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Diagnosis: Collagen type III glomerulopathy (also called collagenofibrotic glomerulopathy)

Type III collagenopathies are rare conditions in which there is diffuse deposition of banded collagen fibrils in the glomerulus and comprise two distinct entities, Nail–Patella syndrome (NPS) and Collagenofibrotic glomerulopathy (CFG). NPS is a pleiotropic autosomal dominant disorder with renal involvement characterized by mesangial and mottled GBM deposits (“moth-eaten” lamina densa) of Type III collagen fibers. CFG, on the other hand, is mostly sporadic in occurrence except few instances of pediatric cases which have shown an autosomal recessive pattern of inheritance. Moreover, the abnormal collagen fibrillary deposition pattern in CFG is characterized by flocculent expansion of mesangial and subendothelial spaces, lamina densa remaining intact. CFG is extremely rare worldwide with only a few dozen cases reported, but is currently being increasingly reported. The pathogenesis of CFG remains elusive with an ongoing debate on whether it is a primary renal disease or secondary manifestation of a systemic disease. Type III collagen is normally found only in renal interstitium and blood vessels and not in the glomerulus. Glomerular deposition has been attributed to local activation of mesangial cells possibly by chemokines such as interleukin-4. In contrast, a systemic origin of the collagen is also suspected based on elevated serum and urinary procollagen Type III peptide (PIIINP) levels. PIIINP is a post-translational cleavage product of Type III collagen, levels of which are mildly elevated in many conditions causing renal fibrosis, but marked elevation of 10–100 times normal is characteristically observed in CFG and serves as a diagnostic serum marker of this entity. While pathogenetic mutations in the LMX1B gene have been identified in the inherited disorder NPS, no underlying genetic basis has been identified yet in CFG, not withstanding an autosomal recessive inheritance pattern documented in pediatric CFG. The natural history of CFG is variable with proteinuria and hypertension as the commonest presenting clinical features. The diagnosis rests on ultrastructural demonstration of curvilinear bundles of Type III collagen fibrils with characteristic cross striations and frayed edges. Immunohistochemistry and IF are also available for confirming the presence of Type III collagen in the glomeruli. CFG often progresses to end-stage renal disease. Treatment is generally supportive and is focused on addressing proteinuria, edema, and hypertension with the use of angiotensin-converting enzyme therapy. Although kidney transplant is not the first line of treatment for CFG, in the few cases where patients received kidney transplants there has been no recurrence of CFG symptoms or pathology (Matthai SM, et al. Collagenofibrotic glomerulopathy - A rare disease diagnosed with the aid of transmission electron microscopy. Indian J Pathol Microbiol. 2020;63(Supplement):S47-S49. [PubMed link]).

See the chapter: kidney involvement in deposit diseases of our Tutorial.

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