Collagenofibrotic glomerulopathy, described mostly from Japan, has been recognized as a distinct entity. The etiology and pathogenesis are unknown. It is usually sporadic and when noticed in siblings the entity has been considered to be an autosomal recessive trait. There has been a speculation whether it is a primary renal disease or manifestation of a systemic disease, i.e., the abnormal collagen is from within the glomerulus or from an extrarenal source.[3
It has been noted that type III collagen, a ubiquitous extracellular structural protein seen only in the interstitium and blood vessels of a normal glomerulus, is also produced by mesangial cells as seen in cell cultures and in situ
hybridization techniques, explaining a local cause for collagen deposition. Interleukin 4 (IL-4) selectively stimulated type III collagen synthesis in human glomerular cells and IL-4 – neutralizing antibodies have prevented renal disease in IL-4 transgenic mice, which developed glomerulosclerosis in the absence of immunoglobulin deposition. These observations have suggested that the disease is a local pathology. Alternatively, the identification of hepatic perisinusoidal fibrosis in collagenofibrotic glomerulopathy and the finding of abnormally high serum procollagen III N-terminal peptide (PIIINP) levels suggest the systemic nature of this disease.[4
Clinically, the most common presenting feature is edema and/or persistent proteinuria that may be of nephrotic range (about 60% of patients). Both the cases discussed here had nephrotic proteinuria but only one of them had edema. Hypertension is seen in two-third of cases at the time of presentation. Anemia may be noticed even before the development of renal dysfunction. Occasionally, microangiopathic hemolytic anemia has been documented in children. Extrarenal symptoms of skeletal or nail abnormalities are absent, unlike in cases of nail-patella syndrome. The natural history of the disease is variable, but is one of inexorable progression. Children are more likely to progress to end-stage renal failure. Successful renal transplantation without recurrence has been documented in one case.
Apart from very high PIIINP levels, other laboratory data are nonspecific. We could not estimate procollagen peptide levels or perform immunohistochemistry for collagen typing. Renal function tests are usually normal or slightly increased at presentation. Urine examination occasionally shows microscopic hematuria and proteinuria but no active sediments. Serologic tests for autoimmunity are negative and monoclonal immunoglobulins are absent in serum or urine.
Pathologic findings on light microscopy are suggestive of a deposition disease. Light microscopy reveals globally enlarged glomerular tufts because of the eosinophilic material in the capillary walls and the mesangium. This material is weakly PAS positive, but Congo red and thioflavin T negative. It also shows strong blue staining with periodic acid-methanamine silver, Aniline blue, and Mason trichrome stains. The thickened peripheral capillary walls resemble the double contour appearance of membranoproliferative glomerulonephritis. No adhesions or crescents are noted. In advanced stages, capillary lumens are narrowed by expanded mesangium and thickened capillary walls and glomeruli show a nodular appearance resembling Kimmelstiel–Wilson lesions. Patchy tubular atrophy and interstitial fibrosis may be present. Arteriolar hyalinosis and thickening of walls of arteries are sometimes seen, secondary to hypertension. Immunofluorescence staining is usually negative.
Immunohistochemistry for specific collagen types shows abundant staining for type III collagen. Electron microscopy is imperative to establish a diagnosis so as to differentiate the immunofluorescence negative deposition diseases such as collagenofibrotic glomerulonephritis, fibronectin glomerulopathy and diabetic glomerulosclerosis. Electron microscopy identifies marked accumulation of fibrillary material in mesangium and subendothelial space of glomerular basement membrane. The material is identified easily on routine staining (gluteraldehyde) or special staining as tannic acid–lead or phosphotungstic acid may be used. The fibers have a transverse band structure with distinct periodicity of approximately 60 nm, same as seen in type III collagen. The fibers are usually curved or frayed (unlike the fibers in the interstitium which are usually straight), forming irregularly arranged bundles on longitudinal section and flower-like or ragged moth-eaten appearance on cross-section. The microtubules as seen in immunotactoid glomerulopathy, fibrin, and amyloid fibrils are not seen. In contrast to nail-patella syndrome, the lamina densa of the glomerular basement membrane in collagenofibrotic glomerulopathy is of normal thickness and lacks the lucent areas or the so-called moth-eaten appearance.
No specific therapy is available. Supportive measures to control hypertension and diuretics to relieve edema are to be employed. Dialysis therapy or renal transplantation may be required for patients who reach end-stage renal disease. Steroid use has been anecdotal and there is no conclusive evidence to prove its efficacy in this disease.
Both cases discussed in this paper were surprise diagnosis on histopathology and suggest the need for electron microscopy for confirmation of this entity. Relative stability of renal dysfunction in both the cases in short term (3–5 years) follow up (from the beginning of symptoms) with standard care therapy looks reassuring. To the best of our knowledge, this could be the first reported case study from India.
To conclude, any type of deposition disease on light microscopy, either immunofluorescence positive or negative should be subjected to electron microscopy so as to differentiate the various fibers based on the size, shape, or presence of transverse bands and make a confirmatory diagnosis.