Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules?

Abstract

Numerous studies in the last decade have set out to clarify the process of progressive deterioration of renal function that occurs in animals and humans after a critical reduction in the number of nephron units either by surgical ablation or by various diseases. Most of these studies were stimulated by Brenner, Meyer and Hostetter's provocative review on 'Dietary protein intake and the progressive nature of kidney disease' published in the New England Journal of Medicine in 1982. This view focused for the first time on the possibility of a common hemodynamic pathway responsible for the progression of renal disease independent of the initial injury. According to Brenner's group hypothesis, the fundamental lesion responsible for progressive renal insufficiency was sclerosis of the glomerular capillary tuft resulting from sustained elevation of glomerular pressures and flows in remnant glomeruli after the loss of a critical number of functioning nephrons. Most of the subsequent studies followed this original interpretation. However, since measurement of glomerular capillary pressures did not produce uniform results in the various models, some of them challenged the hypothesis of hemodynamically-mediated glomerular injury suggesting alternative mechanisms. Thus disorders of lipid metabolism, activation of coagulation and intraglomerular thrombosis, intrarenal calcium deposits and glomerular hypertrophy, all have been claimed as key determinant for glomerulosclerosis. Indeed, in some models correction of these abnormalities prevented renal disease progression. However, none of these studies convincingly clarified the issue of a common determinant of renal disease progression. This review offers and integrated interpretation of renal disease progression, at least in rat models. We have documented that glomerular obsolescence induced by surgery, aging or some toxins share a sustained abnormality in glomerular permeability to macromolecules that is long lasting and can be regarded as the common determinant of glomerulosclerosis more than as a consequence of glomerular injury. There are at least two pathways of disruption of glomerular permselectivity in rat models of glomerulosclerosis. One is through increased glomerular capillary pressures which determine a mechanical injury to the glomerular capillary barrier and operate for instance in remnant kidney or experimental diabetes. The other is initiated by toxins or immune reactants that may alter glomerular permselectivity even in the absence of increased glomerular capillary pressure. Once glomerular permselectivity has been disrupted, the disease progresses to end-stage renal failure by a process triggered by the exposure of renal cells to the abnormal protein load which does not depend on the initial injury. Thus, mesangial cells exposed to an abnormal protein traffic may proliferate and synthesize mesangial matrix in excessive amounts. Similarly, glomerular epithelial cells undergo structural and functional modifications, including focal detachment from basement membrane, with further increase of the passage of macromolecules across the glomerular capillaries. This results in an increased amount of proteins in the ultrafiltrate that overwhelms proximal tubular epithelial cell reabsorption capacity. The abnormal amount of protein delivered to distal tubuli leads to the formation of casts breaking off the tubular basement membrane, and to an insterstitial inflammatory reaction. Inflammatory cells surrounding the glomeruli that subsequently become sclerotic very probably play a major role in this process. They may do so by releasing factors that can - as has been recently documented - induce mesangial cell proliferation and promote abnormal generation of mesangial matrix. If this interpretation is correct, maneuvers that limit abnormalities in glomerular capillary permeability will have a pivotal role in retarding renal disease progression, at least in experimental models. Whether these concepts apply to human renal disease progression is a possibility that merits appropriate investigation. With appropriate experiments the question of whether glomerulosclerosis is a consequence of alterations in membrane permselective properties may hopefully have a definitive answer in the near future, at least in animals. The most promising model appears the model of spontaneous glomerulosclerosis occurring in male MWF/ztm. The possibility to reduce both proteinuria and glomerulosclerosis with enalapril in such a model, which is devoid of glomerular capillary hypertension, represents a powerful investigative tool.