fibrin and Proteinuria

Topics: Female; Fibrin; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphocytes; Proteinuria; Radionuclide Imaging; Time Factors; Tomography; Transplantation, Homologous; Ultrasonography; Urine

Topics: Adrenal Glands; Aldosterone; Anemia; Biopsy, Needle; Cholinesterases; Erythropoietin; Fibrin; Graft Rejection; Humans; Hyperparathyroidism; Hypertension; Juxtaglomerular Apparatus; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Polycythemia; Proteinuria; Radioisotope Renography; Renin; Transplantation, Homologous; Ultrasonography

Topics: Angiography; Animals; Anuria; Cadaver; Diuresis; Dogs; Fibrin; Glomerular Filtration Rate; Graft Rejection; Humans; Hypertension, Renal; Kidney; Kidney Glomerulus; Kidney Transplantation; Kidney Tubules; Postoperative Complications; Proteinuria; Thrombosis; Time Factors; Tissue Preservation; Transplantation Immunology; Transplantation, Autologous; Transplantation, Homologous

Treatment with indomethacin, aspirin, or prednisone has been shown to reduce urinary fibrin/fibrinogen degradation products (F.D.P.) in approximately two-thirds of patients with proliferative glomerulonephritis. This reduction which is dose-dependent for prednisone but not for indomethacin or aspirin in the range of doses used occurs within two to three days of beginning treatment and is thought to result from decreased intraglomerular fibrin deposition rather than alteration of glomerular permeability to F.D.P. In patients who responded in this manner treatment was associated with reductions in the degree of proteinuria and maintenance or improvement in renal function.

Topics: Adolescent; Adult; Aged; Aspirin; Child; Creatinine; Female; Fibrin; Fibrinogen; Glomerulonephritis; Humans; Indomethacin; Kidney Glomerulus; Male; Middle Aged; Plasminogen; Prednisone; Proteinuria; Time Factors; Urea

Preeclampsia is a major cause of maternal and neonatal morbidity and mortality. In mouse models, complement activation in the placenta is associated with abnormal placental development and miscarriage, and inhibiting complement prevents fetal injury. We mated two mouse strains, DBA/2 and CBA/J, expecting that the pregnancies might show features of preeclampsia and of immunologically mediated pregnancy loss. Along with placental dysfunction, these matings resulted in proteinuria, elevated BUN, fibrin deposition, and glomerular endotheliosis. We blocked placental complement activation throughout pregnancy by administering a single dose of the C3 inhibitor CR2-Crry given on day 5 of the pregnancy. This procedure specifically targets the sites of complement activation without inducing any systemic effects. Placental complement inhibition prevented oxidative stress and placental dysfunction, as well as proteinuria and renal pathologic features of preeclampsia. Thus, local blockade of complement activation at the maternal-fetal interface rescues preeclampsia in mice, and identifies new treatments. Hence, complement triggers a feed-forward cycle of placental damage, antiangiogenic factor production, and maternal vascular damage in patients.

Topics: Animals; Blood Urea Nitrogen; Complement Activation; Disease Models, Animal; Female; Fibrin; Injections, Intravenous; Kidney; Mice; Mice, Inbred BALB C; Mice, Inbred CBA; Mice, Inbred DBA; Neovascularization, Physiologic; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Recombinant Fusion Proteins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

The active type of coagulation factor X (factor Xa) activates various cell-types through protease-activated receptor 2 (PAR2). We previously reported that a factor Xa inhibitor could suppress Thy-1 nephritis. Considering that fibrin deposition is observed in diabetic nephropathy as well as in glomerulonephritis, this study examined the roles of the coagulation pathway and factor Xa in the development of diabetic nephropathy using type 2 diabetic model mice. Diabetic (db/db) and normoglycemic (m+/m+) mice were immunohistochemically evaluated for their expression/deposition of PAR2, transforming growth factor (TGF)-β, fibrin, extracellular matrix (ECM) proteins, and CD31 at week 20. Significantly greater numbers of PAR2-positive cells and larger amounts of fibronectin, and collagen IV depositions were observed in the glomeruli of db/db mice than those in m+/m+ mice. Next, expression of PAR2 versus deposition of collagen IV and fibronectin was compared between week 20 and week 30, and the number of PAR2-positive cells in the glomeruli decreased in contrast with the increased accumulation of ECM proteins. In an intervention study, fondaparinux, a factor Xa inhibitor, was subcutaneously administered for ten weeks from week 10 to 20. Fondaparinux treatment significantly suppressed urinary protein, glomerular hypertrophy, fibrin deposition, expression of connective tissue growth factor, and ECM proteins deposition together with CD31-positive capillaries. These results suggest that coagulation pathway and glomerular PAR2 expression are upregulated in the early phase of diabetes, together with the increase of profibrotic cytokines expression, ECM proteins deposition and CD-31-positive vessels. Factor Xa inhibition may ameliorate glomerular neoangiogenesis and ECM accumulation in diabetic nephropathy.

Topics: Animals; Anticoagulants; Blood Coagulation; Capillaries; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Extracellular Matrix Proteins; Factor Xa; Factor Xa Inhibitors; Fibrin; Fondaparinux; Hypertrophy; Kidney; Kidney Glomerulus; Male; Mice; Mice, Obese; Platelet Endothelial Cell Adhesion Molecule-1; Polysaccharides; Proteinuria; Receptor, PAR-2; Transforming Growth Factor beta; Up-Regulation

Preeclampsia (PE) is a placenta-mediated pregnancy complication that results in high maternal and neonatal mortality and morbidity worldwide. Currently, there is no satisfactory pharmacotherapeutic treatment to stop the PE progression. In this study, we investigated the therapeutic effects of anticoagulant agents, including annexin V, heparin, and a fusion protein of annexin V and hirudin (AND), in a murine PE model induced by intravenous injection of phosphatidylserine/phosphatidylcholine (PS/PC) microvesicles. Compared with the control pregnant animals, the pregnant mice injected with PS/PC presented PE-like symptoms, including elevated systolic blood pressure, proteinuria, and reduction of antithrombin III and blood platelets. However, the PE-like symptoms were significantly alleviated after the PS/PC-injected mice were treated with annexin V, AND, or heparin. Furthermore, fibrin deposition in the placentas in the anticoagulant treated mice was remarkably improved, compared with that in the mice injected with PS/PC alone. The data demonstrate that anticoagulants are effective to prevent the occurrence of PE in the murine model and also suggest that hypercoagulation in the placenta is a contributing factor in the pathogenesis of PE.

Topics: Animals; Annexin A5; Anticoagulants; Antithrombin III; Blood Pressure; Female; Fetal Death; Fetal Weight; Fibrin; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Intestines; Liposomes; Male; Mice; Mice, Inbred ICR; Organ Size; Phosphatidylcholines; Phosphatidylserines; Placenta; Platelet Count; Pre-Eclampsia; Pregnancy; Proteinuria

Macrophages are prominent participants in crescentic glomerulonephritis (GN) and have been suggested to be the major source of TNF in this cell-mediated form of glomerular inflammation. Intrinsic renal cells also have the capacity to produce TNF. For dissecting the contribution of local versus bone marrow (BM)-derived TNF in inflammatory renal injury, TNF chimeric mice were created by transplanting normal wild-type (WT) BM into irradiated TNF-deficient recipients (WT-->TNF-/- chimeras) and vice versa (TNF-/- -->WT chimeras). A model of crescentic GN induced by an intravenous injection of sheep anti-murine glomerular basement membrane antibody was studied in WT mice, mice with complete TNF deficiency (TNF-/-), and chimeric mice. Crescentic GN was attenuated in TNF-/- mice with fewer crescents (crescents, 13.7 +/- 1.7% of glomeruli) and reduced functional indices of renal injury (serum creatinine, 15.2 +/- 0.8 micromol/L). Similar protection (crescents, 14.3 +/- 1.9% of glomeruli; serum creatinine, 18.9 +/- 1.1 micromol/L) was observed in chimeric mice with intact BM but absent renal-derived TNF (WT-->TNF-/- chimeras), suggesting a minor contribution of infiltrating leukocytes to TNF-mediated renal injury. Chimeric mice with TNF-deficient leukocytes but intact intrinsic renal cell-derived TNF (crescents, 20.5 +/- 2.0% of glomeruli; serum creatinine, 21.6 +/- 1.4 micromol/L) developed similar crescentic GN to WT mice (crescents, 22.3 +/- 1.4% of glomeruli; serum creatinine, 24.8 +/- 1.9 micromol/L). Cutaneous delayed-type hypersensitivity after subdermal challenge with the nephritogenic antigen was attenuated in the absence of BM cell-derived TNF but unaffected in WT-->TNF-/- chimeric mice. These studies suggest that intrinsic renal cells are the major cellular source of TNF contributing to inflammatory injury in crescentic GN.

