Design and Methods of the Validating Injury to the Renal Transplant Using Urinary Signatures (VIRTUUS) Study in Children
Background. Lack of noninvasive diagnostic and prognostic biomarkers to reliably detect early allograft injury poses a major hindrance to long-term allograft survival in pediatric kidney transplant recipients. Methods. Validating Injury to the Renal Transplant Using Urinary Signatures Children’s Stu...
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Wolters Kluwer
2021
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oai:doaj.org-article:f504408234744dada561d27c3de297ab2021-11-25T07:59:57ZDesign and Methods of the Validating Injury to the Renal Transplant Using Urinary Signatures (VIRTUUS) Study in Children2373-873110.1097/TXD.0000000000001244https://doaj.org/article/f504408234744dada561d27c3de297ab2021-12-01T00:00:00Zhttp://journals.lww.com/transplantationdirect/fulltext/10.1097/TXD.0000000000001244https://doaj.org/toc/2373-8731Background. Lack of noninvasive diagnostic and prognostic biomarkers to reliably detect early allograft injury poses a major hindrance to long-term allograft survival in pediatric kidney transplant recipients. Methods. Validating Injury to the Renal Transplant Using Urinary Signatures Children’s Study, a North American multicenter prospective cohort study of pediatric kidney transplant recipients, aims to validate urinary cell mRNA and metabolite profiles that were diagnostic and prognostic of acute cellular rejection (ACR) and BK virus nephropathy (BKVN) in adult kidney transplant recipients in Clinical Trials in Organ Transplantation-4. Specifically, we are investigating: (1) whether a urinary cell mRNA 3-gene signature (18S-normalized CD3ε, CXCL10 mRNA, and 18S ribosomal RNA) discriminates biopsies with versus without ACR, (2) whether a combined metabolite profile with the 3-gene signature increases sensitivity and specificity of diagnosis and prognostication of ACR, and (3) whether BKV-VP1 mRNA levels in urinary cells are diagnostic of BKVN and prognostic for allograft failure. Results. To date, 204 subjects are enrolled, with 1405 urine samples, including 144 biopsy-associated samples. Among 424 urine samples processed for mRNA, the median A260:280 ratio (RNA purity) was 1.91, comparable with Clinical Trials in Organ Transplantation-4 (median 1.82). The quality control failure rate was 10%. Preliminary results from urine supernatant showed that our metabolomics platform successfully captured a broad array of metabolites. Clustering of pool samples and overlay of samples from various batches demonstrated platform robustness. No study site effect was noted. Conclusions. Multicenter efforts to ascertain urinary biomarkers in pediatric kidney transplant recipients are feasible with high-quality control. Further study will inform whether these signatures are discriminatory and predictive for rejection and infection.Juhi Kumar, MD, MPHKévin Contrepois, PhDMichael Snyder, PhDPaul C. Grimm, MDAsha Moudgil, MDJodi M. Smith, MDAmy E. Bobrowski, MD, MSPriya S. Verghese, MBBS, MPHDavid Hooper, MDElizabeth Ingulli, MDRachel Lestz, MD, MHSPatricia Weng, MDJanaiya L. Reason, MPHTom D. Blydt-Hansen, MDCMManikkam Suthanthiran, MDBrendan Keating, PhDSandra Amaral, MD, MHSWolters KluwerarticleSurgeryRD1-811ENTransplantation Direct, Vol 7, Iss 12, p e791 (2021) |
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Surgery RD1-811 |
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Surgery RD1-811 Juhi Kumar, MD, MPH Kévin Contrepois, PhD Michael Snyder, PhD Paul C. Grimm, MD Asha Moudgil, MD Jodi M. Smith, MD Amy E. Bobrowski, MD, MS Priya S. Verghese, MBBS, MPH David Hooper, MD Elizabeth Ingulli, MD Rachel Lestz, MD, MHS Patricia Weng, MD Janaiya L. Reason, MPH Tom D. Blydt-Hansen, MDCM Manikkam Suthanthiran, MD Brendan Keating, PhD Sandra Amaral, MD, MHS Design and Methods of the Validating Injury to the Renal Transplant Using Urinary Signatures (VIRTUUS) Study in Children |
| description |
Background. Lack of noninvasive diagnostic and prognostic biomarkers to reliably detect early allograft injury poses a major hindrance to long-term allograft survival in pediatric kidney transplant recipients.
