Light microscopic examination of the specimen was not diagnostic. The thickened capillary walls and mesangial expansion would have raised the possibility of membranous glomerulopathy (especially an advanced stage with extensive basement membrane remodeling) and membranoproliferative glomerulonephritis (although there was not much hypercellularity). Fibrillary glomerulonephritis and immunotactoid glomerulopathy also would be in the light microscopic differential diagnosis. The glomerular histologic changes resemble alterations that can be caused by the thrombotic microangiopathies, but there were no extraglomerular vascular changes to support this possibility and the clinical history was not compatible with a thrombotic microangiopathy.
Immunofluorescence microscopy did not support an immune complex mediated glomerulopathy because there was no glomerular staining for immunoglobulins or complement.
The electron microscopy findings were diagnostic for collagenofibrotic glomerulopathy, which is characterized pathologically by massive accumulations of banded collagen in glomerular mesangial and subendothelial zones. Banded collagen (e.g. type I and type III) occurs focally and in small amounts with many forms of glomerular injury, but is usually, but not always, inconspicuous ultrastructurally, even with advanced glomerular sclerosis. Most matrix expansion in the sclerosis of injured glomeruli is caused by increased nonbanded type IV collagen. Abnormal accumulation of banded collagen are an ultrastructural pathologic hallmark of nail-patella syndrome glomerulopathy; however, in this disease, the profiles of banded collagen occur predominantly within the lamina densa of glomerular basement membranes, whereas, in collagenofibrotic glomerulopathy, the abnormal collagen bundles are predominantly in the subendothelial zone and mesangium.
At high magnification, the curvilinear structures have the typical periodicity of banded collagen. This finding, as well as the shape, size and organization of the bundles, clearly differentiates them from other types of organized glomerular deposits, e.g., the deposits of amyloidosis, fibrillary glomerulonephritis and immunotactoid glomerulopathy.
Collagenofibrotic glomerulopathy is a rare disease that usually presents with the nephrotic syndrome and renal insufficiency. Effective treatment for this disease has not been determined. This distinctive glomerulopathy was first reported in 1979 by Masaaki Arakawa at the annual meeting of the Japanese Society of Nephrology (1). Arakawa and Yamanaka subsequently published a collection of 10 cases from Japan in the proceedings of a workshop held in Tokyo in 1989 (2). [One of these patients also has been published in Clinical Nephrology (3).] The 10 patients ranged from 30 to 65 years old, 6 were male, all had proteinuria (ranging from 0.8 to 8.6 g/day), none were noted to have more than slight hematuria, and serum creatinine ranged from 0.7 to 4.2 mg/dl.
A Canadian patient described in 1982 by Dombros and Katz may have been the first example of this disease reported outside Japan (4). In 1991, Imbasciati reported an Italian patient with the typical pathologic features of collagenofibrotic glomerulopathy and demonstrated that the abnormal collagen deposits contained predominantly type III collagen (5), which also had been observed in Japanese patients (2).
The patient described in this month's renal biopsy case was reported in an abstract in 1993 (6).
In 1993, Gubler et al reported 10 French children with collagenofibrotic glomerulopathy who had evidence for familial renal disease with an autosomal recessive transmission (7). Nail-patella syndrome was ruled out. The children had proteinuria, often progressing to nephrotic syndrome, and hypertension. Renal failure developed in four patients.
The pathogenesis of this disease is unknown. Some patients have elevated serum levels of type III procollagen (2,8) suggesting upregulation of collagen synthesis.
Jeffrey Kopp and his associates at the NIH have recently described a transgenic mouse model that develops glomerular lesions similar to human collagenofibrotic glomerulopathy (9). These mice are transgenic for an active form of TGF- B1. Although the transgene is expressed in the liver, there are increased circulating levels of TGF-B1. Lines of transgenic mice with the highest levels of TGF-B1 develop proteinuria, nephrotic syndrome and progressive renal failure. Glomeruli have increased matrix material that contains banded collagen resembling the lesions of collagenofibrotic glomerulopathy. It would be interesting to evaluate patients with collagenofibrotic glomerulopathy for abnormal levels of TGF-B and other cytokines that promote collagen synthesis.
1. Arakawa M, Hueki H, Sato M, Yamashita K, Nakashima S: Idiopathic mesangiodegenerative glomerulonephropathy. A proposal of a new glomerular disease. Jpn J Nephrol 21:1404 (abstract), 1979.
2. Arakawa M, Yamanaka N: Collagenofibrotic glomerulonephropathy. Nishimura Co, Ltd, Niigata, Japan, and Smith-Gordon and Co, Ltd, London, 1991
3. Ikeda K, Yokoyama H, Tomosugi N, Kida H, Ooshima A, Kobayashi K: Primary glomerular fibrosis: a new nephropathy caused by diffuse intra-glomerular increase in atypical type III collagen fibers. Clin Nephrol 33:155, 1990.
4. Dombros N, Katz A: Nail-patella like renal lesion in the absence of skeletal abnormalities. Am J Kidney Dis 1:237, 1982.
5. Imbasciati E, Gheradi G, Morozumi K, Gudat F, Epper R, Basler V, Mihatsch M: Collagen Type III glomerulopathy: A new idiopathic glomerular disease. Am J Nephrol 11:422, 1991.
6. McPhail AH, Harvey DL, Falk RJ, Jennette JC: Collagen glomerulopathy: A patholgically distinct disease. Modern Pathol 1993; 6:118A
7. Gubler MC, Dommergues JP, Foulard M, Bensman A, Leroy JP, Broyer M, Habib R: Collagen type III glomerulopathy: a new type of hereditary nephropathy. Pediatric Nephrology 7:354-360, 1993.
8. Mizuiri S, Hasegawa A, Kikuchi A, Amagasaki Y, Nakamura N, Sakaguchi H: A case of collagenofibrotic glomerulopathy associated with hepatic perisinusoidal fibrosis. Nephron 63:183-187, 1993.
9. Kopp JB, Factor VM, Mozes M, Nagy P, Sanderson N, Bottinger EP, Klotman PE, Thorgeirsson SS: Transgenic mice with increased plasma levels of TGF-B1 develop progressive renal disease., Lab Invest, in press.
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