Urinary elafin and kidney injury in hematopoietic cell transplant recipients.
OBJECTIVE
Graft-versus-host disease (GVHD) is associated with kidney injury after hematopoietic cell transplantation (HCT). Because plasma elafin levels correlate with skin GVHD, this study examined urinary elafin as a potential marker of renal inflammation and injury.


METHODS
Urine was collected prospectively on 205 patients undergoing their first HCT from 2003 to 2010. Collections were done at baseline, weekly through day 100, and monthly through year 1 to measure elafin and urine albumin-to-creatinine ratio (ACR). Associations between urinary elafin levels and microalbuminuria, macroalbuminuria, AKI and CKD, and mortality were examined using Cox proportional hazards or linear regression models. Available kidney biopsy specimens were processed for immunohistochemistry.


RESULTS
Mean urinary elafin levels to day 100 were higher in patients with micro- or macroalbuminuria (adjusted mean difference, 529 pg/ml; P=0.03) at day 100 than in those with a normal ACR (adjusted mean difference, 1295 pg/ml; P<0.001). Mean urinary elafin levels were higher in patients with AKI compared with patients without AKI (adjusted mean difference, 558 pg/ml; P<0.01). The average urinary elafin levels within the first 100 days after HCT were higher in patients who developed CKD at 1 year than in patients without CKD (adjusted mean difference, 894 pg/ml; P=0.002). Among allogeneic recipients, a higher proportion of patients with micro- or macroalbuminuria at day 100 also had grade II-IV acute GVHD (80% and 86%, respectively) compared with patients with a normal ACR (58%; global P<0.01). Each increase in elafin of 500 pg/ml resulted in a 10% increase in risk of persistent macroalbuminuria (hazard ratio, 1.10; 95% confidence interval [95% CI], 1.06 to 1.13; P<0.001) and a 7% increase in the risk of overall mortality (95% CI, 1.02 to 1.13, P<0.01). Renal biopsy specimens from a separate cohort of HCT survivors demonstrated elafin staining in distal and collecting duct tubules.


CONCLUSIONS
Higher urinary elafin levels are associated with an increased risk of micro- and macroalbuminuria, AKI and CKD, and death after HCT.
Departments of Pediatrics, Gastroenterology, and Pathology, University of Washington, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington; and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington sangeeta.hingorani@seattlechildrens.org.
Sangeeta
S
Hingorani
Departments of Pediatrics, Gastroenterology, and Pathology, University of Washington, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington; and.
Laura S
LS
Finn
Seattle Children's Hospital, Seattle, Washington; and.
Emily
E
Pao
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Rick
R
Lawler
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Gary
G
Schoch
Departments of Pediatrics, Gastroenterology, and Pathology, University of Washington, Seattle, Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
George B
GB
McDonald
Departments of Pediatrics, Gastroenterology, and Pathology, University of Washington, Seattle, Washington;
Behzad
B
Najafian
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Brenda
B
Sandmaier
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Ted
T
Gooley
D058186:Acute Kidney Injury / Q000175:diagnosis / Q000209:etiology / Q000401:mortality / Q000652:urine*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000209:etiology / Q000652:urine; D015415:Biomarkers / Q000652:urine; D001706:Biopsy; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000652:urine; D053492:Elafin / Q000652:urine*; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000652:urine; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000652:urine; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation; D055815:Young Adult
D015415:Biomarkers; D053492:Elafin; C506806:PI3 protein, human; D003404:Creatinine
chronic kidney disease; hematopoietic cell transplant; microalbuminuria; proteinuria; renal tubular epithelial cells