Whole body capillary exchange of albumin. Alterations in diabetic microangiopathy.

Until the mid eighties most conceptual knowledge of peripheral transcapillary plasma protein transport has been based on experiments with the lymph collection methods, picturing macromolecular exchange as a slow, mainly unidirectional flux from plasma to lymph. All sieving or restriction is assumed to occur at the capillary membrane level reducing interstitial as well as lymphatic plasma protein concentrations. However, in newer experiments using rapidly resolving tracer techniques, transcapillary albumin fluxes are found 10 to 20 times higher than the lymphatic return. This may imply serial barriers to plasma-lymph transport, i.e. a relatively permeable porous endothelial barrier, and a tight interstitial barrier. The possible outline of this hypothesis and its major implications are discussed. The interstitial barrier is assumed to be formed by the contents of the interstitial space itself, preferentably by the anionic glycosaminoglycanes (GAGs) of the interstitial gel matrix. In the interface between the barriers immediately below the endothelial lining, interstitial plasma protein concentrations may reach close to plasma levels. Thus diseases or conditions that alter plasma protein concentrations, plasma protein fluxes or matrix composition are likely to promote coagulation or precipitation in this interzone. In diabetic microangiopathy loss of fixed anionic charge in the glomerular basal membrane is an important initial step leading to proteinuria. However, the loss of anionic charge seems to be general, afflicting the GAG components of the glomerular membrane, the interstitial matrix, and in the walls of large arteries. By raising the interstitial protein flux as well as by decreasing the antiprecipitating and anticoagulative properties of the matrix, this may lead to increased precipitation. It may therefore be the single pathogenetic factor most likely to explain the perivascular hyalinosis and accelerated atherosclerosis of the disease. Very similar mechanisms may enhance atherosclerosis in nondiabetic patients precipitated by factors like elevated plasma levels of lipoproteins and fibrinogen, aging, and hypertension.