measure of regulatory B-cell activity, which has been implicated in organ rejection.
Results showed that among patients with TCMR, the frequency of T1B cells was lower, as was the ratio of IL-10 to TNFα in these cells, at all time points analyzed in comparison with patients in whom rejection did not occur (P < .001).
The T1B IL-10 to TNFα ratio at 3 months was the strongest predictor of rejection within the first year after transplant. In the training set, there was a 71% reduction in the risk of a patient’s experiencing rejection with every unit increase in the T1B IL-10 to TNFα ratio (P < .001).
“At an optimal cutoff value of 1.3 for the ratio, sensitivity was 86%, specificity was 86%, and the negative predictive value (NPV) was 92%,” the authors report. The positive predictive value (PPV) was also high, at 80%. The same ratio was predictive of subclinical T-cell-mediated rejection (scTCMR) with similarly high rates of sensitivity, specificity, NPV, and PPV, the researchers add.
This is important, Rothstein explained, inasmuch as 70% of late rejections are either subclinical or are clinically silent; the ability of the biomarker to identify patients who will experience kidney rejection later in their first posttransplant year is vital if that rejection is to be preemptively treated.
The biomarker also identified those with late TCMR with an average lead time of 8 months, which would give physicians enough time to increase immunosuppression preemptively to prevent scTCMR and more clinically obvious rejection episodes.
All results were validated in an internal validation set, which had a cutoff value of 1.3. The T1B IL-10 to TNFα ratio predicted both early and late TCMR in the first year after transplant with similar accuracy.
Combining the two datasets, the researchers were able to identify three distinct risk groups: high-risk, intermediate-risk, and low-risk. “In the high-risk group, 60% had early TCMR at the time of biomarker evaluation and, despite antirejection therapy, 48% developed recurrent or recalcitrant late TCMR,” the investigators report.
Among high-risk patients for whom there was no evidence of early TCMR, almost three quarters subsequently developed late TCMR. Overall, 58% of patients in the high-risk group experienced late rejection, they add.
In contrast, only 5% of patients in the low-risk group experienced early TCMR; another 5% had late TCMR.
“Thus, the T1B IL-10/TNFα ratio identified not only patients with markedly high rates of early TCMR but also those with late TCMR,” the investigators confirm.
Independently Validated; Anti-TNF Therapy Dampens Down Effect
The same biomarker was further validated in a separate cohort of 95 kidney transplant recipients at the Royal Free Hospital in London, United Kingdom.
“Again, at an optimal cutoff value of 1.3 for the ratio, sensitivity was 75% and specificity was 92% for rejection anytime for the first year,” Rothstein said. Importantly, among high-risk patients in both cohorts, not only were rates of rejection increased, but there was a significant decrease in allograft survival at 5 years — “a hugely important point, because it means that even if physicians recognize and treat rejection, these kidneys fail,” he said.
In high-risk patients, B cells are predominantly proinflammatory, the researchers explain.
They therefore examined the effect that anti-TNFα therapy might have on this proinflammatory profile. In an in vitro study, they found that treatment with a TNFα blocker desirably increased the IL-10 to TNFα ratio and restored B-cell regulatory activity, which proved in concept that treatment of early rejection may restore B-cell regulatory activity for kidney transplant recipients and reduce their risk for rejection.
“The balance between IL-10 and TNF seems to indicate [what] your immune setpoint [is] — is it going to be quiescent or is it going to be revved up and try to reject the transplant?,” Rothstein noted in a press release from his institution.
“We hope we can restore that balance with anti-TNF drugs,” he added. The other piece of the puzzle that still needs to be worked out is whether the biomarker can be used sequentially, so that physicians will know whether they have successfully treated a high-risk patient and have reduced the risk for rejection.
This would allow them to track patients, and the investigators are planning to study this further.
“Right now, this biomarker can tell us that you are at high risk [for rejection], but hopefully it will be even more useful if it can be used to guide therapy and with successful immunosuppression [or other treatments], the patient’s ratio will change so we can then say, now this patient is at low risk and we can stop any additional therapy,” Rothstein concluded.
Rothstein serves on the scientific advisory board of Verici Dx.
Sci Transl Med. Published online February 24, 2021. Abstract