A quantitative evaluation of anticoagulants in experimental nephrotoxic nephritis.

The protective effects of anticoagulants in nephrotoxic nephritis in rabbits have been studied, using various doses of heparin and defibrination with ancrod. Massive doses of heparin (2000 units/kg/day) were required before significant reduction in glomerular fibrin deposition, extracepillary cell proliferation and urea retention occurred. Doses of 300 and 1000 units/kg/day were insufficient to modify fibrin deposition and cell proliferation. Defibrination with ancrod provided protection, judged by histological and functional criteria, comparable to 2000 units of heparin/kg/day; but fibrin could still be demonstrated in the glomeruli of animals treated with 2000 units of heparin/kg/day, contrasting with the virtual absence of fibrin in animals given ancrod.     

The role of polymorphonuclear leucocytes in the autologous phase of nephrotoxic nephritis.

The role of polymorphonuclear leucocytes (PMN) in the autologous phase of nephrotoxic nephritis (NTN) in the rabbit has been investigated. Depletion of circulating PMN by nitrogen mustard protected renal function and immunofluorescent examination showed reduction in glomerular fibrin deposition. Depletion of circulating PMN using a highly specific goat anti-PMN serum (APS) provided similar protection of renal function, highly significant reduction in proteinuria and histological and immunofluorescent examination showed reduced glomerular PMN infiltration, extracapillary cell proliferation and virtual absence of fibrin deposition. Although protection by nitrogen mustard may have been partly due to immunosuppression, no reduction in antibody response was detected in the APS-treated rabbits. The results implicate the polymorph as the principal injurious agent in this model of NTN, responsible directly or indirectly for both proteinuria and glomerular fibrin deposition.     

Nephrotoxic nephritis in rabbits. The role of the sympathetic nervous system

The sympathetic nervous system and catecholamines play a major role in fibrin deposition in organs in rabbits after endotoxin administration. Glomerular fibrin deposition is also a key factor in the pathogenesis of nephrotoxic nephritis in rabbits, but the role of the sympathetic nervous system in this type of fibrin deposition has not been defined. We investigated sympathetic nervous system involvement in nephrotoxic nephritis using a model of isolated chemical sympathectomy with 6-hydroxydopamine. Different quantities of pooled nephrotoxic serum were injected intravenously into control and sympathectomized rabbits to produce a known spectrum of pathology in normal rabbits. Animals were killed and their organs were analyzed to ascertain that sympathectomy had been accomplished. Biochemical, immunohistologic, and histopathologic evaluation of the animals, comparing controls and sympathectomized rabbits, revealed no differences in the degree of renal damage for a given quantity of nephrotoxic serum. We conclude that, in the rabbit model, the sympathetic nervous system plays no significant role in the pathogenesis of fibrin deposition and glomerular damage in nephrotoxic nephritis.     

The effects of defibrination with ancrod in experimental allergic glomerular injury.

Quantitative studies of the effects of defibrination (with ancrod) have been undertaken in two forms of allergic glomerular damage, nephrotoxic serum nephritis and acute serum sickness in rabbits. No differences in intrarenal fixation of nephrotoxic antibody, complement activation or host antibody response were detected between defibrinated and untreated rabbits with nephrotoxic serum nephritis. Defibrination prevented intraglomerular fibrin deposition in this disease; but some glomerular damage as shown by a rise in blood urea and endothelial proliferation still occurred in defibrinated animals. No differences in immune elimination of BSA, circulating immune complex formation or intrarenal localization of immune complexes were noted in defibrinated animals with acute serum sickness. No intraglomerular fibrin deposition was detected in treated or untreated animals in this disease model. It is concluded that the protective effects of ancrod are directly related to defibrination, and not to any other modification of allergic events.     

Tissue plasminogen activator therapy of rabbit nephrotoxic nephritis.

