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. PATIENTS AND 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.

1st Department of Pediatrics Semmelweis University Budapest Hungary

Bioquant Hamamatsu Tissue Imaging and Analysis Center University of Heidelberg Heidelberg Germany

Center for Cardiovascular Research Charité Universitätsmedizin Berlin Berlin Germany

Center for Pediatric and Adolescent Medicine University of Heidelberg Heidelberg Germany

Coordinating Centre for Children's Rare Diseases Children´s Hospital Affiliate of Vilnius University Hospital Santariskiu Klinikos Vilnius Lithuania

Department of Pediatric Nephrology Charité Universitätsmedizin Berlin Berlin Germany

Department of Pediatric Surgery Charité Universitätsmedizin Berlin Berlin Germany

Department of Pediatric Surgery Klinikum Ernst von Bergmann Potsdam Germany

Department of Pediatric Urology Charité Universitätsmedizin Berlin Berlin Germany

Department of Pediatrics 2nd Faculty of Medicine Charles University Prague Prague 5 Czech Republic

Hospices Civils de Lyon Service de Nephrologie Pediatrique and Epicime Centre d'Investigation Clinique 1407 Hopital Femme Mere Enfant Lyon France

Servicio de Nefrología Pediátrica Hospital Universitari Vall d'Hebron Barcelona Spain

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