Topics: Actins; Animals; Basement Membrane; Bone Marrow Transplantation; CD4-Positive T-Lymphocytes; Creatinine; E-Selectin; Fibrin; Glomerulonephritis; Histocompatibility Antigens Class II; Hypersensitivity, Delayed; Intercellular Adhesion Molecule-1; Kidney; Macrophages; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Confocal; Microscopy, Fluorescence; Proteinuria; Sheep; Tumor Necrosis Factor-alpha

Matrix metalloproteinase (MMP)9/gelatinase B is increased in various nephropathies. To investigate its role, we used a genetic approach. Adult MMP9-deficient (MMP9(-/)-) mice showed normal renal histology and function at 3 mo. We investigated the susceptibility of 3-mo-old mice to the accelerated model of anti-glomerular basement membrane nephritis, in which fibrin is an important mediator of glomerular injury and renal impairment. Unexpectedly, nephritis was more severe in MMP9(-/)- than in control mice, as attested by levels of serum creatinine and albuminuria, and the extent of crescents and fibrin deposits. Circulating or deposited immunoglobulin G, interleukin (IL)-1beta, or IL-10 were the same in MMP9(-/-) and MMP9(+/+) mice. However, we found that fibrin is a critical substrate for MMP9, and in its absence fibrin accumulated in the glomeruli. These data indicate that MMP9 is required for a novel protective effect on the development of fibrin-induced glomerular lesions.

Topics: Animals; Anti-Glomerular Basement Membrane Disease; Basement Membrane; Fibrin; Kidney Function Tests; Kidney Glomerulus; Matrix Metalloproteinase 9; Mice; Mice, Mutant Strains; Proteinuria

In addition to its well-known role in degrading fibrin, recent evidence suggests that plasmin degrades matrix proteins and activates prometalloproteinases. Plasmin is generated from plasminogen by tissue plasminogen activator (t-PA). We hypothesized that t-PA treatment increases plasmin generation in nephritic glomeruli and degrades pathological matrix leading to a therapeutic reduction in matrix accumulation.. Anti-Thy-1 nephritis was induced by injection of OX-7 antibody. Rats were given twice daily intravenous injections of saline (disease control group) or human recombinant t-PA (rt-PA; 1 mg/kg body weight) on days 3 through 5. Proteinuria, glomerular matrix protein staining, and glomerular mRNA levels for transforming growth factor-beta 1 (TGF-beta 1), fibronectin, and plasminogen activator inhibitor type 1 (PAI-1) were evaluated at day 6. Localization of rt-PA, plasmin generation by glomeruli in vitro, and glomerular production and content of active TGF-beta1 were also investigated.. Compared with disease control animals, proteinuria and staining score for periodic acid-Schiff (2.75 +/- 0.17 vs. 1.41 +/- 0.09), fibronectin-EDA+ (19 +/- 2 vs. 14 +/- 1), laminin (35 +/- 2 vs. 25 +/- 2), type I collagen (33 +/- 1 vs. 21 +/- 3), and type IV collagen (27 +/- 2 vs. 23 +/- 1) were significantly reduced in treated rats (P < 0.01). Glomerular TGF-beta 1, fibronectin, and PAI-1 mRNA levels were unchanged. rt-PA colocalized with fibrin along glomerular capillary walls and in the mesangium. Nephritic glomeruli in vitro had decreased plasmin activity, which was elevated by an in vivo presacrifice injection of rt-PA. Glomerular production and content of active TGF-beta 1 were unchanged by the rt-PA injection.. : These results show that injected rt-PA binds to fibrin in nephritic glomeruli, thus increasing plasmin generation and promoting pathological matrix degradation without activating latent TGF-beta. Agents that increase plasmin generation, such as t-PA, may have potential as antifibrotic therapies.

Topics: Animals; Cells, Cultured; Extracellular Matrix; Fibrin; Fibrinogen; Fibrinolysin; Fibronectins; Gene Expression; Glomerulosclerosis, Focal Segmental; Kidney Glomerulus; Male; Plasminogen Activator Inhibitor 1; Plasminogen Activators; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thy-1 Antigens; Tissue Plasminogen Activator; Transforming Growth Factor beta; Transforming Growth Factor beta1

Several recent studies have demonstrated the central role of Fc receptors (FcR) rather than the complement system in triggering hypersensitivity reactions. We investigated the role of FcR for IgG (FcgammaR) using a murine model of accelerated anti-glomerular basement membrane (GBM) antibody-mediated glomerulonephritis as a representative of type II hypersensitivity diseases. Intravenous injection of rabbit anti-GBM antibody after preimmunization with normal rabbit IgG induced proteinuria and azotemia in wild-type C57BL/6 and CD40(+/-) mice but not in FcR gamma chain (FcRgamma)(-/-) mice or CD40(-/-) mice. Light microscopic findings revealed marked tissue damage in the glomeruli of wild-type C57BL/6 and CD40(+/-) mice. However, no tissue damage except polymorphonuclear cell infiltration was observed in the glomeruli of FcRgamma(-/-) mice. The glomeruli of CD40(-/-) mice were almost normal. Immunohistochemistry revealed the binding of rabbit IgG to the GBM in all mice injected with anti-GBM antibody. However, depositions of mouse IgG and complement to the glomeruli were not observed in CD40(-/-) mice, and deposition of fibrin was not observed in FcRgamma(-/-) or CD40(-/-) mice. These findings suggest that FcgammaR may initiate anti-GBM antibody-mediated renal disease. We conclude that FcgammaR rather than the complement system is critically involved in the development of type II hypersensitivity diseases.

Topics: Animals; Anti-Glomerular Basement Membrane Disease; Antigen-Antibody Complex; Autoantibodies; Basement Membrane; CD40 Antigens; Complement System Proteins; Female; Fibrin; Gene Deletion; Immunization; Immunoglobulin G; Kidney Glomerulus; Leukocyte Count; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Neutrophils; Proteinuria; Rabbits; Receptors, IgG; Uremia

The pattern of glomerulonephritis (GN) developing in response to a planted antigen (sheep anti-mouse GBM globulin) was compared in two strains of mice which demonstrated either a predominant Th1 (C57BL/6) or Th2 (BALB/c) response to this antigen. GN was induced with a subnephritogenic i.v. dose of sheep anti-mouse GBM globulin in mice presensitized to sheep globulin. Sensitized C57BL/6 mice showed pronounced cutaneous delayed-type hypersensitivity (DTH) following the challenge with sheep globulin, low titers of circulating anti-sheep globulin antibody and high interferon gamma (IFN-gamma) and low interleukin 4 (IL-4) production by splenic T cells, consistent with a predominant Th1 pattern of immune response. Sensitized BALB/c mice did not develop DTH following cutaneous challenge with sheep globulin, had higher circulating anti-sheep globulin antibody titers, and showed high IL-4 and low IFN gamma production by splenic T cells compared with C57BL/6 mice, consistent with a predominant Th2 response. In C57BL/6 mice, GN developing in response to sheep globulin exhibited a severe crescentic pattern with prominent glomerular T cell and macrophage influx and fibrin deposition. In vivo depletion with a monoclonal anti-CD4 antibody demonstrated that this injury was T helper cell dependent. Treatment with monoclonal anti-mouse IFN gamma antibody significantly reduced glomerular injury and crescent formation and attenuated the cutaneous DTH response. GN induced by the same protocol in BALB/c mice exhibited pronounced glomerular IgG and complement deposition. Crescent formation, fibrin deposition, and glomerular T cell and macrophage infiltration were significantly less than observed in C57BL/6 mice, and injury was not T cell dependent in the effector phase. These data suggest that the pattern of glomerular injury induced by a planted antigen can be determined by the balance of T helper cell subset activation. A Th1 response induces a severe crescentic pattern of GN, which like cutaneous DTH, is T helper cell and IFN gamma dependent.