To study the efficacy of tissue plasminogen activator (PA) therapy to prevent deteriorating renal function in experimental proliferative glomerulonephritis we used a model of nephrotoxic nephritis induced in rabbits by injection of antiglomerular basement membrane antiserum. Saline or recombinant tissue plasminogen activator (rt-PA, 1.3 mg/kg body weight) was infused daily for 7 days starting from day 7 after the injection of antiglomerular basement membrane antiserum when the disease had been already triggered. Animals were killed on day 14. Rabbits given saline had abundant deposits of fibrin and crescents in about 67% of glomeruli. rt-PA significantly protected animals from glomerular fibrin deposition and crescent formation with respect to saline-treated animals. Renal function measured as creatinine clearance was dramatically impaired in rabbits given saline. Treatment with rt-PA ameliorated the renal function impairment of nephrotoxic nephritis. rt-PA did not produce a systemic fibrinolytic state as indicated by alpha 2-antiplasmin level measurement. These results suggest that tissue PA may have important implications in preventing renal function deterioration in humans with crescentic glomerulonephritis and fibrin depositions.     

The effect of defibrination on macrophage participation in rabbit nephrotoxic nephritis: studies using glomerular culture and electronmicroscopy.

Recent studies in experimental crescentic glomerulonephritis, using the technique of glomerular culture, have shown that the macrophage is a major cell type present within the glomeruli and developing crescents. It has been suggested that their accumulation is a consequence of glomerular fibrin deposition. The effect of defibrination with ancrod on the cellular events occurring in experimental crescentic glomerulonephritis in the rabbit was therefore assessed in this disease using the techniques of culture of isolated glomeruli, electronmicroscopy or renal tissue, and light microscopy. Defibrinated animals developed only minimal renal impairment, virtually no fibrin deposition in Bowman's Space and only a mild degree of crescent formation, in contrast to the severe renal failure, fibrin deposition and crescent formation that occurred in the untreated animals. The culture of isolated glomeruli and electronmicroscopy of intact renal tissue demonstrated large numbers of macrophages within and emerging from glomeruli of both defibrinated and untreated animals. However, only in untreated animals were macrophages seen to migrate into Bowman's Space, phagocytose fibrin, transform into epithelioid cells and accumulate to form crescents. These studies suggest that fibrin deposition in Bowman's Space is the major stimulus to the macrophage migration from capillary loops and accumulation in Bowman's Space. However, fibrin deposition does not appear to be the stimulus to macrophage accumulation within capillary loops as this event was not affected by defibrination.     

The Macrophage in the Development of Experimental Crescentic Glomerulonephritis: Studies Using Tissue Culture and Electron Microscopy

The role played by the macrophage in the development of injury in rabbit nephrotoxic nephritis (NTN) has been assessed by electron microscopy and glomerular culture of renal tissue obtained by several biopsies during the course of the disease. These observations have been correlated with the other immune, cellular, and biochemical events occurring in the glomerulus, ie, deposition of immunoglobulin and complement, proteinuria, polymorphonuclear leukocyte (PMN) exudation, fibrin deposition, crescent formation, and renal failure. A biphasic macrophage accumulation was detected, corresponding to the heterologous and autologous phases of the disease. In the autologous or crescentic phase, macrophages accumulated within the glomerular tuft from Day 5; their appearance coincided with the accumulation of PMN and development of proteinuria. Fibrin deposition in Bowman's space, which commenced on Days 6 and 7, was rapidly followed by the migration of macrophages from the glomeruli into Bowman's space. Within Bowman's space, macrophages were observed to phagocytose fibrin, transform into epithelioid and giant cells, and accumulate to form a substantial proportion of the cells forming the crescent. The inflammatory process of PMN exudation, macrophage accumulation, fibrin deposition, and crescent formation and the degree of renal failure reached a maximum by Days 12 to 14. Thereafter, resolution of the inflammatory process occurred so that by Day 40 macrophages had disappeared from the glomeruli. However, varying degrees of glomerular damage and renal failure persisted, occurring largely as a result of glomerulosclerosis and sclerosis of crescents. The tissue culture studies also demonstrated mesangial cell proliferation during the inflammatory process but did not show any abnormality of epithelial cell activity. This study demonstrates that the macrophages participate in NTN by accumulating in damaged glomeruli then migrating into Bowman's space (probably in response to fibrin deposition) where they undergo granulomatous transformation and accumulate, contributing to crescent formation.     

Quantitative assessment of the effects of platelet depletion in the autologous phase of nephrotoxic serum nephritis.

