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Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy.

Weil EJ, Lemley KV, Mason CC, Yee B, Jones LI, Blouch K, Lovato T, Richardson M, Myers BD, Nelson RG - Kidney Int. (2012)

Bottom Line: Podocyte detachment correlated significantly with podocyte number per glomerulus and albuminuria.The mean percentage of endothelial cell fenestration was significantly lower in macroalbuminuria (19.3%) than in normal albuminuria (27.4%) or microalbuminuria (27.2%) and correlated significantly with glomerular basement membrane thickness, albuminuria, fractional mesangial area, and the glomerular filtration rate (iothalamate clearance).Whether podocyte detachment creates conduits for proteins to escape the glomerular circulation and reduced endothelial fenestration lowers glomerular hydraulic permeability requires further study.

View Article: PubMed Central - PubMed

Affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85014-4972, USA. rnelson@nih.gov

ABSTRACT
Podocyte detachment and reduced endothelial cell fenestration and relationships between these features and the classic structural changes of diabetic nephropathy have not been described in patients with type 2 diabetes. Here we studied these relationships in 37 Pima Indians with type 2 diabetes of whom 11 had normal albuminuria, 16 had microalbuminuria, and 10 had macroalbuminuria. Biopsies from 10 kidney donors (not American Indians) showed almost undetectable (0.03%) podocyte detachment and 43.5% endothelial cell fenestration. In patients with type 2 diabetes, by comparison, the mean percentage of podocyte detachment was significantly higher in macroalbuminuria (1.48%) than in normal albuminuria (0.41%) or microalbuminuria (0.37%). Podocyte detachment correlated significantly with podocyte number per glomerulus and albuminuria. The mean percentage of endothelial cell fenestration was significantly lower in macroalbuminuria (19.3%) than in normal albuminuria (27.4%) or microalbuminuria (27.2%) and correlated significantly with glomerular basement membrane thickness, albuminuria, fractional mesangial area, and the glomerular filtration rate (iothalamate clearance). Podocyte detachment and diminished endothelial cell fenestration were not correlated, but were related to classic lesions of diabetic nephropathy. Thus, our findings confirm the important role these injuries play in the development and progression of kidney disease in type 2 diabetes, just as they do in type 1 diabetes. Whether podocyte detachment creates conduits for proteins to escape the glomerular circulation and reduced endothelial fenestration lowers glomerular hydraulic permeability requires further study.

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Correlations of albumin/creatinine ratio (ACR) or glomerular filtration rate (GFR) with percentage of podocyte detachment or percentage of normally fenestrated endothelium. (a, b) ACR (Pearson's r − 0.43, P = 0.0009) and GFR (Pearson's r = − 0.29, P = 0.084) as a function of percentage podocyte detachment in 37 Pima Indians with type 2 diabetes mellitus. The linear functions were not changed substantially by omission of the two individuals with the greatest amount of podocyte detachment. GBM, glomerular basement membrane. (c, d) ACR (Pearson's r = −0.51, P = 0.001) and GFR (Pearson's r = 0.45, P = 0.0005) as a function of the percentage of normally fenestrated endothelium in the same individuals. Regression lines and 95% confidence intervals are shown.
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Figure 3: Correlations of albumin/creatinine ratio (ACR) or glomerular filtration rate (GFR) with percentage of podocyte detachment or percentage of normally fenestrated endothelium. (a, b) ACR (Pearson's r − 0.43, P = 0.0009) and GFR (Pearson's r = − 0.29, P = 0.084) as a function of percentage podocyte detachment in 37 Pima Indians with type 2 diabetes mellitus. The linear functions were not changed substantially by omission of the two individuals with the greatest amount of podocyte detachment. GBM, glomerular basement membrane. (c, d) ACR (Pearson's r = −0.51, P = 0.001) and GFR (Pearson's r = 0.45, P = 0.0005) as a function of the percentage of normally fenestrated endothelium in the same individuals. Regression lines and 95% confidence intervals are shown.

Mentions: Spearman's correlations between structural and functional parameters for diabetic subjects are shown in Table 3; relationships between PD or ECF and functional characteristics are shown in Figure 3. Fractional mesangial area correlated positively with ACR (r=0.55, p<0.001) and negatively (r=−0.35, p=0.036) with GFR. Total surface area (SA) correlated positively with GFR (r=0.49, p=0.002). Foot process width (FPW) correlated positively with ACR (r=0.55, p<0.001), GBM width (r=0.38, p=0.020), and fractional mesangial area (r=0.59, p<0.001). The percentage of PD correlated positively with ACR (r=0.36, p=0.028) and negatively with podocyte number per glomerulus (r= −0.41, p=0.011). The percentage of fenestrated endothelium correlated negatively with GBM width (r=−0.38, p=0.019), FIA (r= −0.33, p=0.049), fractional mesangial area (r=−0.54, p<0.001) and ACR (r=−0.45, p=0.006) and positively with filtration surface area density (r=0.65, p<0.001) and GFR (r=0.44, p=0.006). The percentage of PD and of ECF were not correlated (r=−0.25, p=0.131).


Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy.