Topics: Animals; Antigens; Autoantibodies; CD4 Antigens; Complement System Proteins; Creatinine; Fibrin; Globulins; Glomerulonephritis; Hypersensitivity, Delayed; Immunoglobulin G; Immunoglobulins, Intravenous; Interferon-gamma; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Proteinuria; Sheep; T-Lymphocytes, Helper-Inducer

We examined the potential of in vivo linkage of plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) in the setting of endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of fibrinolysis and extracellular matrix (ECM) turnover. PAI-1 mRNA expression in the kidney was markedly increased (9-fold) at 12 weeks after irradiation (P < 1.001 vs. normal control). In situ hybridization revealed significant association of PAI-1 expression with sites of glomerular injury (signal intensity in injured vs. intact glomeruli, P < 0.001). Angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril) or angiotensin II receptor antagonist (AIIRA, L158,809) markedly reduced glomerular lesions (thrombosis, mesangiolysis, and sclerosis; sclerosis index, 0 to 4+ scale, 0.49 +/- 0.20 in untreated vs. 0.05 +/- 0.02, 0.02 +/- 0.01, 0.04 +/- 0.02 in captopril, enalapril and AIIRA, respectively, all P < 0.01 vs untreated). Further, ACEI and AIIRA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, for captopril, enalapril and AIIRA, compared to untreated irradiated kidney, P < 0.05, < 0.01, < 0.01). This effect was selective in that neither tissue-type nor urokinase-type PA mRNA expression was affected by these interventions. Thus, we speculate that inhibition of the renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, via suppression of PAI-1 expression. In summary, inhibition of Ang II, in addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/thrombotic injury.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Captopril; Cytokines; Enalapril; Fibrin; Fibrinolysin; Fibrosis; Gene Expression Regulation, Enzymologic; Growth Substances; Imidazoles; In Situ Hybridization; Kidney; Male; Plasminogen Activator Inhibitor 1; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Circulation; Renin; RNA, Messenger; Tetrazoles; Thrombosis; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Vasoconstrictor Agents

Increased glomerular tissue factor (TF) expression is associated with glomerular fibrin deposition and renal failure in human and experimental crescentic glomerulonephritis (GN). However, the in vivo functional contribution of TF to the development of glomerular fibrin deposition, crescent formation, and renal failure in GN has not been established. The contribution of TF to fibrin deposition and renal injury was studied in a rabbit model of crescentic GN in which glomerular macrophage infiltration, augmented TF expression, and fibrin deposition are prominent. Administration of anti-TF antibody inhibited glomerular TF activity in nephritic glomeruli by 96%, without affecting macrophage accumulation or systemic indices of coagulation. Anti-TF antibody significantly reduced glomerular fibrin deposition (fibrin scores, 0.43 +/- 0.10 (treated) and 1.40 +/- 0.19 (control); P < 0.0005), crescent formation (0.33 +/- 0.05 (treated) and 1.0 +/- 0.06 (control); P < 0.0005), and development of renal failure (serum creatinine, 168 +/- 22 mumol/l (treated) and 267 +/- 35 mumol/l (control); P < 0.04). This was associated with significant reduction in proteinuria (1189 +/- 277 mg/24 hours (treated) and 2060 +/- 336 mg/24 hours (control); P < 0.03) and expression of MHC class II antigen in glomeruli (1.25 +/- 0.41 (treated) and 2.83 +/- 0.53 (control); P < 0.03) and in tubules and interstitial areas. These data demonstrate that TF is the major in vivo initiator of fibrin deposition in crescentic GN. The reduction in proteinuria and glomerular major histocompatibility class II antigen expression by TF inhibition suggests that TF may also activate other mediators that contribute to glomerular injury.

Topics: Animals; Antibodies; Blood Coagulation; Fibrin; Glomerulonephritis; Histocompatibility Antigens Class II; Immunoconjugates; Kidney Glomerulus; Male; Proteinuria; Rabbits; Renal Insufficiency; Thromboplastin

Crescentic glomerulonephritis (GN) has immunopathological features of delayed type hypersensitivity (DTH) and results from a T helper cell 1 (Th1) dependent immune response. The current study examined the capacity of Th2 cytokines, interleukin (IL)-4 and IL-10, to alter the outcome of crescentic GN, after injury is established. Sensitized, control treated mice developed crescentic GN with functional renal injury (117 +/- 20 microliters/min, normal mouse 182 +/- 8 microliters/min, P < 0.05) 10 days after an i.v. dose of sheep anti-mouse glomerular basement membrane globulin. Combined treatment with IL-4 and IL-10 starting three days after initiation of disease significantly reduced glomerular crescent formation (5.3 +/- 3.2%, control treatment 23.3 +/- 6.4%, P < 0.02) and preserved renal function (165 +/- 15 microliters/min, P = 0.57 compared to normal mice). Treatment with IL-4 alone did not reduce crescent formation or protect renal function. Mice treated with IL-10 showed trends to decreased crescent formation and preservation of renal function. In all cytokine treated groups, the accumulation of effectors of glomerular injury (CD4+ positive T cells, macrophages and fibrin) was reduced, with the combination treatment having the greatest effect. Administration of Th2 cytokines, IL-4 and IL-10 to mice with established GN attenuates the development of glomerular crescent formation and protects renal function.

Topics: Animals; Creatinine; Fibrin; Glomerulonephritis; Hypersensitivity, Delayed; Interferon-gamma; Interleukin-10; Interleukin-4; Kidney; Macrophages; Male; Mice; Mice, Inbred C57BL; Proteinuria; Recombinant Proteins; T-Lymphocytes

Although the importance of injury with consequent activation of endothelium is well-recognized in diseases affecting the glomerular endothelial cell (GEN), research on GEN injury in vivo has been hampered by the lack of adequate animal models. Here we report the establishment and characterization of a new GEN injury model in rats. This model was induced by selective renal artery perfusion with anti-GEN IgG and resulted in the severe acute renal failure with marked platelet deposition and development of a thrombotic microangiopathy involving glomeruli. Peritubular capillary endothelial cells were also damaged that was associated with severe tubular necrosis. Although the glomerular changes were severe, half of the glomeruli recovered by day 10, while interstitial changes remained throughout our observation time course. Proliferation of GEN was observed during the recovery phase. An increased expression of endothelial nitric oxide synthase in GEN was also observed, and may be an adaptive mechanism to counteract the thrombosis and ischemia. This model should be useful to investigate the pathophysiology of renal microvascular diseases and the mechanisms of GEN injury, activation and recovery in vivo.

Topics: Acute Kidney Injury; Anemia; Animals; Blood Urea Nitrogen; Collagen; Complement System Proteins; Disease Models, Animal; Endothelial Growth Factors; Endothelium, Vascular; Fibrin; Kidney; Kidney Glomerulus; Laminin; Lymphokines; Macrophages; Male; Nitric Oxide Synthase; Proteinuria; Rats; Rats, Wistar; Thrombocytopenia; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

We tested the hypothesis that enhanced intravascular coagulation in pregnancy could produce clinical symptoms similar to those of preeclampsia, such as hypertension, proteinuria, and edema. Having confirmed this, we then examined whether the pathological changes caused by intravascular coagulation could be suppressed by administration of antithrombin III (AT III), an endogenous inhibitor active to thrombin and factor X a. Intravascular coagulation was induced in Wistar rats on day 16-20 of pregnancy by 1-h arterial infusion of tissue thromboplastin (TP) through the left ventricle of the heart. One hour after the end of the infusion period, organ blood flows were measured by the radioactive ((57)Co-labeled) microsphere method, and fibrin deposition in organs was measured by radiolabeling with [(125)I] fibrinogen injected before TP infusion. Infusion of TP produced fibrin deposition in the kidney, lung, and liver, but not in the myometrium and placenta, as well as an 80% decrease in renal blood flow (RBF), with oliguria and proteinuria. TP also caused an increase in blood pressure (BP) accompanied by an increase in plasma renin activity (PRA), both of which were suppressed by bilateral nephrectomy before TP infusion. The prophylactic administration of AT III concentrates (60 or 300 U/kg intravenously (i.v.), followed by infusion of 30 or 150 U/kg/2 h, respectively) prevented all pathological changes in a dose-dependent manner. AT III increased placental blood flow regardless of the state of coagulation. These findings suggest that intravascular coagulation plays a significant part in the pathophysiology of preeclampsia and that AT III concentrates may have therapeutic potential in the treatment of this condition.

