Reversal of Glomerular Lesions Involves Coordinated Restructuring of Glomerular Microvasculature

Abstract

Abstract. There is increasing evidence from both human and experimental studies that at least partial reversal of glomerulosclerosis can be achieved by glomerular remodeling. This requires substantial changes in glomerular architecture, specifically of glomerular capillaries. It was the purpose of the present study to characterize the stereologic and topologic characteristics of glomerular capillaries when partial reversal of glomerular lesions is achieved by high-dose angiotensinconverting enzyme inhibitor treatment. Sham-operated male Sprague-Dawley rats were compared with subtotally nephrectomized (SNX) rats. The latter were kept untreated for 8 wk and subsequently randomly divided into one group that was continued without treatment and another group that was treated with enalapril (48 mg/kg body wt per d administered in the drinking fluid for 4 wk). Renal morphology was evaluated after 8 or 12 wk, respectively, by stereologic techniques after pressure-controlled perfusion fixation. In SNX rats at 8 and particularly at 12 wk, the glomerulosclerosis index was significantly higher than in sham-operated rats. At 12 wk, it was lower in rats that had been treated for 4 wk with enalapril compared with untreated SNX rats, suggesting partial reversal of glomerular lesions. This was associated with a decrease in mean glomerular volume and mean glomerular tuft volume, a reduced number of capillaries per glomerulus, and reduced total length of capillaries per glomerulus but without any significant change in the length of individual capillaries. The numerical capillary density (Euler number density) as an index of topologic complexity did not change. The total capillary surface area per glomerulus was strikingly increased after subtotal nephrectomy and partially reversed after enalapril. This was accounted for primarily by fewer capillaries without any change in diameter. In parallel, the number of endothelial cells per glomerulus was strikingly increased after subtotal nephrectomy and decreased with enalapril treatment, but endothelial cell volume remained elevated. The study shows harmonious coordinate remodeling of the entire glomerulus during regression of glomerular lesions after subtotal nephrectomy. Proportionate reduction of glomerular volume and capillary number without change of individual capillary length were found. The numerical capillary density of the tuft therefore remained unchanged.For a long time, the goal of therapeutic intervention in glomerular disease was to halt progression (1). More recently, it had become apparent that glomerular lesions in progressive renal diseases can be reversed to some extent presumably if there has been no major loss of podocytes. This concept was based on clinical observations of partial reversal of basal membrane thickening and mesangial expansion in diabetic patients several years after isolated pancreas transplantation (2). Furthermore, reversal of renal lesions was seen in patients with clinically cured IgA glomerulonephritis (3) as well as in experimental studies of ...

Role of Remission Clinics in the Longitudinal Treatment of CKD

“…44 This remodeling of glomerular architecture suggests some form of regeneration of the capillary network. 45,46 Actually, three-dimensional reconstruction studies of the glomerular tuft showed that RAS inhibitor therapy enlarged the volume of intact capillaries by up 40%-structural changes that allowed the kidney to regain function with time. 47 Glomerular remodeling also was observed in 10 patients with type 1 diabetes after 10 yr of normoglycemia induced by pancreatic transplantation.…”

Increased Capillary Branching Contributes to Angiotensin Type 1 Receptor Blocker (ARB)–Induced Regression of Sclerosis

“…Regression was associated with a decrease in mean glomerular volume, a decreased number of capillary segments per glomerulus, and a decreased total length of capillaries per glomerulus but without any significant change in the length of individual capillary segments and no change of numerical capillary density of the tuft. 10 We then chose to expand on these previous approaches by studying branching patterns of glomerular topology by confocal analysis coupled with a novel graph theory analysis of the morphological complexity of the glomerulus in progressive disease versus regression states. Limitations of this approach include the technical limits on depth of glomeruli that can be adequately visualized and thus analyzed by this method.…”

“…New glomeruli cannot be generated after term birth in humans, but segmentally scarred glomeruli could potentially undergo regression of existing sclerosis by resorption of areas with matrix accumulation and enhanced growth of the remaining capillary loops. 10,12 Our previous data have shown that such ARBinduced improvement in sclerosis was indeed linked to less matrix accumulation in glomeruli, with an associated decrease in plasminogen activator inhibitor-1 (PAI-1) and increased plasmin activity. 4 PAI-1 is the major inhibitor of the plasmin/plasminogen activator system and inhibits both fibrinolysis and proteolysis.…”

Erratum: Maturational regression of glomeruli determines the nephron population in normal mice

“…We initially used coefficients of kidney density (1.04 g/cm 3 ) and shrinkage (1.08) established and commonly used for adult rats 14 . However, these coefficients yielded much higher number of glomeruli than those measured by the fractionator/dissector method at all time points measured.…”