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A morphologic study of 103 dogs, including two with renal amyloidosis, showed that different types of diffuse glomerulonephritis are correlated with different age groups. Membranous and membranoproliferative glomerulonephritis were more common in middle-aged and older animals, whereas mesangial lesions were found predominantly in younger dogs and considered to be early glomerular changes. Glomerulonephritis largely occurred independently of interstitial nephritis. The incidence of interstitial lesions was 71%. Chronic interstitial nephritis was rare in dogs under 1 year old. Glomerulonephritis did not seem to induce interstitial nephritis. Glomerulonephritis occurred not only in kidneys with severe interstitial damage, but also in those with slight damage. The indicated that glomerulonephritis occurred independently of interstitial nephritis. In end-stage kidneys with severe fibrosis, mesangial changes seemed to predominate.
In heterologous immune complex glomerulonephritis glomerular deposition of immune complexes occurs immediately after an injection with heterologous antibody directed against antigen, derived from the brush border of the tubules. The injected antibody is thought to combine with circulating Fx1A antigen to form immune complexes which subsequently are deposited in the glomeruli. However, perfusion of rat kidneys in absence of this antigen likewise resulted in prompt localization of immune complexes along the glomerular basement membrane. Further, Fx1A antigen was shown to be present in the capillary wall, especially in the filtration slits and on the cell membrane of epithelial cells. From these findings it was concluded that in this model of glomerulonephritis the deposited immune complexes are formed locally instead of being deposited from the circulation. This concept of "fixed antigen" may also be relevant to the pathogenesis of other forms of experimental glomerulonephritis and probably also for human glomerulonephritis.
In the morphological course of a poststreptococcal type glomerulonephritis in a 37-year old patient without evidence of streptococcal infection crescents of Bowman's capsule developed after 4 months. The clinical course was rapidly progessive (the patient was uremic 5 months after onset) in contrast to the normal fair prognosis of the poststreptococcal type glomerulonephritis. Two renal biopsies were examined at an interval of 4 months. Both showed closely packed immunecomplex deposits (humps) on the glomerular immunecomplex deposits in the poststreptococcal type glomerulonephritis is a prognostically unfavourable sign.
Intravenous injections of mice three times a day for 3 days with soluble complexes of 3 mg. of moderately avid rabbit antibody to chicken egg albumin prepared by dissolution of equivalence precipitates in 80 times the equivalence amount of antigen resulted in a combined mesangial and loop localization of immune complexes. With complexes formed from antibody of low avidity, injected four times a day for 3 days, a predominately subepithelial loop deposition of complexes was observed. Complexes formed from moderately avid antibody gave rise to a mainly mesangiopathic glomerulonephritis, whereas low avidity complexes were associated with a diffuse glomerulonephritis. These results, in combination with those of the previous paper, successfully reproduce the basic form of the lesions seen in active immune complex disease by passive means and suggest that antibody avidity is a major determinant of the site of localization of immune complexes and therefore of the morphologic form of the resulting glomerulonephritis. The importance of these observations for our understanding of the pathogenesis of human immune complex disease is considered.
Renal biopsies of 44 patients with endocapillary acute glomerulonephritis (gn) and 64 patients with moderately severe mesangioproliferative gn were investigated morphometrically (point-counting-method, tubulometry). In both gn's statistically significant positive corrleations between relative interstitial volume and the concentration of serum creatinine at the time of biopsy were found. Despite severe glomerular lesions the serum creatinine concentration is not increased in most cases of endocapillary acute gn, providing the relative interstitial volume is not increased by more than 15%. Increased serum creatinine concentration without a markedly enlared interstitium was found in 11 cases of endocapillary acute gn with clinically and morphologically proven acute renal failure. In these cases the glomerular function is probably impaired by the Thurau-mechanism. In all other patients, especially in those with moderately severe mesangioproliferative gn, the serum creatinine concentration rises with an enlargement of relative interstitial volume. This reduction of renal function may be explained by a decrease to the total cross-sectional area of postglomerular vessesl, caused by interstitial fibrosis. That may possible lead to diminished renal blood flow and glomerular filtration with an increase of the serum creatinine concentration.