Topics: Animals; Antithrombin III; Blood Coagulation; Female; Fibrin; Hypertension; Kidney; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Proteinuria; Rats; Rats, Wistar; Regional Blood Flow; Renin; Serum Albumin; Thromboplastin

We have established a recombinant inbred strain of mouse named spontaneous crescentic glomerulonephritis-forming mouse/Kinjoh or SCG/Kj. Mice of this strain spontaneously develop rapidly progressive glomerulonephritis. This strain of mice was derived from (BXSB/Mp x MRL/Mp-lpr/lpr)F1 hybrid mice by brother x sister mating coupled with repeated histopathologic selection for breeding of mice whose parents had the highest frequency of crescent formation in the kidneys. In this strain of mice, nephritis appears earlier and is more rapidly progressive than in any other murine model of systemic lupus erythematosus. Histopathologically, the characteristic renal lesions in the mice of this strain express a most dramatic form of crescentic glomerulonephritis. The lesions in the kidneys show only slight fine granular immune deposits along the glomerular basement membrane associated with remarkable extraglomerular proliferation and hemorrhage in Bowman's space. Although selection was not based on vasculitis, mice of this strain also exhibit a high incidence of necrotizing vasculitis. These vascular lesions involve primarily small arteries and arterioles and many organs and tissues but spare the kidneys. Thus this form of vasculitis has been found to be correlated with the crescentic form of glomerulonephritis but not with lymphoid hyperplasia of the spleen. We conclude that, in this strain of mouse, the rapidly progressive glomerulonephritis is genetically restricted and that this genetic restriction is firmly linked to that responsible for the vasculitis.

Topics: Animals; Chromosome Mapping; Coronary Circulation; Crosses, Genetic; Female; Fibrin; Glomerulonephritis; Immunohistochemistry; Kidney; Male; Mice; Mice, Inbred Strains; Ovary; Proteinuria; Selection, Genetic; Sex Factors; Species Specificity; Spleen; Stomach; Vasculitis

Leflunomide (HWA 486, a novel isoxazol derivative), shown to have potent immunosuppressant and antiinflammatory effects, was evaluated for its inhibitory and therapeutic effects on the glomerulonephritis induced in rats by rabbit antiserum against rat glomerular basement membrane. Leflunomide was administered orally to rats at 0.5 and 2 mg/kg/day for 20 days from 2 days before injection of the rabbit antiserum and at 2 mg/kg/day for 14 days from 5 days after the antibody injection. The present study consisting of 2 experiments for inhibitory (I) and therapeutic (II) effects of leflunomide revealed the following effects at 2 mg/kg: in experiment I, significant decreases in (a) urinary total protein, (b) plasma total cholesterol and fibrinogen and (c) thymus weight, and decreased incidences of fibrin deposits in Bowman's space, adhesion of the glomerulus to Bowman's capsule and deposition of rat IgG and C3; and in experiment II, decreases in (a), (b) and (c), though smaller than in experiment I, and decreases deposition of rat C3. Thus, leflunomide had potent inhibitory and limited therapeutic effects on glomerulonephritis, suggesting that the compound is effective in inhibiting the onset and development of glomerulonephritis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Basement Membrane; Cell Division; Complement C3; Fibrin; Fluorescent Antibody Technique; Glomerulonephritis; Immune Sera; Immunoglobulin G; Immunosuppressive Agents; Isoxazoles; Kidney Glomerulus; Leflunomide; Male; Periodic Acid-Schiff Reaction; Proteinuria; Rats; Rats, Inbred Strains

The mechanism involved in glomerular fibrin deposition was investigated during mercuric chloride (HgCl2)-induced autoimmune glomerulonephritis in the Brown Norway rat. To ascertain whether the local hemostatic system was activated secondarily to the immunological conflict, the ability of glomerular lysates to induce coagulation in vitro was assessed in treated and control rats. Glomerular procoagulant activity (PCA) of HgCl2-injected rats was measured on day 12 (latent phase of the disease), day 20 (acme), and days 32 and 42 (recovery phase) after the first mercury injection. PCA rose 3-fold (p less than 0.02) at day 20 and then almost returned to control values. Proteinuria, PCA, and the incidence of glomerular fibrin deposits peaked concomitantly at day 20. Glomerular PCA was characterized as thromboplastin. The number of Ia positive cells detected by monoclonal OX-6 antibody was not different from the control number at any phase of the disease; the number of macrophages per glomerular section detected by electron microscopy at day 20 in HgCl2-injected rats was 1.80 +/- 0.60, versus 0.30 +/- 0.11 in the controls. No correlation was found between glomerular PCA and either the number of monocytes/macrophages or of Ia-positive cells present in the glomeruli. Since glomerular PCA was maximal at the onset of fibrin formation in the glomeruli and then decreased toward its basal level, and since the fibrin disappeared, it is concluded that increased production of thromboplastin by glomeruli, with activation of the extrinsic coagulation pathway, may contribute to intraglomerular fibrin deposition in HgCl2-induced glomerulonephritis.

Topics: Animals; Autoimmune Diseases; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Glomerulonephritis; Histocompatibility Antigens Class II; Kidney Glomerulus; Macrophages; Male; Mercuric Chloride; Proteinuria; Rats; Rats, Inbred BN; Thromboplastin

Fresh human urine was found to contain at least three different molecular forms of fibrin-binding urokinase (UK) or its precursor, all of which were absorbed on a fibrin/Celite column at neutral pH, and could be eluted with 0.3-1.0 mol/l NaCl in phosphate buffer, followed by 0.2 mol/l, Arg, 2 mol/l KSCN, and 2 mol/l urea, respectively. The main molecular form isolated revealed a molecular weight (MW) of approximately 100,000 (UK-100), and the minor ones were estimated to have MW of 150,000-200,000 and 45,000. In contrast, commercially obtained UK preparations contained mostly active enzymes with MW of 53,000 and 32,000, respectively, and the remaining high molecular forms represented less than 2.0% of the total amount. Rabbit monospecific antibody (IgG) against UK subcomponent (active heavy chain; H-chain UK) reacted and inhibited the fibrinolytic activity of all the active UK molecules. The UK-100 isolated was relatively stable in solution at neutral pH and resistant to mild reduction, without molecular change. Although the preparation had a very low specific activity (ca. 300 IU/mg protein), both the pyro-Glu-Gly-Arg-pNA amidolytic and plasminogen activating activities could be partially enhanced by the addition of trace amounts of plasmin. In this process, the appearance of two additional active enzymes of MW 53,000 and 32,000 was also confirmed by zymography.

