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MicroRNA Profile Predicts Acute Kidney Transplant Rejection

NEW YORK (GenomeWeb News) – In a paper appearing online last night in the Proceedings of the National Academy of Sciences, a team of American and French scientists identified a microRNA expression profile that can predict which kidney transplant patients will suffer acute transplant rejection and reduced transplant function.

Using arrays, the researchers identified more than a dozen miRNAs that were differentially expressed in cases of acute kidney transplant rejection compared to stable transplants. They subsequently validated six of these in a larger, independent cohort, linking miRNA levels to both acute rejection and transplant function.

Interestingly, rejection samples and peripheral blood mononuclear cells shared some highly expressed miRNAs, while miRNAs that were under-represented in rejection samples were found at high levels in primary human kidney epithelial cells. Together, the results support the idea that kidney transplant rejection occurs as recipient immune cells enter and attack transplanted tissue. Along with such insights, the team suggested that miRNAs may also serve as markers for kidney transplant or renal allograft status.

"Our studies, in addition to suggesting a cellular basis for the altered intragraft expression of miRNAs, propose that miRNA expression patterns may serve as biomarkers of human renal allograft status," senior author Manikkam Suthanthiran, a nephrology and transplantation researcher at the New York-Presbyterian-Weill Cornell Medical Center, and his colleagues wrote.

Although organ transplantation has become fairly routine, transplant recipients must continue taking immuno-suppressive drugs throughout their lives to prevent transplant rejection. Such rejection occurs when the recipient's immune system recognizes the transplant as foreign and mounts an immune response against it.

Because previous research suggests gene expression — including the expression of genes involved in immunity, cell cycle control, and metabolism — shifts dramatically during transplant rejection, Suthanthiran and his team decided to look at whether they could find miRNA expression changes that heralded acute transplant rejection.

They evaluated 33 transplanted tissue or allograft biopsies, taken from 32 adults who had had kidney transplants — a dozen from 11 individuals with acute rejection and graft dysfunction and 21 from individuals with stable transplanted kidney function.

From these, the team initially evaluated miRNA profiles in three of the acute rejection biopsy samples and four stable transplant samples using an Applied Biosystems TaqMan low-density array human microRNA panel representing 365 mature human miRNAs.

They found roughly 174 miRNAs expressed in each of the samples. But the same miRNAs were not present in all of the biopsies. The researchers identified 17 miRNAs that were expressed at different levels in the acute rejection samples than they were in the stable transplant samples. Of these, ten were under-expressed and seven were over-expressed in the acute rejection samples.

Using modified TaqMan miRNA assays, the researchers confirmed the differential expression of six of the miRNAs in an independent validation set of nine acute rejection and 17 stable transplant biopsy samples. The acute rejection samples showed increased expression of miR-142-5p, miR-155, and miR-223 and decreased expression of miR-10b, miR-30-3p, and let-7c.

All six miRNAs were also linked to the transplanted kidney's function, specifically glomerular filtration rate, though miR-142-5p and miR-10b were most strongly associated with this function.

Of the differentially expressed miRNAs, miR-142-5p and miR-155 seem to be the most promising biomarkers for predicting kidney transplant status. Both predicted acute rejection with 100 percent sensitivity and 90 percent to 95 percent specificity. The other four miRNAs, while diagnostic, predicted rejection less accurately.

When they used real-time quantitative PCR to assess messenger RNA levels in the transplant tissue, the team found that the levels of miR-142-5p, miR-155, and miR-223 correlated with the levels of mRNA for immune genes such as CD30 and CD20. Overall though, miRNA levels appeared to more accurately predict transplant rejection than CD3, CD20 or other mRNA levels tested.

Consistent with the notion that acute transplant rejection involves immune system infiltration of transplanted kidney tissue the team found that rejection miRNA profiles were more similar to normal human peripheral blood mononuclear cells than to primary human kidney epithelial cells.

And miRNAs previously linked to immune system function were among those that were highly expressed in rejection samples whereas miRNAs that appear to contribute to kidney tubule function were down-regulated.

The researchers say even more research is needed to understand just how miRNA profiles are altered in the graft-infiltrating and transplant epithelial cells. But, they added, their results suggest miRNA expression patterns may be a promising tool for predicting and monitoring patients' kidney transplant status.

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