One-shot active immune complex glomerulonephritis was induced in rabbits by intravenous bovine serum albumin (250 mg. per kg.) and the mechanism of glomerular hypercellularity investigated. Most of the extra cells were mononuclear with few polymorphonuclear leukocytes. Fibrin was present in severe lesions. Glomerular mitoses were seen in normal kidneys but were more common in hypercellular glomeruli. This is direct evidence of local proliferation. Also, biopsies taken 1 hour after giving tritiated thymidine contained locally labeled cells. The mitotic rate and degree of local labeling both varied in proportion to the degree of hypercellularity. By electron microscopy both mesangial and endothelial cells were identified in mitosis. The majority of the mononuclear cells in the hypercellular glomeruli could not be identified by position or ultrastructure. Infiltration by nonglomerular cells was confirmed by the presence of macrophages, lymphocytes, and plasma cells.
Intravenous injection of mice with soluble complexes of highly avid rabbit antibody to egg albumin, prepared by dissolution of equivalence precipitates in large quantities of antigen, resulted in a purely mesangial localization of the complexes. When animals received three injections of complexes per day for 1 day it was noted that precipitates dissolved in 80 times the equivalence amount of antigen produced slight mesangial changes. When such complexes were injected for 2 or 3 days, outright mesangiopathic glomerulonephritis was observed in an increasing proportion of the animals. Equivalent amounts of antigen alone did not produce lesions.
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Glomerulonephritis constitutes an important category of renal diseases in animals and has been recognized with increasing frequency in the last decade. We report here the comparative morphologic aspects of glomerulonephritis as a naturally occurring disease of animals. We briefly review the immunopathogenesis of glomerulonephritis. The morphology of renal lesions occurring in glomerulonephritis in dogs, cats, cattle, sheep, horses and swine has been reviewed with emphasis on the range and specificity of various glomerular lesions and on the comparison of lesions between various species. A distinction was made between glomerulonephritis as a primary disease entity and glomerulonephritis associated with other disease processes. Primary idiopathic glomerulonephritis occurred in all species but was most commonly recognized as a clinically important disease in dogs and cats. Glomerulonephritis also occurred in association with other diseases such as equine infectious anemia, chronic hog cholera, canine pyometra, dirofilariasis, feline leukemia virus infection and canine systemic lupus erythematosus.
Thirty-four patients with overt glomerulonephritis and chronic liver disease were studied. Kidney specimens were examined by light, electron and immunofluorescence microscopy. Plasma C3 levels were measured and a search for cryoglobulinemia was carried out in all patients. Twenty-six out of the thirty-four patients had an immune complex type glomerulonephritis (membrano-proliferative glomerulonephritis or glomerulosclerosis with mesangial deposits) suggestive of hepatic glomerulonephritis. The glomerular deposits almost always contained IgA and very frequently other immunoglobulins as well as C3. The membrano-proliferative glomerulonephritis was characterized by severe renal symptoms, mixed cryoglobulinemia and the frequent finding of low C3 levels. These data suggest that there is a linkage between liver disease and glomerulonephritis. The immunomorphological type of glomerulonephritis and the cryoglobulinemia are both suggestive of an immune complex disease. The lowering of the C3 levels could be due to activation of complement components by immune complexes, to hepatic hyposynthesis, or to a combination of the two.
Plasmapheresis together with immunosuppressive drug therapy has been used in the treatment of 17 patients with glomerulonephritis [Goodpasture's syndrome (4), systemic lupus erythematosus (4), mesangiocapillary glomerulonephritis (2), glomerulonephritis associated with cirrhosis (2), nonspecific mesangial proliferative glomerulonephritis (3), Henoch-Schoenlein purpura glomerulonephritis (1) and glomerulonephritis associated with infective endocarditis (1)]. Use of the Haemonetics Model 30 blood cell separator, exchanging two liters of plasma with 5% albumin in Hartmann's solution has provided a safe, effective but relatively expensive procedure, capable of producing a marked reduction of fibrinogen, complement components, anti-glomerular basement membrane antibody and immune complex concentrations. Removal of one or more of these factors is felt to be at least partly responsible for the improvement in renal function and clinical well-being demonstrated in patients with Goodpasture's syndrome, systemic lupus erythematosus and other forms of glomerulonephritis associated with the presence of circulating immune complexes.