Topics: Adolescent; Adult; Chromatography, Affinity; Electrophoresis, Polyacrylamide Gel; Enzyme Precursors; Female; Fibrin; Fibrinolysin; Humans; Immunodiffusion; Male; Methylation; Middle Aged; Molecular Weight; Oxidation-Reduction; Proteinuria; Trypsin; Urokinase-Type Plasminogen Activator

Topics: Female; Fibrin; Humans; Pregnancy; Proteinuria; Thrombosis; Trophoblastic Neoplasms

Although acute infection with murine cytomegalovirus (MCMV) resulted in a transient focal glomerulonephritis characterized by mesangial inclusions, infection of HA/ICR mice given antilymphocyte globulin (ALG) led to progressive glomerulonephritis and renal failure. ALG alone without virus failed to produce progressive renal disease. Mice given both MCMV and ALG developed severe proteinuria and azotemia with glomerular crescents by 30 days. By immunofluorescence, viral antigen was limited to mesangial zones and glomerular axial poles. Granular deposits of rabbit IgG from ALG, mouse IgG, and C3 along the peripheral glomerular capillary walls were first observed 12 days after infection. By electron microscopy, virus was found only in glomerular mesangial cells that resembled macrophages. Intramembranous and subepithelial deposits in peripheral capillary walls were associated with accumulations of polymorphonuclear leukocytes dissecting into glomerular basement membranes. These observations best fit a multiphasic mechanism of glomerular injury initiated by persistent virus in the mesangium, followed by deposits of rabbit IgG from ALG, mouse IgG, and C in the peripheral capillary walls, resulting in an amplified immune-complex-mediated injury. Because other viruses localize within the glomerular mesangium, viruses should be considered potential causes of mesangial injury and progressive glomerulonephritis.

Topics: Animals; Antigens, Viral; Antilymphocyte Serum; Blood Urea Nitrogen; Complement C3; Cytomegalovirus Infections; Disease Models, Animal; Female; Fibrin; Glomerulonephritis; Immunoglobulin G; Kidney Function Tests; Kidney Glomerulus; Mice; Mice, Inbred ICR; Proteinuria; Rabbits

Urinary casts from 46 healthy volunteers and 60 patients with glomerulonephritis were examined for the presence of Tamm-Horsfall glycoprotein and other proteins. All samples gave immunofluorescence evidence of Tamm-Horsfall protein in casts. Casts from 59 of the patients but only three of the controls contained other proteins in addition (p less than 0.001). Immunoglobulins (IgG, IgM, IgA) were detected in casts from 53 of the patients but none of the healthy volunteers. Examination of urinary casts for immunoglobulins, complement, and fibrin provides a non-invasive method for distinguishing patients with active glomerular disease.

Topics: Complement Activating Enzymes; Complement C1q; Complement C3; Fibrin; Glomerulonephritis; Humans; Immunoglobulins; Mucoproteins; Proteinuria; Uromodulin

We studied the relationship between plasma soluble fibrin monomer complexes (SFMC) and diabetic microangiopathy. SFMC concentrations were investigated in 7 patients with advanced retinopathy (group II) and in 10 patients with both retinopathy and proteinuria (group III), and also in 12 control patients (group I). The age of the patients in each group was similar and overnight fasting blood sugar levels were below 220 mg/dl. Group II had higher levels of SFMC (21.8-3.8 mg/dl) than group I (7.3-4.8 m/dl). Group III showed the higher value of blood urea nitrogen (BUN) than other groups and showed higher levels of SFMC (31.5-12.3 mg/dl) than group II. There was no significant correlation between the levels of SFMC and blood sugar, but positive correlation between BUN concentrations and SFMC was recognized in group III. Increasing of SFMC levels were correlated to fibrinogen (Fbg) levels in all subjects. There was no correlation between the levels of SFMC and antithrombin (AT-III) except in group II. The 24-h urinary protein was significantly correlative to SFMC, and Fbg was also considered to be closely associated with microangiopathy and act to promote it.

Topics: Adult; Aged; Blood Urea Nitrogen; Creatinine; Diabetic Angiopathies; Diabetic Retinopathy; Female; Fibrin; Fibrinogen; Humans; Macromolecular Substances; Male; Middle Aged; Proteinuria; Solubility

Topics: Female; Fibrin; Fibrinogen; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Proteinuria; Reference Values; Streptokinase

Correlations between immunofluorescent protein deposits in the glomeruli, urinary sediment and proteinuria selectivity pattern have been attempted in different glomerulonephritis. The overall study showed following results: a) Glomerular and urinary casts deposits of immunoglobulins, C3 and fibrin/fibrinogen are related to moderately selective proteinuria; b) IgG and IgA are most often found in urinary sediment and c) Glomerular deposits of IgG and IgA are well correlated with the presence of these immunoglobulins in urinary casts. Analysis according to different histological types of nephritis: a) In "minimal changes" nephropathy, deposits are infrequent and well correlated with urinary sediment, when they are present; b) In lupus nephritis, constant and intense glomerular deposits of immunoglobulins, fibrin/fibrinogen are correlated with the same proteins found in urinary casts; c) Inconstant correlations are found in membranous nephritis and in IgA-IgG nephropathy.

Topics: Complement C3; Fibrin; Fibrinogen; Fluorescent Antibody Technique; Glomerulonephritis; Humans; Immunoelectrophoresis; Immunoglobulins; Kidney Glomerulus; Proteinuria

A model of antiglomerular basement membrane nephritis in the rat was used to elucidate the origin of urinary fibrin-fibrinogen-related antigen (FRA). The intrarenal distribution and excretion of 125I-rat fibrinogen was examined to determine whether there was increased filtration of bibrinogen or fibrin degradation products (FDP) or lysis of intraglomerular fibrin. 125I-protein appeared in the urine immediately after injection of 125I-fibrinogen and fell in parallel with the fall in plasma 125I-fibrinogen. Renal retention of 125I-fibrin averaged less than 0.2 percent of the administered dose of 125I-fibrinogen. The infusion of epsilon aminocaproic acid (EACA) had no significant effect on either FRA excretion or 125I-protein excretion. Plasma FDP levels and the elution patteren of 125I-protein from the urine were not significantly changed by EACA infusion. These observations support the view that ruinary FRA excretion in glomerulonephritis is derived predominantly from increased filtration of plasma fibrinogen rather than from breakdown of intraglomerular fibrin.

Topics: Aminocaproates; Animals; Antibodies; Antigens; Basement Membrane; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Glomerulonephritis; Humans; Infusions, Parenteral; Inulin; Kidney Function Tests; Proteinuria; Rats; Sodium Chloride

Topics: Animals; Disease Models, Animal; Factor VIII; Fibrin; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Immunoglobulin G; Immunoglobulin M; Injections, Intraperitoneal; Kidney Glomerulus; Male; Nephrectomy; Proteinuria; Puromycin Aminonucleoside; Rats; Sialoglycoproteins

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.

Topics: Animals; Antibodies; Basement Membrane; Blood Coagulation Tests; Cell Division; Complement C3; Complement System Proteins; Creatinine; Fibrin; Immunoglobulin G; Kidney Glomerulus; Leukocyte Count; Leukocytes; Male; Nephritis; Proteinuria; Rabbits; Snake Venoms; Time Factors; Urea

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.

Topics: Animals; Antibodies; Antilymphocyte Serum; Complement C3; Fibrin; Fluorescent Antibody Technique; Kidney; Kidney Glomerulus; Leukocytes; Male; Mechlorethamine; Nephritis; Neutrophils; Proteinuria; Rabbits

The urinary concentration of fibrin-fibrinogen degradation products (F.D.P.) was measured in 90 patients with proteinuria above 2 g/1 and correlated with proteinuria, differential protein clearances, serum urea and creatinine, and renal biopsy findings. There was a linear correlation (r equals 0-7; P less than 0-001) between the urinary F.D.P. excretion and the selectivity of the proteinuria such that patients with highly selective proteinuria excreted only small amounts of F.D.P. whereas those with non-selective proteinuria excreted much higher levels. There was a significant correlation between the urinary F.D.P. excretion and the urine:serum (U:S) ratio of IgG excretion but not with the U:S ratio or urinary excretion of albumin or transferrin. Sephadex G200 column chromatography of the concentrated urine in 26 cases showed that patients with highly selective proteinuria excreted predominantly F.D.P. of low molecular weight in the urine whereas those with non-selective proteinuria excreted mainly fibrinogen and products of high molecular weight. Hence the type and quantity of F.D.P. in the urine are determined primarily by the differential filtration of fibrinogen and the various degradation products from the plasma through the glomerular basement membrane, which in turn is determined by the "pore size" of the basement membrane. In clinical nephrology measurement of the urinary F.D.P. level provides a rapid and convenient means of estimating the differential protein clearance.

