Mechanisms Of Albuminuria

Even if correlation between albumin excretion and structural lesions have been observed we still lack the deeper insight into the mechanisms behind the increment in albumin leakage. The increase in BM thickness in itself is unlikely to be responsible for the increased albumin excretion rate, but qualitative changes, e.g. reduced negative charge and/or presence of large pores, which develop concomitantly with the increase in thickness, may be decisive.

The urinary excretion of negatively charged proteins, e.g. albumin, is restricted by the negatively charged basement membrane. In the aforementioned prospective study [6] the charge selectivity index (clearances of IgG/IgG4) was not associated with BM thickness at the beginning of the study. However, a striking correlation was found between the increase of BM thickness and the loss of charge selectivity during the study [43]. This may imply that the increase in BM thickness takes place concomitant with qualitative changes (e.g. loss of negative charge).

It is not known which substances that are responsible for the early thickening of BM and matrix expansion in diabetes. In the BM collagen IV predominates quantitatively, while laminin and heparan-sulphate proteoglycan probably play an important role as well. The mesangial matrix contains in addition collagen V, fibronectin, and chondroitin/dermatan sulfate proteoglycans [44]. Short-term experimental studies show that hyperglycaemia induces increased production of most of the aforementioned proteins [45-47], increased levels of the proteins' respective mRNA [48,49], increased matrix synthesis [50], and reduced amount of heparan-sulphate proteoglycan [51,52]. Furthermore, hyperglycaemia leads to accumulation of advanced glycated end products of proteins (AGE). These glycated proteins do contribute to the formation of pathological tissue deposits [53]. In our study [31] the level of serum-AGEs at the start of the study was related to the changes in structural parameters during the study period [54]. In experimental diabetes accumulation of AGE was inhibited by aminoguanidin and ACEI [55].

An interesting observation in advanced glomerulopathy [56] and in the early stage in microalbuminuric patients [57] is capillary loops with extremely thin and fluffy BM, contrasting markedly the other capillaries in the biopsies. They may be an expression of a compensatory glomerular growth, setting in at this early stage, and could represent the large pores.

The BM-thickening develops in parallel with matrix expansion. Matrix changes, quantitative and qualitative, may interfere with the function of the mesangial cells [58]. Mesangial cell function plays a role in many aspects of glomerular physiology [59] and one immediate consequence of the matrix expansion is that the distance between mesangial cells increases. This may impair the cell-to-cell interaction.

A rather new area of interest in diabetic nephropathy is the podocytes and the slit diaphragms. A longitudinal study provided evidence for an association between loss of podocytes and AER [60]. In young patients with normo- and microalbuminuria Berg et al found a positive correlation between AER and foot process (nm) width and a negative correlation with the slit pore (^m-2), [14]. In experimental diabetic nephropathy amelioration of the podocyte foot process broadening was obtained by RAS-blockade [61] and in biopsies from patients with type-2 diabetes, the expression of messenger-RNA of one of the slit pore membrane proteins, nephrin, was modulated by ACEI [62]. Hyperglycaemia and TGF-^1 in concert seem to induce the production of collagen IV and VEGF in the podocytes [63].

Fig. 3 Urinary albumin excretion (UAE) expressed in log values, in relation to a. foot process width (r=0.645, n=30, /><0.001) and b. length density of filtration slits Lv (slit pore/glom) (r=0.683, n=30, ^<0.001)

Altogether, the present data indicate that the increased loss of albumin across the glomerular filtration barrier is a sign associated with early structural lesions of diabetic glomerulopathy and that the further development can be arrested or at least slowed by intensive insulin and/or antihypertensive treatment.


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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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