The role of capillary density, macrophage infiltration and interstitial scarring in the pathogenesis of human chronic kidney disease.
To assess the relationship between interstitial capillary density and interstitial macrophages we prospectively measured these factors in situ in 110 patients with chronic kidney disease. Macrophage numbers and urinary MCP-1/CCL2 levels significantly correlated inversely with capillary density which itself significantly correlated inversely with chronic damage and predicted disease progression. In 54 patients with less than 20% chronic damage, there was a significant correlation between the urinary albumin to creatinine ratio and MCP-1/CCL2, and MCP-1/CCL2 and macrophages but not between MCP-1/CCL2 and capillary density. Conversely, in 56 patients with over 20% chronic damage there was no correlation between MCP-1/CCL2 and macrophages but there were significant inverse correlations between capillary density and both macrophages and chronic damage. The expression of VEGF mRNA significantly correlated with macrophage infiltration, capillary density and chronic scarring. In an ischemic-hypertensive subgroup there was upregulation of the hypoxia marker carbonic anhydrase IX and with over 20% chronic damage an increased macrophage to CCR2 ratio. Our study shows that proteinuria and MCP-1/CCL2 are important for macrophage recruitment in early disease. As renal scarring evolves, alternative pathways relating to progressive tissue ischemia secondary to obliteration of the interstitial capillary bed predominate.
Eardley
Kevin S
KS
Department of Nephrology, Royal Shrewsbury Hospital, Shrewsbury, UK.
Kubal
Chandrashekhar
C
Zehnder
Daniel
D
Quinkler
Marcus
M
Lepenies
Julia
J
Savage
Caroline O
CO
Howie
Alec J
AJ
Kaur
Kirrenjit
K
Cooper
Mark S
MS
Adu
Dwomoa
D
Cockwell
Paul
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000419:Albuminuria / Q000235:genetics / Q000473:pathology; D002196:Capillaries / Q000378:metabolism*; D002452:Cell Count; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism / Q000652:urine*; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D011507:Proteinuria / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D018932:Chemokine CCL2; D012333:RNA, Messenger; D003404:Creatinine