Topics: Albuminuria; Amyloidosis; Chromatography; Fibrin; Fibrinogen; Filtration; Glomerular Filtration Rate; Glomerulonephritis; Humans; Hypersensitivity; Hypertension, Malignant; Immunodiffusion; Immunoglobulin G; Lupus Erythematosus, Systemic; Molecular Weight; Nephrotic Syndrome; Proteinuria; Purpura; Thrombosis; Transferrin

During experimental Masugi nephritis in the rabbit, were demonstrated various disturbances in hemostasis: a) during the initial stage: immediate, severe and transient fall in the platelet count without any change in Factor V;b)during the secondary stage, from the 7th to the 8th day onwards, increase in platelets and fibrinogen, in relation with the intensity of the nephrotic syndrome; c) in parallel, appearance of urinary fibrinogen split products in relation to the intensity of the glomerular lesions, evidence for the presence of intraglomerular fibrin. These facts confirm the role played by platelets in coagulation phenomena secondary to the immune reaction. They indicate, furthermore, the existence of hemostasis disorders during the nephrotic syndrome.

Topics: Animals; Antigens; Blood Cell Count; Blood Coagulation; Blood Platelets; Complement System Proteins; Ducks; Factor V; Fibrin; Fibrinogen; Glomerulonephritis; Hematocrit; Immune Sera; Kidney Glomerulus; Nephrotic Syndrome; Platelet Aggregation; Proteinuria; Rabbits

The concentration of fibrin/fibrinogen degradation products in urine (FDPu) was measured in samples obtained from 114 patients and 63 clinically healthy volunteers, once or repeatedly. The FDP titers measured by the hemagglutination inhibition (HI) method corresponded to less than 2.6 mug/ml FDP in all samples from healthy controls. Slightly elevated FDP concentrations were found in urine obtained from a few patients with disorders not primarily involving the urinary tract. The clinical importance of these isolated findings remains unclear. Urinary tract infections were not frequently accompanied by elevated FDPu concentrations. In patients with glomerulonephritis FDP excretion correlated somewhat better with severity of the renal affection. A further group of patients showed an unequivocal correlation between FDP excretion in the urine and postoperative complications following renal transplantation. However, the clinical diagnosis of acute rejection crisis was usually established at the same time or even before an increase in FDPu was found. Our results suggest that among diagnostic procedures the measurement of FDPu contributes little specific information for the evaluation of urinary tract disease. FDPu measurements in the immediate postoperative phase following renal transplantation may however be important for prognostic evaluation and, in individual cases, predict transplant rejection. We also attempted to define the FDPu qualitatively by simultaneous measurements using HI and the staphylococcal clumping test (SCT). Immunoelectrophoresis confirmed the well-known fact that the SCT detects only high-molecular FDP; this limits its clinical usefulness, despite its high sensitivity.

Topics: Female; Fibrin; Fibrinogen; Glomerulonephritis; Graft Rejection; Hemagglutination Inhibition Tests; Humans; Hydronephrosis; Kidney Calculi; Kidney Transplantation; Male; Pregnancy; Pregnancy Complications; Proteinuria; Pyelonephritis; Time Factors; Transplantation, Homologous; Urologic Diseases

Four patients had clinical manifestations of the hemolytic-uremic syndrome. No evidence of active intravascular coagulation was found during the acute phase of the illness, using a sensitive assay to measure soluble circulating fibrin in the plasma of these patients, three of whom developed the clinical syndrome while hospitalized for gastro-enteritis. These findings, coupled with the findings of others, suggest that either the episode of intravascular coagulation precedes the development of the clinical manifestations, or that platelet thrombosis is occurring in the absence of activation of plasma clotting factors. In any case, heparin anticoagulant therapy does not seem indicated.

Topics: Anuria; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Blood Pressure; Blood Urea Nitrogen; Carbon Radioisotopes; Child; Child, Preschool; Creatinine; Disseminated Intravascular Coagulation; Factor V; Factor VIII; Female; Fibrin; Fibrinogen; Hematuria; Hemoglobins; Hemolytic-Uremic Syndrome; Heparin; Humans; Infant; Male; Proteinuria; Prothrombin Time; Thromboplastin; Thrombosis

Host-versus-graft (HVG) disease is the fatal result of the allogenic reaction which occurs in parental strain mice perinatally inoculated with F(1) hybrid spleen cells. The principal manifestations of the syndrome in RFM/(T(6) X RFM)F(1) mice are thrombocytopenia, intestinal hemorrhage, hepatic necrosis, lymphoproliferative disorders and renal disease due to immune complexes. The discovery of intravascular fibrin deposits in the present studies establishes disseminated intravascular coagulation (DIC) as an intermediary mechanism of HVG disease. It is suggested that the characteristic declines in blood platelet levels, intestinal hemorrhages and hepatic infarcts are triggered principally by immune complexes. Cellular infiltrates of the liver, granulocytosis and hypergammaglobulinemia are other abnormalities which are regularly found in HVG mice and which are also thought to predispose to DIC.

Topics: Animals; Antigen-Antibody Complex; Blood Vessels; Chimera; Disseminated Intravascular Coagulation; Fibrin; Graft vs Host Disease; Hybridization, Genetic; Immunoglobulin G; Infarction; Injections, Intraperitoneal; Kidney; Leukocyte Count; Liver; Mice; Mice, Inbred Strains; Mosaicism; Proteinuria; Spleen; Thrombocytopenia

In view of the association between pre-eclampsia and disseminated intravascular coagulation, three patients presenting with severe pre-eclampsia before the 28th week of pregnancy were treated with heparin. In all three patients, there was deterioration of hypertension and proteinuria that necessitated the withdrawal of treatment after five to six days. During treatment, serum and urinary fibrinolytic degradation products (FDPs) continued to rise or remained unaltered, plasminogen levels showed a steady fall, and the platelet count remained at a reduced level. These data suggest that heparin was an ineffective form of treatment and did not prevent the intravascular fibrin deposition associated with severe pre-eclampsia.

Topics: Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Dipyridamole; Disseminated Intravascular Coagulation; Female; Fibrin; Heparin; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Second; Proteinuria

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.

Topics: Ancrod; Animals; Antibodies; Antigen-Antibody Complex; Basement Membrane; Disease Models, Animal; Endopeptidases; Fibrin; Immunoglobulin G; Kidney Glomerulus; Male; Nephritis; Proteinuria; Rabbits; Serum Albumin, Bovine; Serum Sickness; Urea

Topics: Complement C6; Fibrin; Humans; Immunoglobulin A; Kidney Glomerulus; Nephrotic Syndrome; Obesity; Proteinuria

Topics: Adult; Animals; Blood Urea Nitrogen; Creatinine; Disseminated Intravascular Coagulation; Female; Fibrin; Glomerulonephritis; Humans; Hyalin; Kidney; Kidney Glomerulus; Lung; Male; Middle Aged; Pneumococcal Infections; Pneumonia, Pneumococcal; Proteinuria; Rats; Sepsis; Streptococcus pneumoniae; Thrombosis; Uremia

Topics: Acute Kidney Injury; Biopsy; Cell Migration Inhibition; Fibrin; Fluorescent Antibody Technique; Glomerulonephritis; Humans; Immune Complex Diseases; Male; Necrosis; Peritoneal Dialysis; Proteinuria; Remission, Spontaneous; Streptococcal Infections

Topics: Acute Kidney Injury; Anemia; Basement Membrane; Blood Coagulation Disorders; Capillaries; Epithelial Cells; Fibrin; Fluorescent Antibody Technique; Glomerulonephritis; Hematuria; Histocytochemistry; Humans; Immunoglobulins; Kidney; Kidney Glomerulus; Kidney Tubules; Microscopy, Electron; Prognosis; Proteinuria; Statistics as Topic

Topics: Adult; Biopsy; Blood Platelets; Blood Pressure; Complement System Proteins; Female; Fibrin; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Kidney; Liver; Male; Nephritis; Pedigree; Proteinuria; Renin; Reticulocytes; Uremia

The relations between glomerular fibrin deposition, urinary excretion of fibrinogen derivatives (F.D.), and proteinuria were explored in 81 patients with glomerulonephritis. A positive correlation existed between proteinuria and F.D. excretion even when no fibrin could be detected in the glomerulus. In two patients with tubular proteinuria F.D. excretion was also raised, suggesting that tubular reabsorption or catabolism of F.D. or both normally occur.Disproportionately high titres of F.D. were observed when fibrin was deposited in an extracapillary site, but mesangial fibrin deposition was not accompanied by a higher excretion of F.D. than that observed in patients in whom intraglomerular fibrin was not detected. These observations suggest that the immunofluorescent findings on renal biopsies should be the major criteria on which a trial of anticoagulants in proliferative glomerulonephritis might be instituted and that measurement of urinary F.D. is likely to be of value in monitoring therapy in patients with extracapillary fibrin deposition.

