Sherry G Mansour1,2, Caroline Liu3, Yaqi Jia3, Peter P Reese4,5,6, Isaac E Hall7, Tarek M El-Achkar8, Kaice A LaFavers8, Wassim Obeid3, Avi Z Rosenberg9, Parnaz Daneshpajouhnejad9, Mona D Doshi10, Enver Akalin11, Jonathan S Bromberg12,13, Meera N Harhay14,15,16, Sumit Mohan17,18, Thangamani Muthukumar19,20, Bernd Schröppel21, Pooja Singh22, Joe M El-Khoury1, Francis L Weng23, Heather R Thiessen-Philbrook3, Chirag R Parikh3. 1. Department of Internal Medicine, Section of Nephrology, Program of Applied Translational Research, Yale University School of Medicine, New Haven, CT. 2. Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT. 3. Division of Nephrology, School of Medicine, Johns Hopkins University, Baltimore, MD. 4. Department of Medicine, Renal-Electrolyte and Hypertension Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 5. Department of Biostatistics, Epidemiology & Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 6. Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 7. Department of Internal Medicine, Division of Nephrology & Hypertension, University of Utah School of Medicine, Salt Lake City, UT. 8. Division of Nephrology, Department of Medicine, The Indianapolis VA Medical Center, Indiana University School of Medicine, Indianapolis, IN. 9. Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD. 10. Department of Internal Medicine, Division of Nephrology, University of Michigan Medical School, Ann Arbor, MI. 11. Department of Internal Medicine, Division of Nephrology, Albert Einstein College of Medicine, Bronx, NY. 12. Department of Surgery, Division of Transplantation, University of Maryland School of Medicine, Baltimore, MD. 13. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD. 14. Department of Medicine, Drexel University College of Medicine, Philadelphia, PA. 15. Department of Epidemiology and Biostatistics, Drexel University Dornsife School of Public Health, Philadelphia, PA. 16. Tower Health Transplant Institute, Tower Health System, West Reading, PA. 17. Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY. 18. Department of Medicine, Division of Nephrology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY. 19. Department of Medicine, Division of Nephrology and Hypertension, New York-Presbyterian Hospital-Weill Cornell Medical Center, New York, NY. 20. Department of Transplantation Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY. 21. Department of Internal Medicine, Section of Nephrology, University Hospital, Ulm, Germany. 22. Department of Medicine, Division of Nephrology, Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA. 23. Department of Internal Medicine, Section of Nephrology, Saint Barnabas Medical Center, RWJBarnabas Health, Livingston, NJ.
Abstract
BACKGROUND: Deceased-donor kidneys experience extensive injury, activating adaptive and maladaptive pathways therefore impacting graft function. We evaluated urinary donor uromodulin (UMOD) and osteopontin (OPN) in recipient graft outcomes. METHODS: Primary outcomes: all-cause graft failure (GF) and death-censored GF (dcGF). Secondary outcomes: delayed graft function (DGF) and 6-month estimated glomerular filtration rate (eGFR). We randomly divided our cohort of deceased donors and recipients into training and test datasets. We internally validated associations between donor urine UMOD and OPN at time of procurement, with our primary outcomes. The direction of association between biomarkers and GF contrasted. Subsequently, we evaluated UMOD:OPN ratio with all outcomes. To understand these mechanisms, we examined the effect of UMOD on expression of major histocompatibility complex II in mouse macrophages. RESULTS: Doubling of UMOD increased dcGF risk (adjusted hazard ratio [aHR], 1.1; 95% confidence interval [CI], 1.02-1.2), whereas OPN decreased dcGF risk (aHR, 0.94; 95% CI, 0.88-1). UMOD:OPN ratio ≤3 strengthened the association, with reduced dcGF risk (aHR, 0.57; 0.41-0.80) with similar associations for GF, and in the test dataset. A ratio ≤3 was also associated with lower DGF (aOR, 0.73; 95% CI, 0.60-0.89) and higher 6-month eGFR (adjusted β coefficient, 3.19; 95% CI, 1.28-5.11). UMOD increased major histocompatibility complex II expression elucidating a possible mechanism behind UMOD's association with GF. CONCLUSIONS: UMOD:OPN ratio ≤3 was protective, with lower risk of DGF, higher 6-month eGFR, and improved graft survival. This ratio may supplement existing strategies for evaluating kidney quality and allocation decisions regarding deceased-donor kidney transplantation.
BACKGROUND: Deceased-donor kidneys experience extensive injury, activating adaptive and maladaptive pathways therefore impacting graft function. We evaluated urinary donor uromodulin (UMOD) and osteopontin (OPN) in recipient graft outcomes. METHODS: Primary outcomes: all-cause graft failure (GF) and death-censored GF (dcGF). Secondary outcomes: delayed graft function (DGF) and 6-month estimated glomerular filtration rate (eGFR). We randomly divided our cohort of deceased donors and recipients into training and test datasets. We internally validated associations between donor urine UMOD and OPN at time of procurement, with our primary outcomes. The direction of association between biomarkers and GF contrasted. Subsequently, we evaluated UMOD:OPN ratio with all outcomes. To understand these mechanisms, we examined the effect of UMOD on expression of major histocompatibility complex II in mouse macrophages. RESULTS: Doubling of UMOD increased dcGF risk (adjusted hazard ratio [aHR], 1.1; 95% confidence interval [CI], 1.02-1.2), whereas OPN decreased dcGF risk (aHR, 0.94; 95% CI, 0.88-1). UMOD:OPN ratio ≤3 strengthened the association, with reduced dcGF risk (aHR, 0.57; 0.41-0.80) with similar associations for GF, and in the test dataset. A ratio ≤3 was also associated with lower DGF (aOR, 0.73; 95% CI, 0.60-0.89) and higher 6-month eGFR (adjusted β coefficient, 3.19; 95% CI, 1.28-5.11). UMOD increased major histocompatibility complex II expression elucidating a possible mechanism behind UMOD's association with GF. CONCLUSIONS: UMOD:OPN ratio ≤3 was protective, with lower risk of DGF, higher 6-month eGFR, and improved graft survival. This ratio may supplement existing strategies for evaluating kidney quality and allocation decisions regarding deceased-donor kidney transplantation.
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