Long Noncoding RNAs in Urine Are Detectable and May Enable Early Detection of Acute T Cell-Mediated Rejection of Renal Allografts.
BACKGROUND
Long noncoding RNAs (lncRNAs) are novel intracellular noncoding ribonucleotides regulating the genome and proteome. They are detectable in the blood of patients with acute kidney injury. We tested whether lncRNAs are present in urine and may serve as new predictors of outcome in renal transplant patients with acute rejection.


METHODS
A global lncRNA expression analysis was performed with RNA from urine of patients with acute T cell-mediated renal allograft rejection and control transplant patients. Deregulated lncRNAs were confirmed in kidney biopsies and urine in a validation cohort of 62 patients with acute rejection, 10 of them after successful antirejection therapy, and 31 control transplant patients.


RESULTS
A global screen revealed several lncRNAs to be deregulated in urine of patients with acute rejection. Three intergenic lncRNAs, LNC-MYH13-3:1, RP11-395P13.3-001, and RP11-354P17.15-001, were most strongly altered. These were validated in the whole cohort of patients. RP11-395P13.3-001 and RP11-354P17.15-001 were upregulated in patients with acute rejection compared with controls. Only levels of RP11-354P17.15-001 normalized in patients with acute rejection after successful antirejection therapy. RP11-354P17.15-001 was associated with higher decline in glomerular filtration rate 1 year after transplantation. In vitro, in tubular epithelial cells, all lncRNAs were enriched by interleukin-6 treatment, but only RP11-395P13.3-001 and RP11-354P17.15-001 increased in cell culture supernatant, indicating that these lncRNAs might be secreted under inflammatory conditions.


CONCLUSIONS
lncRNAs are strongly altered in urine of patients with acute rejection. Urinary RP11-354P17.15-001 may serve as a novel biomarker of acute kidney rejection, identifying patients with acute rejection and predicting loss of kidney function.
Institute of Molecular and Translational Therapeutic Strategies and Department of Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany. lorenzen.johan@mh-hannover.de Thum.Thomas@mh-hannover.de.
Johan M
JM
Lorenzen
Institute of Molecular and Translational Therapeutic Strategies and.
Celina
C
Schauerte
Institute of Molecular and Translational Therapeutic Strategies and.
Malte
M
Kölling
Institute of Molecular and Translational Therapeutic Strategies and.
Anika
A
Hübner
Institute of Molecular and Translational Therapeutic Strategies and.
Monika
M
Knapp
Department of Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
Hermann
H
Haller
Institute of Molecular and Translational Therapeutic Strategies and lorenzen.johan@mh-hannover.de Thum.Thomas@mh-hannover.de.
Thomas
T
Thum
D000208:Acute Disease; D058186:Acute Kidney Injury / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000652:urine; D002478:Cells, Cultured; D015331:Cohort Studies; D042241:Early Diagnosis; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000652:urine*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000378:metabolism / Q000652:urine*
D015415:Biomarkers; C508600:IL6 protein, human; D015850:Interleukin-6; D062085:RNA, Long Noncoding