The effects of platelet depletion with antibody have been studied in two models of the autologous phase of nephrotoxic nephritis in the rabbit. In the 'telescoped' model (animals pre-immunized to sheep IgG injected with sheep nephrotoxic antibody), platelet depletion did not alter intraglomerular fibrin deposition or evidence of glomerular damage, but did significantly reduce proteinuria during the first 3 days of the 5 day experiment. In the 'passive' model (animals injected with hyperimmune rabbit antiserum to sheep IgG 48 hr after sheep nephrotoxic antibody and killed 3 hr later), platelet depletion was associated with significantly fewer intraglomerular polymorphonuclear leucocytes (PMN), but again did not alter intraglomerular fibrin deposition. The results indicate that platelets are involved in the initiation of glomerular PMN localization in the autologous phase, but that fibrin-induced glomerular injury is platelet-independent.     

The role of coagulation and fibrinolysis in the development of rabbit Masugi nephritis.

The role of coagulation and fibrinolysis in the pathogenesis of rabbit Masugi nephritis was studied. Fibrinolytic activity of urine decreased rapidly to the minimum values at the peak of the disease. Histologic observations showed a severe proliferative glomerulonephritis. Immunofluorescent studies revealed localization of rabbit gamma globulin along the glomerular basement membrane in a typical linear pattern. Fibrin was positive in glomeruli not only within fibrinoid deposits, but also often diffusely in the places where no obvious fibrin was detected in histologic sections. Bright strands of fibrin was present between the cells forming a cresent. Electron microscopy indicated accumulation of fibrinoid materials beneath the endothelium. The basement membrane was damaged by the deposition of fibrinoid and followed by massive escape of intracapillary contents into the Bowman's space. Abundant fibrin and fibrinoid were seen in newly formed "monocytic-epithelial" crescents. Todd's fibrinolysis autography revealed diminished fibrinolytic activity in the severely affected glomeruli. Treatment with heparin prevented crescent formation and glomerular disorganization, while treatment with t-AMCHA increased fibrin and fibrinoid deposition and aggravated the glomerular injuries. It was concluded that the coagulation-fibrinolysis system could play an important role in the course of rabbit Masugi nephritis.     

THE ROLE OF COAGULATION AND FIBRINOLYSIS IN THE DEVELOPMENT OF RABBIT MASUGI NEPHRITIS

The role of coagulation and fibrinolysis in the pathogenesis of rabbit Masugi nephritis was studied. Fibrinolytic activity of urine decreased rapidly to the minimum values at the peak of the disease. Histologic observations showed a severe proliferative glomerulonephritis. Immunofluorescent studies revealed localization of rabbit gamma globulin along the glomerular basement membrane in a typical linear pattern. Fibrin was positive in glomeruli not only within fibrinoid deposits, but also often diffusely In the places where no obvious fibrin was detected in histologic sections. Bright strands of fibrin was present between the cells forming a crescent. Electron microscopy indicated accumulation of fibrinoid materials beneath the endothelium. The basement membrane was damaged by the deposition of fibrinoid and followed by massive escape of intracaplllary contents into the Bowman's space. Abundant fibrin and fibrinoid were seen in newly formed "monocytlceplthelial" crescents. Todd's fibrinolysis autography revealed diminished fibrinolytic activity in the severely affected glomeruli. Treatment with heparin prevented crescent formation and glomerular disorganization, while treatment with t-AMGHA Increased fibrin and fibrinoid deposition and aggravated the glomerular injuries. It was concluded that the coagulation-fibrinolysis system could play an Important role in the course of rabbit Masugi nephritis.     

Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis.

We examined the functional role of interleukin (IL)-1 in mesangial cell proliferation during rat anti-Thy-1 nephritis by blocking its action with IL-1 receptor antagonist (IL-1ra). Anti-Thy-1 nephritis was induced by intravenous injection of 5 mg/kg OX-7 IgG (day 0) into inbred Wistar rats. Groups of animals (n = 9) were implanted with a micro-osmotic pump on day -1, which delivered 25 micrograms/hour human recombinant IL-1ra or saline continuously until the rats were killed at day 6, the peak of mesangial cell proliferation. Immunostaining showed that IL-1 was expressed by mesangial cells during disease. IL-1ra treatment did not affect the mild, but significant, proteinuria seen after OX-7 injection. Compared with saline treatment, IL-1ra treatment reduced mesangial cell proliferation (decreases 24% P < 0.05), glomerular hypercellularity (decreases 29%; P < 0.05), and glomerular macrophage accumulation (decreases 20%; P < 0.05). However, IL-1ra treatment had no effect on glomerular IL-1 beta mRNA expression and caused only a small reduction in the high levels of glomerular expression of platelet-derived growth factor-beta protein (decreases 6%; P < 0.05). IL-1ra caused a modest reduction in the marked up-regulation of glomerular transforming growth factor-beta 1 mRNA expression on day 6 (decreases 26%; P < 0.05), although urinary excretion of this factor was unaffected. Interestingly, IL-1ra treatment had relatively little effect upon glomerular deposition of laminin, fibronectin, and collagen type IV seen in this acute disease. In conclusion, this study has 1) demonstrated that IL-1 is expressed by mesangial cells in vivo, 2) demonstrated that IL-1 is a mesangial cell growth factor in experimental mesangioproliferative nephritis, and 3) suggests that IL-1 has little or no fibrogenic activity in mesangial matrix deposition.     

