fibrin and Lupus-Nephritis

The risk for endstage renal failure in patients with proliferative lupus nephritis (PLN) depends largely on the severity and reversibility of the inflammatory process as determined by light microscopy (LM). As the intrarenal formation of immune complexes is thought to initiate this inflammation, we studied whether renal immunofluorescence microscopy (IFM) provides clinical or prognostic information in addition to LM findings. Clinical data at the time of renal biopsy and during a mean follow-up of 46 months were extracted from the records of 69 SLE patients with proliferative LN (WHO class III/IV). Biopsy specimens were analyzed by LM for AI and CI, while IFM was performed on cryostat sections with the use of antisera against IgG, IgM, IgA, C3, C1q and fibrin. IFM findings were recorded in terms of the localization (glomerular, tubular or vascular) and intensity of fluorescence (score from zero to three). IFM findings were then related to clinical and LM findings and its prognostic value studied by survival analysis. Glomerular immune deposits were present in 99% of patients, tubular deposits in 38% and vascular deposits in 17%. A 'full-house' pattern (all three Ig classes) was found in 67% of biopsies and C3 and C1q deposits in 93% and 74% respectively. Median scores for AI and CI were 6 (1-18) and 3 (0-10); aside from a negative correlation between IgA deposits and CI, we found no other correlation between the amount or type of immune deposits and AI or CI. IgM deposits were associated with high serum levels of anti-dsDNA, while IgG deposits correlated with high ESR and serum creatinin levels. IFM scores were not related to steroid dose at the time of biopsy and neither type of glomerular, tubular or overall renal immune deposits had prognostic value for renal survival. Renal immunofluorescence does not reflect light microscopy findings in patients with PLN and does not contribute prognostic information in patients with PLN. Lupus (2000) 9, 504-510.

Topics: Adolescent; Adult; Complement C1q; Complement C3; Female; Fibrin; Fluorescent Antibody Technique; Humans; Immunoglobulin A; Immunoglobulin M; Inflammation; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Lupus Nephritis; Male; Microscopy, Fluorescence; Middle Aged; Predictive Value of Tests; Risk Factors; Survival Analysis

Coagulation and fibrinolytic processes are involved in the pathogenesis of some forms of glomerulonephritis. In human renal disease extensive fibrin deposition is mainly associated with severe diseases such as rapidly progressive glomerulonephritis. Staining methods for fibrin have problems and many immunohistochemical methods do not distinguish fibrinogen from fibrin and its degradation products, which result from coagulation. The presence of cross-linked fibrin in the glomerulus indicates that coagulation has occurred, but the presence of fibrinogen may be a result of non-specific protein permeation. A monoclonal antibody (DD3B6) has been used to demonstrate cross-linked fibrin in 30 renal biopsies in systemic lupus erythematosus. The biopsies were also stained with an 'antifibrinogen' and an antiplatelet antibody. The severity of renal disease in each biopsy was graded by both the World Health Organization (WHO) classification and Austin's Activity and Chronicity Indices. Three of the renal biopsies were shown to stain with DD3B6 and five stained with antiplatelet antibody. Twenty-seven contained fibrinogen and there was no evidence of intraglomerular coagulation in these biopsies. The biopsies containing cross-linked fibrin were all in WHO group IVc. The severity of disease measured by Austin's Activity Index was no greater in these biopsies than in other biopsies in WHO Group IVc in which cross-linked fibrin was not detected. The presence of cross-linked fibrin may be associated with intraglomerular coagulation and more severe disease.

Topics: Antigens, Human Platelet; Biopsy; Blood Platelets; Female; Fibrin; Fibrinogen; Humans; Immunohistochemistry; Kidney; Lupus Nephritis; Male; Severity of Illness Index; World Health Organization

Circulating lupus anticoagulant (LA) is associated with thrombosis in large and small vessels. To determine how often the presence of LA is associated with thrombosis within the renal microcirculation, 33 patients with systemic lupus erythematosus (SLE), renal dysfunction, and LA were identified over a 25-year period (LA group) and 32 patients with renal SLE but with normal gross coagulation screen were matched for age, sex, and biopsy timing (C group). Prevalences of serositis, neuropsychiatric illness, leukopenia, thrombocytopenia, hemolysis, anti-DS-DNA elevation, and complement reduction were similar. Arthritis was less and biologic false-positive (BFP) syphilis serology more common in LA. More LA patients had thrombotic events (LA 39% v C 13%; P = 0.014); bleeding episodes, including postbiopsy, were similar. At biopsy, hypertension (LA 55%, C 41%), serum creatinine (mean +/- SD: LA 186 +/- 168 mumol/L [2.1 +/- 1.9 mg/dL] v C 150 +/- 168 mumol/L [1.7 +/- 1.9 mg/dL]) and proteinuria (LA 2.6 +/- 3.1 g/24 h v C 3.1 +/- 2.7) were similar. Lesions by World Health Organization (WHO) class, activity, and chronicity indices, as well as immunofluorescence (IF) and electron microscopy (EM) findings, were not significantly different. Occlusive glomerular, arteriolar, and arterial fibrin thrombi, along with varying degrees of renal thrombotic microangiopathy, were seen in five of 33 patients with LA, but zero of 32 C patients (P = 0.053); three of these five patients died soon after biopsy. Overall, mortality was not different between LA and C. We conclude that the majority of patients with SLE, renal dysfunction, and LA exhibit renal morphologic findings indistinguishable from patients without LA. However, a significant minority of LA patients have thrombotic microangiopathy in their biopsy, which is accompanied by a worse prognosis.

Topics: Adolescent; Adult; Blood Coagulation; Capillaries; Female; Fibrin; Hemorrhage; Humans; Kidney; Kidney Glomerulus; Lupus Coagulation Inhibitor; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Thrombosis

The effect of ancrod, a defibrinating agent, on murine lupus glomerulonephritis in the male BXSB mouse was studied to determine the relationship between macrophage procoagulant activity (PCA), fibrin deposition and glomerulonephritis. Marked renal disease and fibrin deposition were noted by three months of age in control mice, whereas little or no disease was seen in ancrod treated mice until five months of age. Similar high titers of anti-DNA antibodies and renal deposition of IgG were seen in both groups of mice. PCA rose with age in both ancrod treated and untreated mice, although it was significantly higher in control animals than in the ancrod treated group. Furthermore, ancrod therapy resulted in a decrease in plasma PCA inducing activity (PIF) and a decrease in the effectiveness of PIF to induce PCA in peritoneal macrophages in vitro. No mortality was observed in the 20 ancrod treated mice, whereas 10 of 20 control animals died. We conclude that defibrination with ancrod delays the development of renal fibrin deposition and glomerulonephritis and improves survival in BXSB mice. This was associated with a decrease in plasma PCA inducing activity and with an inhibitory effect on PCA induction. These results suggest that PCA contributes to injury in murine lupus glomerulonephritis by promoting fibrin deposition.

Topics: Ancrod; Animals; Blood Coagulation Factors; Fibrin; Fibrinogen; Lupus Nephritis; Macrophages; Male; Mice; Time Factors