Methods. Validating Injury to the Renal Transplant Using Urinary Signatures Children’s Study, a North American multicenter prospective cohort study of pediatric kidney transplant recipients, aims to validate urinary cell mRNA and metabolite profiles that were diagnostic and prognostic of acute cellular rejection (ACR) and BK virus nephropathy (BKVN) in adult kidney transplant recipients in Clinical Trials in Organ Transplantation-4. Specifically, we are investigating: (1) whether a urinary cell mRNA 3-gene signature (18S-normalized CD3ε, CXCL10 mRNA, and 18S ribosomal RNA) discriminates biopsies with versus without ACR, (2) whether a combined metabolite profile with the 3-gene signature increases sensitivity and specificity of diagnosis and prognostication of ACR, and (3) whether BKV-VP1 mRNA levels in urinary cells are diagnostic of BKVN and prognostic for allograft failure.
Results. To date, 204 subjects are enrolled, with 1405 urine samples, including 144 biopsy-associated samples. Among 424 urine samples processed for mRNA, the median A260:280 ratio (RNA purity) was 1.91, comparable with Clinical Trials in Organ Transplantation-4 (median 1.82). The quality control failure rate was 10%. Preliminary results from urine supernatant showed that our metabolomics platform successfully captured a broad array of metabolites. Clustering of pool samples and overlay of samples from various batches demonstrated platform robustness. No study site effect was noted.
Conclusions. Multicenter efforts to ascertain urinary biomarkers in pediatric kidney transplant recipients are feasible with high-quality control. Further study will inform whether these signatures are discriminatory and predictive for rejection and infection. |
| format |
article |
| author |
Juhi Kumar, MD, MPH Kévin Contrepois, PhD Michael Snyder, PhD Paul C. Grimm, MD Asha Moudgil, MD Jodi M. Smith, MD Amy E. Bobrowski, MD, MS Priya S. Verghese, MBBS, MPH David Hooper, MD Elizabeth Ingulli, MD Rachel Lestz, MD, MHS Patricia Weng, MD Janaiya L. Reason, MPH Tom D. Blydt-Hansen, MDCM Manikkam Suthanthiran, MD Brendan Keating, PhD Sandra Amaral, MD, MHS |
| author_facet |
Juhi Kumar, MD, MPH Kévin Contrepois, PhD Michael Snyder, PhD Paul C. Grimm, MD Asha Moudgil, MD Jodi M. Smith, MD Amy E. Bobrowski, MD, MS Priya S. Verghese, MBBS, MPH David Hooper, MD Elizabeth Ingulli, MD Rachel Lestz, MD, MHS Patricia Weng, MD Janaiya L. Reason, MPH Tom D. Blydt-Hansen, MDCM Manikkam Suthanthiran, MD Brendan Keating, PhD Sandra Amaral, MD, MHS |
| author_sort |
Juhi Kumar, MD, MPH |
| title |
Design and Methods of the Validating Injury to the Renal Transplant Using Urinary Signatures (VIRTUUS) Study in Children |
| title_short |
Design and Methods of the Validating Injury to the Renal Transplant Using Urinary Signatures (VIRTUUS) Study in Children |
| title_full |
Design and Methods of the Validating Injury to the Renal Transplant Using Urinary Signatures (VIRTUUS) Study in Children |
| title_fullStr |
Design and Methods of the Validating Injury to the Renal Transplant Using Urinary Signatures (VIRTUUS) Study in Children |
| title_full_unstemmed |
Design and Methods of the Validating Injury to the Renal Transplant Using Urinary Signatures (VIRTUUS) Study in Children |
| title_sort |
design and methods of the validating injury to the renal transplant using urinary signatures (virtuus) study in children |
| publisher |
Wolters Kluwer |
| publishDate |
2021 |
| url |
https://doaj.org/article/f504408234744dada561d27c3de297ab |
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