Pathways to Recovery and Loss of Nephrons in Anti-Thy-1 Nephritis

Abstract

Abstract. The present histopathologic study of anti-Thy-1.1 models of mesangioproliferative glomerulonephritis in rats provides a structural analysis of damage development and of pathways to recovery and to nephron loss. As long as the disease remains confined to the endocapillary compartment, the damage may be resolved or recover with a mesangial scar. Irreversible lesions with loss of nephrons emerge from extracapillary processes with crucial involvement of podocytes, leading to tuft adhesions to Bowman's capsule (BC) and subsequent crescent formation. Two mechanisms appeared to be responsible: (1) Epithelial cell proliferation at BC and the urinary orifice and (2) misdirected filtration and filtrate spreading on the outer aspect of the nephron. Both may lead to obstruction of the tubule, disconnection from the glomerulus, and subsequent degeneration of the entire nephron. No evidence emerged to suggest that the kind of focal interstitial proliferation associated with the degeneration of injured nephrons was harmful to a neighboring healthy nephron.Glomerular diseases starting with mesangiolysis have a high probability of recovery. However, not all nephrons recover; some always undergo destruction; we therefore raised the following questions: (1) what is the crucial stage of damage that determines the subsequent recovery or progression and (2) what are the sequences of events leading either to the restitution or to the degeneration of the respective nephron? Thus, our primary question was not why a nephron degenerated or recovered but how these outcomes were achieved. A glomerulus, and all the more a nephron, are both complex structures; we therefore wanted to analyze to which extent the loss and, on the other hand, the reestablishment of the higher order structure were decisive for damage progression and recovery, respectively.The most common models used to study mesangiolysis and damage development starting therefrom are those that induce mesangial cell lysis with antibodies against the Thy 1.1 antigen of mesangial cells; the resulting disease is generally referred to as anti-Thy-1 nephritis. The classical experiments were performed either with polyclonal antibodies (1,2) or with the monoclonal antibody OX-7 (3). More recently, the monoclonal antibody 1-22-3 (4) has been shown to produce more severe damage. Administration of these antibodies in rats leads to a brisk complement-dependent lysis of the mesangial cells followed by the development of a mesangioproliferative glomerulonephritis.We used both the OX-7 and the 1-22-3 antibodies in two originally separate studies. Because disease development was more or less identical in both models, we combined both studies. This permitted us to analyze complete pathways of damage development and to provide step-by-step sequences of events leading from mesangiolysis via various intermediate stages to either the recovery or loss of a nephron. We think that these results are of considerable general interest when asking how nephrons degenerate in chronic renal disease. M...

Reversal of Glomerular Lesions Involves Coordinated Restructuring of Glomerular Microvasculature

“…Previous authors emphasized the similarities and potentially analogous mechanistic pathways when microvascular repair and glomerular development are compared (8,27). An early proliferative response of glomerular endothelial cells during the development of glomerular lesions has also been documented (28).…”

“…One exception is a study (8) in the anti-Thy-1 nephritis model that does not allow, however, direct comparison with reversal of glomerulosclerosis in the noninflammatory renal ablation model.…”

“…It has been shown that remodeling of the glomerulus recapitulates some of the processes, which are taking place during organogenesis and glomerular development in the fetal phase (8), but several questions had remained unresolved. Do glomerular volume and the capillary tuft volume change in parallel?…”

From tubular sublimate nephropathy via urinary concentrating mechanism to glomerular disease—Wilhelm Kriz’s contribution to modern nephrology

“…Inflammatory glomerular degeneration was analyzed in a number of studies together with yet another long-term guest and collaborator from Japan, Isao Shirato, along with his postdoctoral fellow Marcus Möller, Jürgen Floege from Aachen, Michel LeHir from Zurich, Roger Wiggins from Ann Arbor, Larry Holzman from Philadelphia, and the Bachmann group [47,63,73,82,92,93,97]. Chiefly, the basic structure-related idea was developed that podocytes, when challenged in glomerular disease, develop general, stereotyped structural changes which include hypertrophy, cell body attenuation, pseudocyst formation, foot process effacement, intracellular accumulation of debris, and detachment from the glomerular basement membrane [93].…”

“…Studying recovery from damage, remodeling of the foot processes was considered to follow a programmed course in which effacement was considered an adaptive change that can be transitory in nature. Studying mesangioproliferative glomerulonephritis in anti-Thy-1 nephritic rats, a closer look on the role of Bowman's capsule came into play and a meticulously developed concept for the chain of events including the deleterious extracapillary changes, adhesion of the podocytes to Bowman's capsule, and the consequent route of misdirected glomerular filtrate obstructing and disconnecting the tubule, eventually leading to degeneration of the entire nephron, was a novelty with significant impact on the pathologist's view of inflammatory degenerative changes of the glomerulus [47]. It was further stressed then that no evidence could be found that injured nephrons were harmful to neighboring healthy nephrons, a view which was debated substantially at that time in the light of prevailing concepts of tubulointerstital fibrotic changes.…”