Familial glomerulonephritis characterized by massive deposits of fibronectin

Abstract

• In recent years more than 150 cases of glomerulonephritis characterized by deposits of irregularly arranged fibrils have been documented. In the majority of these cases immunoglobulins and complement are the prime constituents of these deposits. We recently made a diagnosis of fibrillary glomerulonephritis without immunoglobu lin deposition in two members of a family, a father and a son. In the father, proteinuria was first discovered 18 years ago. In 1985 he was referred to our outpatient clinic because of hypertension and increasing proteinuria. From that time onward he was regularly seen for blood pressure control, Nephrotlc-range proteinuria persisted, without hardly any evidence of deterioration of renal function. Renal biopsies were performed in 1985 and 1993. His son underwent a renal biopsy in 1993 because of moderate proteinuria. The biopsies of both patients disclosed a distinct form of fibrillary glomerulonephritis that w as characterized by massive deposits of a homogeneous, eosinophilic material in the mesangial and subendothelial areas. Staining for amyloid was negative. Immunofluo rescence revealed that the biopsy specimens only stained faintly for immunoglobulins, complement factors C lq and C3, the extracellular matrix proteins, collagen IV, and laminln, However, they strongly stained for fibronectin. Using monoclonal antibodies specific for cell-derived fibronectin (lST-9) and plasma-and cell-derived fibronectin (IST-4), in the biopsy of the son we demonstrated that the fibronectin deposited in the glomeruli was mainly derived from the plasma, and to a lesser extent from resident glomerular cells. In addition, a moderate staining for amyloid P and vitronectin also was present. No or minor enhanced staining for collagen I, HI, or V, heparan sulfate proteoglycan or its glycosaminoglycan side chains, tenascin, or thrombospondin could be observed. By electron microscopy the deposits in the mesangîum and the subendothelial spaces appeared focally to be com posed of irregularly arranged fibrils or microtubules 10 to 12 nm in diameter. Fibrillary glomerulonephritis with massive deposits of fibronectin represents a rare form of familial glomerulonephritis. In our patients the glomerulo nephritis has an indolent course with hardly any deterioration of renal function.

Mutations in FN1 cause glomerulopathy with fibronectin deposits

“…Based on this evidence and on the results of functional studies presented here, we suggest that GFND-associated mutations in FN1 impair the control of the assembly of FN into fibrils and the balance between soluble and insoluble FN, which could explain the abnormal incorporation of nonfibrillary pFN in the glomerular matrix that has been documented in renal biopsy specimens of patients participating to the present study. GFND is a very rare disease (1,8,10,11,28) however, the present data may have implications for the understanding of the pathogenesis of more common renal diseases characterized by FN glomerular deposits, such as diabetic nephropathy (29), IgA nephropathy (30), and lupus nephritis (31).…”

“…Renal biopsy showed glomerular lesions similar to those seen in his father with massive deposits in the mesangial area and to a lesser extent in the subendothelium (10) that showed a fine granular pattern alternating with areas containing more regularly arranged fibrils. Immunofluorescence showed strong staining for plasma FN (10). At the last update, the other son, 21 years old, was healthy.…”

“…The family is from The Netherlands and includes two affected subjects (10). The index case is a male who developed low-grade proteinuria at 29 years of age.…”

“…Overall, we have studied 15 different families, including most of the published (1,8,10,11) and additional unpublished pedigrees, six of which (40%) carried FN1 mutations. All affected subjects carried the mutation, and segregation was compatible with autosomal dominant inheritance (Fig.…”

“…Renal biopsy specimens of GFND patients showed extensive FN deposits in the mesangium and subendothelial space that are mainly granular with only some admixture of irregularly arranged fibrils (1,8,10). By using specific antibodies for pFN and cellular FN, it was documented that glomerular FN deposits are mainly derived from plasma and to a lesser extent from resident glomerular cells (1,8,10).…”