Glomerular Volume and Glomerulosclerosis at Different Depths within the Human Kidney

Abstract

Background: Age, CKD risk factors, and kidney function are associated with larger glomerular volume and a higher percentage of globally sclerotic glomeruli. Knowledge of how these associations may differ by cortical depth is limited.

Methods: To investigate glomerular volume and glomerulosclerosis across different depths of cortex, we studied wedge sections of the renal parenchyma from 812 patients who underwent a radical nephrectomy (for a tumor), separately characterizing glomeruli in the superficial (subcapsular), middle, and deep (juxtamedullary) regions. We compared the association of mean nonsclerotic glomerular volume and of glomerulosclerosis (measured as the percentage of globally sclerotic glomeruli) with age, obesity, diabetes, smoking, kidney function, and structural pathology in the superficial, middle, and deep regions.

Results: The superficial, middle, and deep regions showed significant differences in glomerular volume (0.0025, 0.0031, and 0.0028 µm³, respectively) and in glomerulosclerosis (18%, 7%, and 11%, respectively). There was a marked increase in glomerulosclerosis with age in the superficial region, but larger glomerular volume was not associated with age at any cortical depth. Glomerulosclerosis associated more strongly with arteriosclerosis and ischemic-appearing glomeruli in the superficial region. Hypertension, lower eGFR, and interstitial fibrosis associated with glomerulosclerosis and glomerular volume to a similar extent at any depth. Diabetes and proteinuria more strongly associated with glomerulosclerosis in the deep and middle regions, respectively, but neither associated with glomerular volume differently by depth. Obesity associated more strongly with glomerular volume in the superficial cortex.

Conclusions: Most clinical characteristic show similar associations with glomerulosclerosis and glomerulomegaly at different cortical depths. Exceptions include age-related glomerulosclerosis, which appears to be an ischemic process and is more predominant in the superficial region.

Keywords: Renal pathology; glomerulosclerosis; glomerulus; interstitial fibrosis; kidney biopsy; risk factors.

Graphical abstract

Figure 1.

Representative wedge sections of thin and thick kidney cortex. (A) Thin cortex allowed measurements and quantification of glomeruli in three regions, superficial (glomeruli in red trace), middle (glomeruli in light green trace), and deep (glomeruli in blue trace). (B) Thick cortex allowed measurements and quantification of glomeruli in additional two regions, superficial/middle (glomeruli in dark green trace), and middle/deep (glomeruli in yellow trace). Black dashed lines in each biopsy section represent the two measurements of cortical thickness used to classify patients into thin versus thick cortex. Arcuate arteries are denoted with black arrowheads. Globally sclerotic glomeruli in all zones, in both panels were shown in pink trace.

Figure 2.

Nonsclerotic glomerular volume and percentage of glomerulosclerosis depends on the cortical depth. (A) In each of the three cortical regions (superficial, middle, and deep), glomerular volume was larger in patients with thick (n=406) than thin (n=386) cortex. The additional two regions were in those with thick cortex (superficial/middle and middle/deep) had glomerular volumes that were more similar to the middle region than the superficial or deep region. (B) The %GSG was higher in thin than thick cortex, although this was more evident in the superficial region. Among the biopsy sections with thick cortex, the superficial/middle and middle/deep region had %GSG that was more similar to the middle region than the superficial or deep region. Data presented with mean±1 SD.

Figure 3.

Age-related differences in nonsclerotic glomerular volume and percentage glomerulosclerosis in superficial, middle, and deep regions. (A) The glomerular volume was log transformed and plotted against age. Throughout the age spectrum, middle glomeruli (dashed line) were larger than both deep glomeruli (solid line) and the superficial glomeruli (dotted line). Smooth fits are shown, but by linear regression, there is smaller glomerular volume with older age; superficial glomerular volume declined −1.8% per 10 years (P=0.12), middle glomerular volume declined −3.1% per 10 years (P=0.002), and deep glomerular volume declined −2.4% per 10 years (P=0.02). (B) After age 50 years, superficial regions had a faster increase in percentage globally sclerotic glomeruli (%GSG) with age. With a linear fit, the superficial glomerulosclerosis increased 6.2% per 10 years and middle glomerulosclerosis increased 1.9% per 10 years, whereas in the deep region it increased 1.2% per 10 years (P<0.001 for all). (C) The percentage ischemic glomeruli increased faster with age in the superficial than in the middle or deep regions of cortex. With a linear fit, the superficial ischemic NSG increased 1.5% per 10 years (P<0.001), middle ischemic NSG increased 0.6% per 10 years (P=0.003), whereas in the deep region ischemic NSG increased 0.4% per 10 years (P=0.05). Gray shaded areas represent 95% confidence intervals around the smoother fits. NSG, nonsclerotic glomeruli.

Figure 4.

A conceptual model for how clinical characteristics are associated with glomerulosclerosis by depth. Age most strongly associates with superficial glomerulosclerosis and diabetes with deep glomerulosclerosis, whereas hypertension, lower GFR, proteinuria, and interstitial fibrosis are associated with glomerulosclerosis in all three cortical regions to a similar extent. Empty circles denote nonsclerotic glomeruli, and black filled circles denote globally sclerotic glomeruli.