Heymann nephritis: Mechanisms of renal injury

Abstract

The Heymann nephritis (HN) models of rat membranous nephropathy are extraordinarily valuable tools to investigate the immunopathology of glomerular subepithelial immune deposit formation and the mechanism by which such deposits injure glomeruli. The immunopathology of HN is reviewed by Brentjens and Andres in this volume [1]. In this review we will largely confine ourselves to a discussion of the mediators, mechanisms and pathophysiological consequences of renal injury in rat membranous nephropathy. The primary manifestation of glomerular injury in HN is proteinuria; however there are also subtle, but not trivial, changes in glomerular hemodynamics and tubular function, and alterations in renal hormone production. The alterations in glomerular permselectivity that lead to proteinuria closely resemble the defect in human membranous nephropathy, and the rat model has been used to study mechanisms of renal sodium retention, edema formation and metabolic abnormalities in nephrotic syndrome. Investigators have also used the HN models to study the impact of systemic hypertension on pre-existing glomerular disease, in terms of both altered glomerular function and progressive renal injury. Mostly, the mechanisms and effects of glomerular injury in rat membranous nephropathy have been investigated in the standard active and passive (PHN) models of HN; however, both models have also been extensively modified to elucidate specific mechanisms or mediators. Such modifications, which include the use of the isolated perfused kidney, renal transplantation, partial renal ablation and, more recently, cell and tissue culture, will be discussed in context later in this review. Active HN is induced by immunizing susceptible strains of rats (such as, Lewis, Fisher) with certain fractions of homologous or proximal tubular brush border and is characterized by granular glomerular capillary wall deposits of rat IgG and subepithelial electron-dense deposits after three to four weeks. Proteinuria develops in 30 to 80% of rats within eight to ten weeks of immunization. PHN is induced by a single intravenous injection of anti-brush border antiserum (anti-Fx1A) that produces IgG deposits which accumulate in glomeruli over hours and days. When an appropriate complement-fixing antiserum is used, proteinuria occurs in almost all animals within five days [2, 3]. This heterologous is then followed by an autologous phase during which rat IgG antibodies with specificity for the glomerular-bound IgG are deposited and induce a further increase in proteinuria. HN more closely resembles human membranous nephropathy in its slow evolution than does PHN and it is truly an autoimmune disease. In those HN rats that become proteinuric, urine protein excretion and glomerular dysfunction tend to be more severe than in PHN; however, the variability between animals and the duration of onset make it a less suitable model than PHN for studying the mediators of injury.