Quantitative studies of immunoglobulin deposition in the kidney, glomerular cell proliferation and glomerulosclerosis in NZB/NZW F1 hybrid mice.

Using the NZB and NZB/NZW F1 (B/W) hybrid mouse as a model for systemic lupus erythematosus, an effort has been made to quantitate: (1) immune complex deposition in the glomeruli by immunofluorescent staining of immunoglobulin, (2) glomerular cellular proliferation by radioautographic measurement of [3H]Tdr incorporation into the glomerular cells in vivo, and (3) glomerular scarring by PAS staining. The relationship between these changes and increasing age has been examined. By radioautography it was observed that dividing glomerular cells were labelled in vivo after injection of [3H]Tdr. This provided a reproducible measure of the proliferative process in the nephritis of B/W mice. In C57B1/6J and CBA/J mice, which have a low incidence of glomerular disease, little change in the amount of glomerular cell proliferation was observed with increasing age. The NZB strain of animals showed a somewhat increased level of proliferation but this did not increase with age. In striking contrast, glomerular cell proliferation in the B/W mice increased rapidly with age. The earliest change observed in the kidney was the deposition of immunofluorescent material in the mesangium and glomerular capillary basement membrane beginning between 3 and 5 months of age and reaching a peak at 9 months. Increase in glomerular cell proliferation began about 2 months after the onset of immune complex deposition but also reached a maximum at 7 months. Glomerular sclerosis was the last change to appear and continued after the other two parameters measured has begun to decline. These data suggest that the deposition of immune complexes in the glomerulus may be an important triggering mechanism for renal cell proliferation and glomerulosclerosis in the B/W mouse. The techniques described would provide a sensitive and reproducible quantitative method for analysing the differential effects of various types of treatment of immune complex nephritis in animals.     

Antibody-mediated proliferation of proximal tubule cells.

We have proposed that the deposition in vivo of anti-brush border antibodies on proximal tubule cells in Heymann nephritis stimulates those cells to divide. To evaluate that hypothesis, we have investigated the temporal relationship between antibody deposition and kidney cell proliferation, using autoradiography to detect dividing cells in rats with Heymann nephritis and in age-matched controls treated with Freund's adjuvant alone. To assess the possible stimulation of proximal tubule cell proliferation by factors associated with proteinuria and/or nephrotic syndrome, kidney cell proliferation was measured in rats with chronic serum sickness glomerulonephritis. Proteinuric rats with chronic serum sickness also served as recipients of anti-brush border antibodies in passive transfer experiments. Cell division rates were not altered by adjuvant treatment or ageing. In both active Heymann nephritis and passive transfer experiments, a highly elevated stimulation of 3H-thymidine incorporation, reflecting mitotic activity, was detected in the proximal tubule epithelium immediately following the deposition of antibodies on the brush border. Significant enhancement of cell division was not noted in other nephron segments. A much smaller increase in proximal tubule cell proliferation accompanied proteinuria in chronic serum sickness. A similar small elevation compared to controls was also detected in late stages of Heymann nephritis when the proximal tubules were free of immunoglobulin deposits. It appears that the reaction of divalent antibodies with plasma membrane antigens can produce proliferative pathology of the proximal tubule epithelium. Furthermore, a significant, if less dramatic, enhancement of cell proliferation may be secondary to proteinuria and/or other manifestations of the nephrotic syndrome.     

