title: A rapid noninvasive assay for the detection of renal transplant injury.
abstract: BACKGROUND
  The copy number of donor-derived cell-free DNA (dd-cfDNA) in blood correlates with acute rejection (AR) in heart transplantation. We analyzed urinary dd-cfDNA as a surrogate marker of kidney transplant injury.
  
  
  METHODS
  Sixty-three biopsy-matched urine samples (41 stable and 22 allograft injury) were analyzed from female recipients of male donors for chromosome Y (donor)-specific dd-cfDNA. All biopsies were semiquantitatively scored by a single pathologist. Standard statistical measures of correlation and significance were used.
  
  
  RESULTS
  There was baseline scatter for urinary dd-cfDNA/μg urine creatinine across different patients, even at the time of stable graft (STA) function (undetected to 12.26 copies). The mean urinary dd-cfDNA in AR (20.5 ± 13.9) was significantly greater compared with STA (2.4 ± 3.3; P<0.0001) or those with chronic allograft injury (CAI; 2.4 ± 2.4; P=0.001) but no different from BK virus nephropathy (BKVN; 20.3±15.7; P=0.98). In AR and BKVN, the intrapatient drift was highly significant versus STA or CAI patients (10.3 ± 7.4 in AR; 12.3 ± 8.4 in BKVN vs. -0.5 ± 3.5 in STA and 2.3 ± 2.6 in CAI; P<0.05). Urinary dd-cfDNA correlated with protein/creatinine ratio (r=0.48; P<0.014) and calculated glomerular filtration rate (r=-0.52; P<0.007) but was most sensitive for acute allograft injury (area under the curve=0.80; P<0.0006; 95% confidence interval, 0.67-0.93).
  
  
  CONCLUSIONS
  Urinary dd-cfDNA after renal transplantation has patient specific thresholds, reflecting the apoptotic injury load of the donor organ. Serial monitoring of urinary dd-cfDNA can be a surrogate sensitive biomarker of acute injury in the donor organ but lacks the specificity to distinguish between AR and BKVN injury.
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA
authors.forename: Tara K
authors.initials: TK
authors.lastname: Sigdel
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Vitalone
authors.forename: Tim Q
authors.initials: TQ
authors.lastname: Tran
authors.forename: Hong
authors.initials: H
authors.lastname: Dai
authors.forename: Szu-Chuan
authors.initials: SC
authors.lastname: Hsieh
authors.forename: Oscar
authors.initials: O
authors.lastname: Salvatierra
authors.forename: Minnie M
authors.initials: MM
authors.lastname: Sarwal
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D001739:BK Virus / Q000235:genetics; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002648:Child; D041322:Chromosomes, Human, Y; D004247:DNA / Q000097:blood; D056915:DNA Copy Number Variations; D005260:Female; D006084:Graft Rejection / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D027601:Polyomavirus Infections / Q000175:diagnosis; D015427:Reperfusion Injury / Q000175:diagnosis* / Q000378:metabolism; D012680:Sensitivity and Specificity; D012737:Sex Factors; D014184:Transplantation, Homologous; D014412:Tumor Virus Infections / Q000175:diagnosis; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D004247:DNA