title: Reduced Microvascular Density in Omental Biopsies of Children with Chronic Kidney Disease.
abstract: BACKGROUND
  Endothelial dysfunction is an early manifestation of cardiovascular disease (CVD) and consistently observed in patients with chronic kidney disease (CKD). We hypothesized that CKD is associated with systemic damage to the microcirculation, preceding macrovascular pathology. To assess the degree of "uremic microangiopathy", we have measured microvascular density in biopsies of the omentum of children with CKD.
  
  
  METHODS
  Omental tissue was collected from 32 healthy children (0-18 years) undergoing elective abdominal surgery and from 23 age-matched cases with stage 5 CKD at the time of catheter insertion for initiation of peritoneal dialysis. Biopsies were analyzed by independent observers using either a manual or an automated imaging system for the assessment of microvascular density. Quantitative immunohistochemistry was performed for markers of autophagy and apoptosis, and for the abundance of the angiogenesis-regulating proteins VEGF-A, VEGF-R2, Angpt1 and Angpt2.
  
  
  RESULTS
  Microvascular density was significantly reduced in uremic children compared to healthy controls, both by manual imaging with a digital microscope (median surface area 0.61% vs. 0.95%, p<0.0021 and by automated quantification (total microvascular surface area 0.89% vs. 1.17% p = 0.01). Density measured by manual imaging was significantly associated with age, height, weight and body surface area in CKD patients and healthy controls. In multivariate analysis, age and serum creatinine level were the only independent, significant predictors of microvascular density (r2 = 0.73). There was no immunohistochemical evidence for apoptosis or autophagy. Quantitative staining showed similar expression levels of the angiogenesis regulators VEGF-A, VEGF-receptor 2 and Angpt1 (p = 0.11), but Angpt2 was significantly lower in CKD children (p = 0.01).
  
  
  CONCLUSIONS
  Microvascular density is profoundly reduced in omental biopsies of children with stage 5 CKD and associated with diminished Angpt2 signaling. Microvascular rarefaction could be an early systemic manifestation of CKD-induced cardiovascular disease.
authors.affiliation: Department of Pediatric Nephrology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Burkhardt
authors.affiliation: Center for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Bartosova
authors.affiliation: Center for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.
authors.forename: Betti
authors.initials: B
authors.lastname: Schaefer
authors.affiliation: Bioquant, Hamamatsu Tissue Imaging and Analysis (TIGA) Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Bioquant, Hamamatsu Tissue Imaging and Analysis (TIGA) Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lahrmann
authors.affiliation: Center for Cardiovascular Research, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Hamoud
authors.initials: H
authors.lastname: Nasser
authors.affiliation: Center for Cardiovascular Research, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Freise
authors.affiliation: Department of Pediatric Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Department of Pediatric Urology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Lingnau
authors.affiliation: Department of Pediatric Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Department of Pediatric Surgery, Klinikum Ernst von Bergmann, Potsdam, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Degenhardt
authors.affiliation: Hospices Civils de Lyon, Service de Nephrologie Pediatrique and Epicime-Centre d'Investigation Clinique 1407, Hopital Femme Mere Enfant, Lyon, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ranchin
authors.affiliation: First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Sallay
authors.affiliation: Coordinating Centre for Children's Rare Diseases, Children´s Hospital, Affiliate of Vilnius University Hospital Santariskiu Klinikos, Vilnius, Lithuania.
authors.forename: Rimante
authors.initials: R
authors.lastname: Cerkauskiene
authors.affiliation: Department of Pediatrics, Second Faculty of Medicine, Charles University-Prague, Prague 5, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Malina
authors.affiliation: Servicio de Nefrología Pediátrica, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Ariceta
authors.affiliation: Center for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.
authors.forename: Claus Peter
authors.initials: CP
authors.lastname: Schmitt
authors.affiliation: Department of Pediatric Nephrology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Center for Cardiovascular Research, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Querfeld
mesh_terms: D000293:Adolescent; D042683:Angiopoietin-1 / Q000097:blood*; D042702:Angiopoietin-2 / Q000097:blood*; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D002318:Cardiovascular Diseases / Q000097:blood* / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008833:Microcirculation / Q000235:genetics; D055806:Microvessels / Q000473:pathology; D010530:Peritoneal Dialysis; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000235:genetics / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood*
chemical_list: C467630:ANGPT1 protein, human; C586513:ANGPT2 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D015415:Biomarkers; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2