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Subthreshold rejection activity in many kidney transplants currently classified as having no rejection
PF. Halloran, KS. Madill-Thomsen, G. Böhmig, J. Bromberg, K. Budde, M. Barner, M. Mackova, J. Chang, G. Einecke, F. Eskandary, G. Gupta, M. Myślak, O. Viklicky, E. Akalin, T. Alhamad, S. Anand, M. Arnol, R. Baliga, M. Banasik, A. Bingaman, CD....
Language English Country United States
Document type Journal Article
- MeSH
- Biopsy MeSH
- Adult MeSH
- Glomerular Filtration Rate MeSH
- Isoantibodies immunology MeSH
- Middle Aged MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Graft Survival immunology MeSH
- Prognosis MeSH
- Graft Rejection * pathology immunology etiology MeSH
- Risk Factors MeSH
- T-Lymphocytes immunology MeSH
- Kidney Transplantation * adverse effects MeSH
- Kidney Function Tests MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (from 4170 patients). An updated molecular archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower estimated glomerular filtration rate, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR, respectively, diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.
Albert Einstein College of Medicine Montefiore Medical Center USA
Alberta Transplant Applied Genomics Centre Canada
Cleveland Clinic Foundation USA
Department of Immunology Transplantology and Internal Diseases Warsaw Medical University Poland
Department of Internal Medicine Division of Nephrology Virginia Commonwealth University USA
Department of Kidney Medicine Cleveland Clinic Foundation USA
Department of Medicine Division of Nephrology University of Maryland USA
Department of Medicine Hennepin County Medical Centre USA
Department of Medicine Johns Hopkins University School of Medicine USA
Department of Medicine University of Wisconsin USA
Department of Nephrology and Kidney Transplantation Pomeranian Medical University Poland
Department of Nephrology and Transplantation Medicine Medical University of Wrocław Poland
Department of Nephrology Charite Medical University of Berlin Germany
Department of Nephrology Institute for Experimental and Clinical Medicine Czech Republic
Department of Nephrology Medical University of Hannover Germany
Department of Nephrology The Royal Melbourne Hospital Australia
Department of Nephrology Transplantation and Internal Medicine Silesian Medical University Poland
Department of Nephrology Transplantology and Internal Diseases Medical University of Gdańsk Poland
Department of Nephrology Transplantology and Internal Medicine Medical University of Gdańsk Poland
Department of Nephrology Transplantology and Internal Medicine Pomeranian Medical University Poland
Department of Nephrology University Hospital Merkur Croatia
Department of Nephrology University of Ljubljana Slovenia
Department of Pathology University of Ljubljana Slovenia
Department of Renal Medicine Manchester Royal Infirmary United Kingdom
Department of Renal Research Manchester Royal Infirmary United Kingdom
Department of Surgery and Transplantation University Hospital Zurich Switzerland
Department of Surgery Division of Transplantation University on Minnesota USA
Department of Surgery Methodist Transplant and Specialty Hospital USA
Department of Surgery PinnacleHealth Transplant Associates USA
Department of Surgery University of Maryland USA
Department of Transplantation Medicine Warsaw Medical University Poland
Division of Nephrology and Dialysis Department of Medicine 3 Medical University of Vienna Austria
Division of Nephrology Department of Medicine University of Alabama at Birmingham USA
Division of Nephrology Department of Medicine University of Alberta USA
Division of Nephrology Department of Medicine Virginia Commonwealth University USA
Division of Nephrology University of Michigan USA
Division of Nephrology Washington University at St Louis USA
Henry Ford Transplant Institute USA
Intermountain Transplant Services USA
Johns Hopkins University School of Medicine USA
Kashi Clinical Laboratories USA
Nephrology Department University Hospital Zurich Switzerland
PinnacleHealth Transplant Associates USA
Pomeranian Medical University Poland
Renal Replacement Therapy Department of Nephrology University Hospital Merkur Croatia
University Hospital Cleveland Medical Center USA
References provided by Crossref.org
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- $a Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (from 4170 patients). An updated molecular archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower estimated glomerular filtration rate, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR, respectively, diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.
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