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Glomerular changes in microscopic haematuria, studied by quantitative immunoelectron microscopy and in situ
Sawsan M Jalalah1, Ibrahim H Alzahrani, Peter N Furness
1Department of Pathology, King Abdulaziz University, Jeddah, Saudi Arabia.
Background:
Haematuria of glomerular origin, even if mild, implies the development of defects in the glomerular basement membrane (GBM). In diseases where there is no infiltration of leukocytes into the glomerulus-such as thin basement membrane disease (TBMD) and histologically mild cases of IgA nephropathy (IgAN)-the mechanism by which such defects form is unclear.
Methods:
Frozen renal tissue from 18 cases of TBMD, 18 of mild IgAN and 18 cases with no detectable abnormality were studied: (i) by quantitative in situ zymography, to estimate the activity of glomerular collagenases; and (ii) by quantitative immunoelectron microscopy to estimate the amount of major basement membrane proteins per unit length and per unit area of glomerular basement membrane.
Results:
Cases of IgAN showed considerably more glomerular collagenase activity than normal (P=0.001). Thin basement membrane disease showed no difference in collagenase activity. A count of LCA-positive cells in glomeruli confirmed that the IgAN cases did not show glomerular leukocyte infiltration. Conversely, cases of IgAN showed no difference in GBM composition from normal, nor was any difference in GBM thickness detected in this group. However, cases of TBMD showed considerably less laminin (P=0.0008), fibronectin (P=0.002) and type VI collagen (P=0.0005) per unit length of basement membrane. Collagen IV showed a smaller reduction per unit length (P=0.01), but unlike the other protein studies it appeared to be present in higher concentration per unit area (P=0.03), suggesting that it is more 'compact' in TBMD disease.
Conclusions:
Two distinct mechanisms of haematuria seem to be involved in these two conditions. In IgAN there is increased activity of enzymes that can degrade GBM, probably reflecting mesangial cell activation. In TBMD an abnormal composition of the thinned GBM is confirmed. When considered with published reports of genetic abnormalities in TBMD, these results raise the possibility of an abnormal interaction between collagen IV and laminin.
Insights
Mild haematuria suggests glomerular basement membrane defects. IgA nephropathy involves increased collagenase activity, while thin basement membrane disease shows altered GBM protein composition, indicating distinct causes.
Area of Science:
- Nephrology
- Glomerular Biology
- Pathology
Background:
- Haematuria of glomerular origin indicates glomerular basement membrane (GBM) defects.
- The mechanisms causing GBM defects in thin basement membrane disease (TBMD) and IgA nephropathy (IgAN) are unclear, especially when leukocytes are not involved.
Purpose of the Study:
- To investigate the mechanisms behind GBM defects in TBMD and IgAN.
- To compare glomerular collagenase activity and GBM composition in TBMD, IgAN, and normal kidney tissue.
Main Methods:
- Quantitative in situ zymography to assess glomerular collagenase activity.
- Quantitative immunoelectron microscopy to measure GBM protein content (laminin, fibronectin, collagens IV and VI).
- Analysis of renal tissue from 18 TBMD, 18 mild IgAN, and 18 control cases.
Main Results:
- IgA nephropathy cases exhibited significantly higher glomerular collagenase activity than controls, without leukocyte infiltration or altered GBM composition.
- Thin basement membrane disease cases showed no difference in collagenase activity but had significantly reduced amounts of laminin, fibronectin, and type VI collagen per unit length of GBM.
- In TBMD, Collagen IV showed a smaller reduction per unit length but increased concentration per unit area, suggesting a more compact structure.
Conclusions:
- Two distinct mechanisms underlie haematuria in IgAN and TBMD.
- IgA nephropathy involves increased GBM-degrading enzyme activity, potentially from mesangial cell activation.
- Thin basement membrane disease is characterized by an abnormal GBM composition, possibly due to altered interactions between collagen IV and laminin.
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