Topics: Biopsy; Fibrin; Fibrinogen; Fluorescent Antibody Technique; Glomerulonephritis; Hemagglutination Inhibition Tests; Humans; Kidney Glomerulus; Proteinuria

Topics: Azathioprine; Blood Coagulation; Cadaver; Creatinine; Drug Evaluation; Fibrin; Graft Rejection; Hemoglobins; Humans; Immunosuppression Therapy; Kidney Function Tests; Kidney Transplantation; Prednisone; Proteinuria; Transplantation, Homologous; Urea; Warfarin

In 15 out of 35 patients with myelomatosis histological examination showed intravascular fibrin within the glomeruli, and this was associated with proliferation of the mesangial complex in 12. The presence of intravascular fibrin and mesangial proliferation was not associated with any specific immunoglobulin abnormality or with the presence or absence of Bence Jones proteinuria. In addition to fibrin being present within glomerular capillaries it was also shown in intertubular capillaries in three cases of myelomatosis with acute tubular necrosis. It is suggested that intraglomerular coagulation and fibrin deposition may contribute to the genesis of renal failure in myelomatosis.

Topics: Acute Kidney Injury; Autopsy; Bence Jones Protein; Biopsy, Needle; Capillaries; Disseminated Intravascular Coagulation; Female; Fibrin; Fluorescent Antibody Technique; Humans; Immunoglobulin A; Immunoglobulin D; Immunoglobulin G; Kidney; Kidney Glomerulus; Kidney Tubules; Male; Microscopy; Multiple Myeloma; Proteinuria; Retrospective Studies; Thromboembolism; Urea

Topics: Adolescent; Basement Membrane; Biopsy; Child; Child, Preschool; Female; Fibrin; Fibrinogen; Fluorescent Antibody Technique; Follow-Up Studies; Humans; Kidney; Kidney Function Tests; Kidney Glomerulus; Male; Microscopy, Electron; Microscopy, Fluorescence; Proteinuria

Topics: Aspirin; Blood Coagulation; Complement System Proteins; Diabetic Nephropathies; Dipyridamole; Fibrin; Fibrinogen; Glomerulonephritis; Hemolytic-Uremic Syndrome; Heparin; Humans; Iodine Radioisotopes; Kidney; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Plasminogen; Proteinuria; Thrombosis; Transplantation, Homologous; Uremia; Warfarin

Topics: Child; Child, Preschool; Female; Fibrin; Fibrinogen; Hematuria; Humans; Infant; Kidney Diseases; Male; Nephritis; Nephrosis; Nephrotic Syndrome; Proteinuria; Purpura; Urinary Tract Infections

Indomethacin given to adults with glomerulonephritis usually reduces their urinary excretion of protein and fibrinogen/fibrin-related (F.R.) antigen. Nevertheless, non-responders exist. Platelet aggregation is significantly more strongly inhibited by indomethacin in good responders than in nonresponders. This supports the hypothesis that the reduction of urinary excretion of F.R. antigen during indomethacin administration is related, at least in part, to inhibition of intrarenal platelet aggregation and of the subsequent fibrin deposition.

Topics: Adolescent; Adult; Antigens; Blood Coagulation; Blood Platelets; Chronic Disease; Creatinine; Female; Fibrin; Glomerulonephritis; Humans; Indomethacin; Male; Middle Aged; Platelet Adhesiveness; Proteinuria

Topics: Female; Fibrin; Fibrinogen; Fibrinolysis; Hematuria; Humans; Kidney Diseases; Kidney Pelvis; Male; Prostate; Proteinuria; Ureter; Urethra; Urinary Bladder; Urinary Tract

Topics: Adolescent; Adult; Animals; Antibodies; Child; Chromatography, Gel; Electrophoresis, Polyacrylamide Gel; Fibrin; Fibrinogen; Fibrinolysis; Fluorescent Antibody Technique; Glomerulonephritis; Humans; Hydrocortisone; Immunodiffusion; Immunoelectrophoresis; Middle Aged; Nephrosis, Lipoid; Proteinuria; Rabbits

Topics: Animals; Biopsy; Disease Models, Animal; Fibrin; Immunoglobulin G; Injections, Intravenous; Kidney; Kidney Glomerulus; Kidney Transplantation; Kidney Tubules; Nephrotic Syndrome; Proteinuria; Puromycin; Rats; Time Factors; Transplantation, Homologous

Topics: Aminocaproates; Animals; Blood Pressure; Blood Vessels; Creatinine; Disease Models, Animal; Female; Fibrin; Fibrinolysis; Half-Life; Iodine Isotopes; Kidney; Kidney Glomerulus; Liver; Lung; Placenta; Povidone; Pre-Eclampsia; Pregnancy; Proteinuria; Rabbits; Renin

Topics: Adolescent; Adult; Aged; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Complement System Proteins; Creatinine; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Fibrinolysis; Glomerulonephritis; Humans; Kidney Diseases; Kidney Glomerulus; Lupus Erythematosus, Systemic; Male; Middle Aged; Proteinuria; Prothrombin Time

Topics: Adolescent; Child; Child, Preschool; Female; Fibrin; Glomerulonephritis; Hematuria; Humans; Hypersensitivity; Immunoglobulin A; Immunoglobulin G; Immunosuppression Therapy; Male; Proteinuria; Purpura; Respiratory Tract Infections; Serum Globulins

Topics: Animals; Antibodies, Heterophile; Biopsy; Fibrin; Glomerulonephritis; Immune Sera; Kidney; Proteinuria; Rabbits

Topics: Acute Disease; Acute Kidney Injury; Adult; Biopsy; Blood Vessels; Capillaries; Female; Fibrin; Follow-Up Studies; Humans; Kidney; Kidney Glomerulus; Microscopy, Electron; Microscopy, Fluorescence; Pre-Eclampsia; Pregnancy; Prognosis; Proteinuria; Puerperal Disorders

Topics: Adolescent; Adult; Aged; Antigens; Child; Chromatography, Gel; Creatinine; Female; Fibrin; Fibrinogen; Follow-Up Studies; Glomerulonephritis; Humans; Indomethacin; Kidney; Kidney Function Tests; Male; Middle Aged; Proteinuria

Topics: Abortion, Induced; Adolescent; Biopsy; Female; Fibrin; Glomerulonephritis; Humans; Kidney; Kidney Function Tests; Lupus Erythematosus, Systemic; Pregnancy; Pregnancy Complications; Prognosis; Proteinuria

Topics: Female; Fibrin; Glomerulonephritis; Humans; Pre-Eclampsia; Pregnancy; Proteinuria

The possible role of fibrin deposition in the development of diabetic glomerulosclerosis has been investigated by light, immunofluorescence, and electron microscopy examination of renal tissue obtained by percutaneous biopsy from seven diabetic patients having minimal clinical evidence of renal involvement and at necropsy on nine diabetic patients. Although the biopsy specimens showed only early to moderate diffuse glomerulosclerosis without either nodular or exudative lesions, approximately 70% of glomeruli examined showed specific fluorescence for fibrinogen in a discontinuous linear pattern along the capillary basement membrane and diffusely in the mesangium. Moreover the immunofluorescence findings correlated well with the distribution patterns of material thought to be fibrin both in the light microscopy studies, by virtue of its staining properties, and by electron microscopy, because of periodicity, texture, and electron density. It is suggested that electron-dense granular deposits seen on electron microscopy may represent intermediate compounds in the fibrinogen to fibrin conversion, and that endothelial and mesangial trapping of fibrinogen or other macromolecules may initiate or accelerate mesangial enlargement, nodule formation, and irregularity of the basement membrane.