Weil EJ, Lemley KV, Mason CC, Yee B, Jones LI, Blouch K, Lovato T, Richardson M, Myers BD, Nelson RG - Kidney Int. (2012)

Correlations of albumin/creatinine ratio (ACR) or glomerular filtration rate (GFR) with percentage of podocyte detachment or percentage of normally fenestrated endothelium. (a, b) ACR (Pearson's r − 0.43, P = 0.0009) and GFR (Pearson's r = − 0.29, P = 0.084) as a function of percentage podocyte detachment in 37 Pima Indians with type 2 diabetes mellitus. The linear functions were not changed substantially by omission of the two individuals with the greatest amount of podocyte detachment. GBM, glomerular basement membrane. (c, d) ACR (Pearson's r = −0.51, P = 0.001) and GFR (Pearson's r = 0.45, P = 0.0005) as a function of the percentage of normally fenestrated endothelium in the same individuals. Regression lines and 95% confidence intervals are shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472108&req=5

Figure 3: Correlations of albumin/creatinine ratio (ACR) or glomerular filtration rate (GFR) with percentage of podocyte detachment or percentage of normally fenestrated endothelium. (a, b) ACR (Pearson's r − 0.43, P = 0.0009) and GFR (Pearson's r = − 0.29, P = 0.084) as a function of percentage podocyte detachment in 37 Pima Indians with type 2 diabetes mellitus. The linear functions were not changed substantially by omission of the two individuals with the greatest amount of podocyte detachment. GBM, glomerular basement membrane. (c, d) ACR (Pearson's r = −0.51, P = 0.001) and GFR (Pearson's r = 0.45, P = 0.0005) as a function of the percentage of normally fenestrated endothelium in the same individuals. Regression lines and 95% confidence intervals are shown.
Mentions: Spearman's correlations between structural and functional parameters for diabetic subjects are shown in Table 3; relationships between PD or ECF and functional characteristics are shown in Figure 3. Fractional mesangial area correlated positively with ACR (r=0.55, p<0.001) and negatively (r=−0.35, p=0.036) with GFR. Total surface area (SA) correlated positively with GFR (r=0.49, p=0.002). Foot process width (FPW) correlated positively with ACR (r=0.55, p<0.001), GBM width (r=0.38, p=0.020), and fractional mesangial area (r=0.59, p<0.001). The percentage of PD correlated positively with ACR (r=0.36, p=0.028) and negatively with podocyte number per glomerulus (r= −0.41, p=0.011). The percentage of fenestrated endothelium correlated negatively with GBM width (r=−0.38, p=0.019), FIA (r= −0.33, p=0.049), fractional mesangial area (r=−0.54, p<0.001) and ACR (r=−0.45, p=0.006) and positively with filtration surface area density (r=0.65, p<0.001) and GFR (r=0.44, p=0.006). The percentage of PD and of ECF were not correlated (r=−0.25, p=0.131).

Bottom Line: Podocyte detachment correlated significantly with podocyte number per glomerulus and albuminuria.The mean percentage of endothelial cell fenestration was significantly lower in macroalbuminuria (19.3%) than in normal albuminuria (27.4%) or microalbuminuria (27.2%) and correlated significantly with glomerular basement membrane thickness, albuminuria, fractional mesangial area, and the glomerular filtration rate (iothalamate clearance).Whether podocyte detachment creates conduits for proteins to escape the glomerular circulation and reduced endothelial fenestration lowers glomerular hydraulic permeability requires further study.

View Article: PubMed Central - PubMed

Affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85014-4972, USA. rnelson@nih.gov

ABSTRACT
Podocyte detachment and reduced endothelial cell fenestration and relationships between these features and the classic structural changes of diabetic nephropathy have not been described in patients with type 2 diabetes. Here we studied these relationships in 37 Pima Indians with type 2 diabetes of whom 11 had normal albuminuria, 16 had microalbuminuria, and 10 had macroalbuminuria. Biopsies from 10 kidney donors (not American Indians) showed almost undetectable (0.03%) podocyte detachment and 43.5% endothelial cell fenestration. In patients with type 2 diabetes, by comparison, the mean percentage of podocyte detachment was significantly higher in macroalbuminuria (1.48%) than in normal albuminuria (0.41%) or microalbuminuria (0.37%). Podocyte detachment correlated significantly with podocyte number per glomerulus and albuminuria. The mean percentage of endothelial cell fenestration was significantly lower in macroalbuminuria (19.3%) than in normal albuminuria (27.4%) or microalbuminuria (27.2%) and correlated significantly with glomerular basement membrane thickness, albuminuria, fractional mesangial area, and the glomerular filtration rate (iothalamate clearance). Podocyte detachment and diminished endothelial cell fenestration were not correlated, but were related to classic lesions of diabetic nephropathy. Thus, our findings confirm the important role these injuries play in the development and progression of kidney disease in type 2 diabetes, just as they do in type 1 diabetes. Whether podocyte detachment creates conduits for proteins to escape the glomerular circulation and reduced endothelial fenestration lowers glomerular hydraulic permeability requires further study.

Show MeSH
Related in: MedlinePlus