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Donor-derived Cell-free DNA and the Prediction of BK Virus-associated Nephropathy.

ABSTRACT: Approximately 15% of kidney transplant recipients (KTRs) develop BK viremia (BKV), with 1%-10% developing BK virus-associated nephropathy (BKVAN), which histologically resembles rejection. The Diagnosing Acute Rejection in Kidney Transplant Recipients (DART) study showed that donor-derived cell-free DNA (dd-cfDNA) levels <1% have a negative predictive value of 85% for active allograft rejection. Using data from this study, we evaluated the association of dd-cfDNA with plasma BK viral loads and biopsy findings to determine if dd-cfDNA can distinguish asymptomatic BKV from BKVAN. Methods:Data on dd-cfDNA, plasma BK viral loads, and biopsy findings from patients from the DART study were retrospectively examined. BKV was defined as 500-10 000 copies/mL. Presumptive BKVAN was defined as BK >10 000 copies/mL. Results:Of 102 participants with biopsies, 10 patients with BKV and BKVAN had paired dd-cfDNA, and viral loads available for analysis. Patients diagnosed with BKV and BKVAN had a median dd-cfDNA of 0.58% (IQR 0.43-1.15) and 3.38% (IQR 2.3-4.56, P = 0.001), respectively. dd-cfDNA titers correlated with BK PCR viral loads (R = 0.874, P = 0.01) and the presence of histologic evidence of BKVAN (100% sensitivity, 50% specificity). Five of 7 patients with BKVAN, but only 2 of 7 with BKV, had biopsies meeting Banff criteria for T-cell-mediated rejection. Median dd-cfDNA in nonrejection patients was 0.43% versus 2.84% in rejection patients (P = 0.001). Conclusion:Higher dd-cfDNA titers were associated with higher BK viral loads, biopsy-diagnosed BVAN, as well histologic changes meeting Banff criteria for as T-cell-mediated rejection. dd-cfDNA may be a useful noninvasive test to assess for progression of BKV to BKVAN.

SUBMITTER: Kant S

PROVIDER: S-EPMC7587413 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Donor-derived Cell-free DNA and the Prediction of BK Virus-associated Nephropathy.

Kant Sam S Bromberg Jonathan J Haas Mark M Brennan Daniel D

Transplantation direct 20201023 11

Approximately 15% of kidney transplant recipients (KTRs) develop BK viremia (BKV), with 1%-10% developing BK virus-associated nephropathy (BKVAN), which histologically resembles rejection. The Diagnosing Acute Rejection in Kidney Transplant Recipients (DART) study showed that donor-derived cell-free DNA (dd-cfDNA) levels <1% have a negative predictive value of 85% for active allograft rejection. Using data from this study, we evaluated the association of dd-cfDNA with plasma BK viral loads and b ...[more]

PMID: 33134498

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Project description:There is a need to improve personalized immunosuppression in organ transplantation to reduce premature graft loss. Biomarkers are needed to better detect rejection, asymptomatic graft injury, and under-immunosuppression. Assessment of minimal necessary exposure to guide tapering and prevent immune activation is also important. There is robust clinical evidence from a large number of published studies supporting the role of dd-cfDNA for monitoring graft integrity and detection or exclusion of rejection. Dd-cfDNA indicates graft cell death without being rejection specific. It can be determined in plasma through droplet digital PCR using preselected SNPs or next generation sequencing. Changes in recipient cfDNA (e.g., by infection) can affect the results of dd-cfDNA fractional determination. This limitation can be overcome using absolute dd-cfDNA quantification. The combination of fractional and absolute determination including total cfDNA is recommended for meaningful interpretation of the results. The value proposition for the patient includes earlier transplant injury detection and intervention, less full blown rejection risk, an alternative to invasive biopsies, and personalized immunosuppression with potential for improved long-term outcome. Transplant physicians benefit from better immunosuppressive guidance and having an alternative when biopsies are refused or contraindicated. Further advantages are improved biopsy interpretation, less trial and error changes in immunosuppression, and less time dealing with complications. The laboratory medicine specialist can provide more effective services. Hospital management and insurance companies could benefit from more cost-effective surveillance of transplant recipients. Potential cost savings would result from fewer biopsies as a result of the tests' high negative predictive value, fewer re-transplantations, and less organ failure with return to dialysis. A pathway to implementation and metrics is suggested to measure the effectiveness of dd-cfDNA testing.

Dataset Information

Donor-derived Cell-free DNA and the Prediction of BK Virus-associated Nephropathy.

Publications

Donor-derived Cell-free DNA and the Prediction of BK Virus-associated Nephropathy.

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