title: Macrophage density in early surveillance biopsies predicts future renal transplant function.
abstract: Inflammation impairs renal allograft survival but is difficult to quantify by eye at low densities. Here we measured leukocyte abundance in early surveillance biopsies by digital image analysis to test for a role of chemokine receptor genotypes and analyze the predictive value of leukocyte subsets to allograft function. In six-week surveillance biopsies, T-cell (CD3), B-cell (CD20), macrophage (CD68), and dendritic cell (CD209) densities were assessed in whole slide scans. Renal cortical CD3, CD20, and CD68 were significantly higher in histologic rejection. The CCR2 V64I genotype was associated with lower CD3 and CD209 densities. Above-median CD68 density was significantly associated with lower combined patient and graft survival with a hazard ratio of 3.5 (95% confidence interval 1.1-11.0). Both CD20 and CD68 densities inversely correlated with estimated glomerular filtration rate (eGFR) four years after transplantation. Additionally, CD68 correlated with eGFR loss. Among histological measurements including a complete Banff classification, only CD68 density was a significant predictor of an eGFR under 30ml/min after four years (odds ratio 7.4, 1.8-31.0) and part of the best eGFR prediction set in a multivariable linear regression analysis of multiple clinical and pathologic parameters. In a second independent cohort, the original CD68 median maintained its discriminative power for survival and eGFR. Thus, digital high-resolution assessment of CD68+leukocyte infiltration significantly improves prognostic value of early renal transplant biopsies.
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Jan Hinrich
authors.initials: JH
authors.lastname: Bräsen
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Abedalrazag
authors.initials: A
authors.lastname: Khalifa
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Schmitz
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Einecke
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Schwarz
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hallensleben
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Bernhard M W
authors.initials: BMW
authors.lastname: Schmidt
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Kreipe
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany. Electronic address: vonVietinghoff.Sibylle@mh-hannover.de.
authors.forename: Sibylle
authors.initials: S
authors.lastname: von Vietinghoff
mesh_terms: D064591:Allografts / Q000276:immunology*; D015703:Antigens, CD / Q000378:metabolism; D018951:Antigens, CD20 / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1 / Q000235:genetics; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007668:Kidney / Q000276:immunology* / Q000378:metabolism; D016030:Kidney Transplantation / Q000706:statistics & numerical data*; D018655:Lymphocyte Count; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D054390:Receptors, CCR2 / Q000235:genetics; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D018951:Antigens, CD20; D015214:Antigens, Differentiation, Myelomonocytic; D000073883:CX3C Chemokine Receptor 1; D054390:Receptors, CCR2; C515334:CCR2 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C095235:CX3CR1 protein, human
keywords: CD68(+) macrophage; chemokine receptor; digital image analysis; inflammation; kidney transplantation, surveillance biopsy