Topics: Adult; Aged; Autopsy; Basement Membrane; Biopsy; Blood Pressure; Creatinine; Diabetic Nephropathies; Epithelium; Female; Fibrin; Fibrinogen; Fluorescent Antibody Technique; Histocytochemistry; Humans; Kidney Glomerulus; Male; Microscopy, Electron; Middle Aged; Nephrosclerosis; Proteinuria

The concentration of serum fibrinogen-fibrin-related antigen (F.R.-antigen) was measured in a group of 142 patients with various renal disorders, in 38 of whom urine F.R.-antigen was also estimated. Raised serum F.R.-antigen levels were present in 48% of the patients, with no particular preponderance in any diagnostic category apart from acute reversible intrinsic renal failure in which high levels were invariably present. Significantly-raised serum levels were also present in the patients with microangiopathic haemolytic anaemia and in those with the more severe degrees of renal impairment. Urine F.R.-antigen was increased in 34 of the 38 patients. The amount of F.R.-antigen in the urine correlated with the degree of proteinuria but not with the serum F.R.-antigen levels. The evidence relating to intravascular coagulation in renal disease is reviewed, and it is suggested that there is a high incidence of localized fibrinogen or fibrin degradation in the kidney, which is related more to factors such as the presence of uraemia and microangiopathic haemolytic anaemia rather than to the diagnostic category.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Anemia, Hemolytic; Antigens; Child; Child, Preschool; Female; Fibrin; Fibrinogen; Glomerulonephritis; Hemagglutination Inhibition Tests; Humans; Hypertension, Malignant; Kidney Diseases; Male; Middle Aged; Proteinuria; Uremia

Topics: Adolescent; Azathioprine; Biopsy; Child; Child, Preschool; Female; Fibrin; Glomerulonephritis; Humans; Immunoglobulin G; Infant; Kidney Glomerulus; Male; Microscopy, Fluorescence; Nephrotic Syndrome; Prednisone; Proteinuria; Purpura; Skin; Syndrome

Topics: Adolescent; Adult; Arteries; Azaserine; Azathioprine; Basement Membrane; Creatine; Cryptococcosis; Dactinomycin; Epithelial Cells; Female; Fibrin; Fluorescent Antibody Technique; Follow-Up Studies; Graft Rejection; Hematuria; Humans; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Papillary Necrosis; Kidney Transplantation; Male; Mercaptopurine; Pneumonia; Prednisone; Proteinuria; Thrombosis; Transplantation Immunology; Transplantation, Homologous

Topics: Centrifugation, Density Gradient; Female; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Hemagglutination Inhibition Tests; Humans; Immunoelectrophoresis; Indicators and Reagents; Male; Physical Exertion; Plasminogen; Proteinuria; Time Factors

The coagulation and fibrinolytic mechanisms were investigated in a group of patients with severe pre-eclampsia and eclampsia and the findings were compared with those of healthy women in late pregnancy. In patients with pre-eclampsia the following significant differences were found: (1) greater depression of plasma fibrinolytic activity (euglobulin lysis time) than in normal pregnancy, (2) a higher level of inhibitor to urokinaseinduced lysis, (3) increased levels of serum fibrin degradation products, and (4) reduced platelet counts.In patients with eclampsia a progressive increase of the level of serum fibrin degradation products was found over the three days following eclamptic seizures. No such increase occurred after grand mal seizures in late pregnancy. The findings in this study support the view that intravascular clotting is taking place in pre-eclampsia and that this disturbance of the balance between coagulation and fibrinolysis may be localized to certain areas of the vascular compartment, particularly the placental and renal circulations. Fibrin deposition in the maternal vessels supplying the placenta would impair the placental blood flow, which may explain the placental insufficiency which occurs in pre-eclampsia. Likewise fibrin deposition in the renal vasculature will result in glomerular damage and proteinuria. Hypertension may be related to the renal ischaemic changes or a compensatory response to the presence of fibrin deposition in the vascular compartment. This evidence of intravascular fibrin deposition raises the question of the possible therapeutic value of antithrombotic agents to inhibit the clotting process. On a theoretical basis such treatment might be expected to improve blood flow to the placenta and thereby fetal growth.

Topics: Adult; Blood Coagulation; Blood Platelets; Eclampsia; Embryonic and Fetal Development; Epilepsy, Tonic-Clonic; Female; Fibrin; Fibrinolysis; Fibrinolytic Agents; Humans; Hypertension; Ischemia; Kidney; Kidney Diseases; Maternal-Fetal Exchange; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Serum Globulins

The serum and urine concentrations of fibrin/fibrinogen degradation products (F.D.P.) were estimated in 172 patients with glomerulonephritis. In each case the diagnosis was established on the basis of clinical, renal histological, and ultrastructural findings. Serum F.D.P. concentrations were often raised in all types of glomerulonephritis, though more consistently in active proliferative forms. The urinary concentration provided a reliable and sensitive index of activity, progression, and natural history in proliferative glomerulonephritis. In these forms the urinary F.D.P. content was thought to reflect predominantly lysis of intraglomerular fibrin deposits. In minimal lesion and membranous glomerulonephritis low but abnormal concentrations of urinary F.D.P. were consistently found. It is suggested that in these cases the products are derived from limited proteolysis of fibrinogen filtered through an abnormally permeable basement membrane.Daily measurement of urinary F.D.P. concentration is of potential value in the differential diagnosis of patients with glomerulonephritis and at the same time provides a sensitive assessment of the activity and natural history of proliferative disease.

Topics: Basement Membrane; Biopsy; Creatinine; Diagnosis, Differential; Fibrin; Fibrinogen; Fibrinolytic Agents; Glomerulonephritis; Hemagglutination Tests; Humans; Kidney; Microscopy, Electron; Proteinuria

Topics: Animals; Dicumarol; Female; Fibrin; Fibrinogen; Fibrinolytic Agents; Heparin; Mice; Nephritis; Proteinuria

Topics: Animals; Basement Membrane; Complement System Proteins; Fibrin; Fibrinogen; Fibrinolytic Agents; Fluorescent Antibody Technique; gamma-Globulins; Glomerulonephritis; Heparin; Immune Sera; Kidney; Kidney Glomerulus; Mice; Nephritis; Proteinuria; Rabbits

Topics: Animals; Blood Coagulation; Fibrin; Fibrinogen; Fibrinolysis; Fluorescent Antibody Technique; Glomerulonephritis; Kidney; Mice; Phenols; Proteinuria; Streptococcus; Sulfonic Acids

Topics: Animals; Fibrin; Fibrinogen; Fibrinolysis; Fluorescent Antibody Technique; Glomerular Filtration Rate; Histocompatibility; Humans; Immune Sera; Immunoassay; Immunoelectrophoresis; Ischemia; Kidney; Kidney Transplantation; Macromolecular Substances; Prednisone; Proteinuria; Rabbits; Time Factors; Transplantation Immunology; Transplantation, Homologous

Topics: Animals; Antigens; Electrophoresis; Fibrin; Humans; Immunodiffusion; Jaundice; Kidney; Kidney Transplantation; Macromolecular Substances; Proteinuria; Rabbits; Transplantation Immunology; Transplantation, Homologous

Topics: Animals; Fever; Fibrin; Fibrinogen; Fluorescent Antibody Technique; Humans; Immunodiffusion; Immunoelectrophoresis; Immunosuppressive Agents; Kidney; Kidney Transplantation; Prednisone; Proteinuria; Rabbits; Transplantation Immunology; Transplantation, Homologous

Topics: Animals; Antigen-Antibody Reactions; Blood Coagulation; Electrons; Fibrin; Fluorescent Antibody Technique; Glomerulonephritis; Microscopy; Microscopy, Electron; Pathology; Proteinuria; Rabbits; Research; Warfarin

Topics: Blood Proteins; Body Fluids; Fibrin; Humans; Multiple Myeloma; Plasma Cells; Proteinuria; Urine