Fourteen patients with membranoproliferative glomerulonephritis as their original kidney disease received 16 renal allografts. All 14 patients are alive, 11 currently have functioning allografts, and one graft was lost to recurrence of membranoproliferative glomerulonephritis. Originally depressed serum complement (C3) concentrations returned to normal soon after transplantation in those patients with no clinical evidence of recurrence. Two patients with type II membranoproliferative glomerulonephritis had recurrence of disease. Nephritic factor (C3NeF) was high in both these patients before they received their transplants and was absent soon thereafter. However, abnormally high levels were again detected in their course. The one recurrence of type I membranoproliferative glomerulonephritis was associated with depressed C3, Clq, C4 and factor B but without C3NeF activity. Despite warnings of "high risks/ and "high mortality" associated with renal transplants in patients with membranoproliferative glomerulonephritis, we, because of these results and a review of the literature, continue to recommend renal transplants from both living related (LRD) and cadaver (CAD) donors in otherwise suitable patients who have renal failure due to membranoproliferative glomerulonephritis.
As a means of studying mechanisms of response to injury in glomerulonephritis, glomeruli from normal sheep and rabbits and from sheep and rabbits with experimental crescentic glomerulonephritis have been isolated and grown in tissue culture. The cellular outgrowths from the normal and diseased glomeruli have been compared. The outgrowth of glomeruli from normal animals contained only two cell populations whose microscopic and ultrastructural appearances were of epithelial and mesangial cells. The same cells were also observed in the outgrowths of glomeruli from animals with crescenti nephritis but in addition a third population of cells was present in large numbers. These cells were identified as macrophages by their mobility, ultrastructure, phagocytic capacity, and presence of Fc receptors. Glomerular outgrowth from sheep with crescentic glomerulonephritis contained 170 +/- 20 (SEM) macrophages and outgrowths from rabbits with crescentic nephritis contained 64 +/- 6 (SEM) macrophages per glomerulus. We have previously observed large numbers of macrophages in the outgrowth of isolated glomeruli from humans with rapidly progressive crescentic glomerulonephritis. The predominance of the macrophage in cultures of glomeruli from both human and animal crescentic glomerulonephritis suggests that this is an important cell in the inflammatory reaction occurring in crescentic glomerulonephritis and may comprise a substantial proportion of the cells forming the crescent.
Proliferative glomerulonephritis was induced in rats by a single injection in the hind footpads of the glycoprotein isolated from pronase digests of homologous renal cortex, in spite of the evidence that the glycoprotein no longer possessed the antigenic activity with respect to producing the nephrotoxic antibody. In rats given the glycoprotein (without trichloroacetic acid (TCA) treatment) prepared from pronase digests of homologous renal cortex, morphologic changes of proliferative glomerulonephritis were followed (3--4 months after injection) by those of typical membranous glomerulonephritis with an immunofluorescent 'granular' pattern, but in animals which received the glycoprotein (with TCA treatment), the morphologic changes of the kidney were those of proliferative glomerulonephritis with an immunofluorescent 'mesangial' pattern throughout the whole course. Morphologic changes of membranous glomerulonephritis induced in the group given the glycoprotein (without TCA treatment) can be explained by an immune-complex mechanism, superimposed on the basic pathogenesis (common to both groups) of proliferative glomerulonephritis with immunofluorescent 'mesangial' pattern.
Proportions and total numbers of peripheral blood T and B lymphocytes as well as their activity measured in the leukocyte migration inhibition test were estimated in 47 patients with acute or chronic glomerulonephritis and in 30 individuals serving as a control group. The obtained results indicated that glomerulonephritis was associated with altered proportions of peripheral blood lymphocytes. In acute glomerulonephritis high B lymphocyte levels were found while chronic proliferative glomerulonephritis was characterized by high proportions and high absolute levels of T lymphocytes. Few months observation of T: B lymphocyte proportions during the disease indicated that exacerbation of the disease was associated with lowered proportions of T lymphocytes. Moreover, it was shown that cell mediated hypersensitivity to GBM antigens was detectable in 80% patients with glomerulonephritis and was absent from patients with pyelonephritis. The latter results indicate participation of cell-mediated hypersensitivity in pathomechanisms of glomerulonephritis in most of the patients.
Twenty-one cases of acute glomerulonephritis in children with no previous history of renal disease were studied. Urinary infection with a rising titre of serum agglutinins against the organisms isolated from urine was found in 5 cases. No evidence of previous streptococcal infection was found in these cases. In the meantime all 8 cases with post-streptococcal glomerulonephritis remained without bacteriuria. In one case acute glomerulonephritis followed virus hepatitis, and in the remaining 7 cases the cause of glomerulonephritis was unknown. It is suggested that in predisposed patients the bacteria present in urinary infections might act as antigens starting immunologic reactions in the glomeruli, leading to glomerulonephritis. The final proof of this theory awaits immunofluorescence identification of these antigens in the glomeruli.