Association of kidney function with changes in the endothelial surface layer.
OBJECTIVE
ESRD is accompanied by endothelial dysfunction. Because the endothelial glycocalyx (endothelial surface layer) governs interactions between flowing blood and the vessel wall, perturbation could influence disease progression. This study used a novel noninvasive sidestream-darkfield imaging method, which measures the accessibility of red blood cells to the endothelial surface layer in the microcirculation (perfused boundary region), to investigate whether renal function is associated with endothelial surface layer dimensions.


METHODS
Perfused boundary region was measured in control participants (n=10), patients with ESRD (n=23), participants with normal kidney function after successful living donor kidney transplantation (n=12), and patients who developed interstitial fibrosis/tubular atrophy after kidney transplantation (n=10). In addition, the endothelial activation marker angiopoietin-2 and shed endothelial surface layer components syndecan-1 and soluble thrombomodulin were measured using ELISA.


RESULTS
Compared with healthy controls (1.82 ± 0.16 µm), ESRD patients had a larger perfused boundary region (+0.23; 95% confidence interval, 0.46 to <0.01; P<0.05), which signifies loss of endothelial surface layer dimensions. This large perfused boundary region was accompanied by higher circulating levels of syndecan-1 (+57.71; 95% confidence interval, 17.38 to 98.04; P<0.01) and soluble thrombomodulin (+12.88; 95% confidence interval, 0.29 to 25.46; P<0.001). After successful transplantation, the perfused boundary region was indistinguishable from healthy controls (without elevated levels of soluble thrombomodulin or syndecan-1). In contrast, however, patients who developed interstitial fibrosis and tubular atrophy showed a large perfused boundary region (+0.36; 95% confidence interval, 0.09 to 0.63; P<0.01) and higher levels of endothelial activation markers. In addition, a significant correlation between perfused boundary region, angiopoietin-2, and eGFR was observed (perfused boundary region versus GFR: Spearman's ρ=0.31; P<0.05; perfused boundary region versus angiopoietin-2: Spearman's ρ=-0.33; P<0.05).


CONCLUSIONS
Reduced renal function is strongly associated with low endothelial surface layer dimensions. After successful kidney transplantation, the endothelial surface layer is indistinguishable from control.
Department of Nephrology, Einthoven Laboratory for Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands;, †Department of Physiology, Maastricht University Medical Center, Maastricht, The Netherlands, ‡Department of Nephrology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Martijn J C
MJ
Dane
Meriem
M
Khairoun
Dae Hyun
DH
Lee
Bernard M
BM
van den Berg
Bart J M
BJ
Eskens
Margien G S
MG
Boels
Jurgen W G E
JW
van Teeffelen
Angelique L W M M
AL
Rops
Johan
J
van der Vlag
Anton Jan
AJ
van Zonneveld
Marlies E J
ME
Reinders
Hans
H
Vink
Ton J
TJ
Rabelink
D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood; D000818:Animals; D001284:Atrophy; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D019276:Glycocalyx / Q000473:pathology*; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D007676:Kidney Failure, Chronic / Q000097:blood / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D051379:Mice; D008833:Microcirculation; D055806:Microvessels / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008875:Middle Aged; D011237:Predictive Value of Tests; D012039:Regional Blood Flow; D015203:Reproducibility of Results; D053668:Syndecan-1 / Q000097:blood; D018180:Thrombomodulin / Q000097:blood; D014059:Tongue / Q000098:blood supply*; D016896:Treatment Outcome
C586513:ANGPT2 protein, human; D042702:Angiopoietin-2; D015415:Biomarkers; C508241:SDC1 protein, human; D053668:Syndecan-1; C546931:THBD protein, human; D018180:Thrombomodulin