Fibrinogen, fibrin and fibrin degradation products in relation to atherosclerosis

Many human atherosclerotic lesions, showing no evidence of fissure or ulceration, contain a large amount of fibrin which may be in the form of mural thrombus on the intact surface of the plaque, in layers within the fibrous cap, in the lipid-rich centre, or diffusely distributed throughout the plaque. Small mural thrombi are invaded by SMCs and collagen is deposited in patterns closely resembling the early proliferative gelatinous lesions. In experimental animals, thrombi are converted into lesions with all the characteristics of fibrous plaques, and in saphenous-vein bypass grafts, fibrin deposition is the main cause of wall thickening and occlusion. There seems little doubt that fibrin deposition can both initiate atherogenesis and contribute to the growth of plaques. Epidemiological studies indicate that increased levels of fibrinogen and clotting activity are associated with accelerated atherosclerosis, and although blood fibrinolytic activity has given inconsistent results, in arterial intima both fibrinolytic activity and plasminogen concentration are decreased in cardiovascular disease. Fibrin may stimulate cell proliferation by providing a scaffold along which cells migrate, and by binding fibronectin, which stimulates cell migration and adhesion. Fibrin degradation products, which are present in the intima, may stimulate mitogenesis and collagen synthesis, attract leukocytes, and alter endothelial permeability and vascular tone. In the advanced plaque fibrin may be involved in the tight binding of LDL and accumulation of lipid. Thus there is extensive evidence that enhanced blood coagulation is a risk factor not only for thrombotic occlusion, but also for atherogenesis. Enhanced blood coagulation frequently coexists with hyperlipidaemia and, together, these may have a synergistic effect on atherogenesis.     

Effects of ancrod and rtPA on fibrin accumulation, glomerular inflammation and renal function in nephrotoxic nephritis.

We have compared the effects of ancrod and recombinant tissue plasminogen activator (rtPA) on nephrotoxic nephritis induced in pre-immunized rabbits by the administration of nephrotoxic globulin (NTG; sheep anti-rabbit glomerular basement membrane). We used three different doses of NTG: in each experiment three groups of six rabbits were preimmunized with normal sheep globulin and given NTG: group A received no further treatment; group B received rtPA, 2 mg/kg 12 hourly; group C received ancrod 2 U/kg 12 hourly. Animals were bled daily for estimation of plasma fibrinogen and serum creatinine, then killed on day 5 and kidneys removed for histology. 1 ml/kg of NTG caused massive glomerular necrosis, all three groups having severe renal failure. With 0.5 ml/kg of NTG, ancrod and rtPA both effectively prevented fibrin deposition in Bowman's space, but all animals had severe proliferative glomerulonephritis and marked renal failure. With 0.25 ml/kg of NTG, control animals developed severe proliferative nephritis and advanced renal failure, ancrod provided almost complete protection, and the rtPA group had renal injury and functional impairment intermediate between the other two groups. We conclude that renal failure in severe nephrotoxic nephritis is fibrin-independent, but in less fulminant nephritis renal function can be protected by defibrination with ancrod. rtPA is capable of reducing glomerular fibrin accumulation as effectively as ancrod, but provides inferior protection of renal function.     

The role of C3 in the autologous phase of nephrotoxic nephritis.

The role of complement has been studied in the autologous phase of nephrotoxic nephritis (NTN) in rabbits. No reduction in glomerular fibrin deposition, crescent formation or protection from renal failure was observed in either the standard model of NTN when decomplementing doses of cobra venom factor (CVF) were given before the autologous phase or in a telescoped model when CVF was administered before the nephrotoxic antibody. In the latter situation glomerular fibrin deposition and crescent formation were found in the absence of detectable deposition of C3. However, substantial protection was observed when circulating polymorphonuclear leucocytes (PMN) were depleted by antipolymorph serum. These observations establish the existence of a system of allergic glomerular injury mediated by PMN but independent of C3. It is postulated that this system may account for the glomerular injury seen in patients with Goodpasture's syndrome in whom glomerular C3 deposition is not found.     

Diffuse glomerulonephritis in rabbits with Streptococcus viridans endocarditis.

Intravenous administration of live microorganisms to rabitts with cardiac catheters produces an experimental model of infective endocarditis. Despite the development of infected valvular vegetations, positive blood cultures, splenomegaly, and focal embolic renallesions, glomerulonephritis has not been found in these animals. In the present study, acute diffuse proliferative glomerulonephritis, featuring endothelial and mesangial proliferation, capillary occlusion, and leukocytic infiltration was produced in rabbits immunized withthe infecting agent prior to the establishment of left sided alpha-streptococcal endocarditis. Controls receiving immunization alone, immunization and sterileendocarditis, or infective endocarditis alone did not develop diffuse glomerulonephritis.Electron microscopic findings of occasional subendothelial electron-dense deposits and immunofluorescence deposition of IgG and C3 in a peripheral granular capillary pattern were consistent with an immune complex type nephritis. Decreased serum complement levels were demonstrated in those animals developing diffuse glomerulonephritis, and some animals developed circulating rheumatoid factor. In view of the morphologic findings and the necessity of preimmunization for development of glomerular changes, it is concluded that immune mechanisms play a role in the diffuse glomerulonephritis associated with this model of infective endocarditis.     

Controlled compaction with ruthenium-catalyzed photochemical cross-linking of fibrin-based engineered connective tissue

Tissue engineering utilizing fibrin gel as a scaffold has the advantage of creating a completely biological replacement. Cells seeded in a fibrin gel can induce fibril alignment by traction forces when subjected to appropriate mechanical constraints. While gel compaction is key to successful tissue fabrication, excessive compaction can result due to low gel stiffness. This study investigated using ruthenium-catalyzed photo-cross-linking as a method to increase gel stiffness in order to minimize over-compaction. Cross-links between the abundant tyrosine molecules that comprise fibrin were created upon exposure to blue light. Cross-linking was effective in increasing the stiffness of the fibrin gel by 93% with no adverse effects on cell viability. Long-term culture of cross-linked tubular constructs revealed no detrimental effects on cell proliferation or collagen deposition due to cross-linking. After 4 weeks of cyclic distension, the cross-linked samples were more than twice as long as non-cross-linked controls, with similar cell and collagen contents. However, the cross-linked samples required a longer incubation period to achieve a UTS and modulus comparable to controls. This study shows that photo-cross-linking is an attractive option to stiffen the initial fibrin gel and thereby reduce cell-induced compaction, which can allow for longer incubation periods and thus more tissue growth without compaction below a useful size.     

Endotoxin-Induced Disseminated Intravascular Coagulation in Nonpregnant Rats: A New Experimental Model

Disseminated intravascular coagulation as indicated by glomerular capillary thrombosis was induced in unprepared virgin rats by the infusion of endotoxin. Dose-time curves revealed that the minimal amount necessary was 0.9 mg and the time required was 3 hours. A marked difference in susceptibility between the summer and winter seasons was observed, the animals being more sensitive in the former. The platelet count decreased in a dose-related manner; however, there was no difference between an infusion and injection regimen. There was no difference in platelet numbers between the animals who had fibrin deposits and those free of fibrin. Plasma hemoglobin increased by 500% in those animals who developed glomerular fibrin deposition and the hematocrit decreased less profoundly. The data demonstrate that unprepared virgin rats can be used as an experimental model for studying glomerular fibrin deposition, the hallmark of what is generally referred to as the generalized Shwartzman reaction, if endotoxin is continuously infused rather than injected.     

A comparison of fibrinolytic and defibrinating agents in established experimental glomerulonephritis

The effect of fibrinolysis with Streptokinase and defibrination with Ancrod on the progression of established fibrin-related glomerular injury was assessed in rabbits developing anti-glomerular basement membrane antibody-induced glomerulonephritis. Untreated rabbits developed renal failure and a severe crescentic nephritis with prominent fibrin deposition after 5 days. Rabbits with established injury and glomerular fibrin deposition were treated with Streptokinase or Ancrod over the last 4 days of this model. Both treatments resulted in significant protection from loss of renal function and reduced crescent formation by day 5. Glomerular fibrin deposition was also significantly reduced by both agents, although Streptokinase produced a greater reduction than Ancrod. Two further groups of rabbits with advanced disease, were treated over the last two days of this model. Although treatment reduced glomerular fibrin deposition, no protection from loss of renal function was observed. These studies indicate that both treatments were effective, if used early, in preserving renal function in established fibrin related glomerulonephritis, but they did not effect the outcome of more advanced disease. Both agents prevented further glomerular fibrin deposition, although only early treatment with Streptokinase reduced glomerular fibrin to below pre-treatment levels.