Keywords

Introduction/Historical Perspective

This entity was first reported by Arakawa in 1979 (Arakawa et al. 1979). Dombros and Kats published a case in 1982 which they thought was a variant of nail-patella glomerulopathy without skeletal abnormalities (Dombros and Katz 1982), and a second case was published 2 years later (Salcedo 1984). Ikeda recognized the peculiar fibers present in glomeruli in 1990 (Ikeda et al. 1990). In 1995, collagenofibrotic glomerulopathy was first included in the World Health Organization classification of glomerular diseases. Since then, more than 40 cases have been published, and understanding of this disorder has been significantly advanced (see Pathogenesis). Most cases have been identified in Asia, and the first patients in Latin America were reported in 2009 (Ferreira et al. 2009).

Clinical Presentation/Epidemiology Initial presentation of this disease is quite variable. The patients have ranged from 6 to 72 years with no sex predilection. Familial occurrence of this disorder has been documented, and an autosomal recessive pattern of inheritance has been proposed. Extrarenal symptoms and findings are almost always absent. The first symptoms of this disease may appear in early childhood or in late adulthood. The most common clinical presentation is persistent proteinuria with or without associated nephrotic syndrome with minor alterations in renal function. These patients can also exhibit varying degrees of hematuria (though hematuria is often absent) and hypertension (Duggal et al. 2012; Patro et al. 2011; Imbasciati et al. 1991; Gubler et al. 1993; Tamura et al. 1996; Yoshioka et al. 1989). No skeletal manifestations are present. Renal function deterioration appears to be a late event.

The disease appears to be primarily a renal process, but in one case, liver involvement with perisinusoidal fibrosis has been reported (Mizuiri et al. 1993). Collagen III deposition may be detected in other organs including the heart, liver, spleen, and thyroid gland, among other sites (Yasuda et al. 1999).

Hemolytic anemia, hemolytic uremic syndrome, and unexplained respiratory symptoms have been reported (Gubler 2008). A few cases have been associated with factor H deficiency (Gubler 2008; Vogt et al. 1995). A link between collagenofibrotic glomerulopathy and complement system defects has been proposed.

Many of the cases have been reported in Japan suggesting racial and geographic predilection; however, sporadic cases continue being reported (Tamura et al. 1996; Yoshioka et al. 1989).

Histology/Pathologic Findings/Differential Diagnosis

Gross Pathology

There are no gross descriptions of the kidneys in this disorder.

Light Microscopy

The glomerular compartment is the one typically affected in this condition. Glomerular findings are generally diffuse and generalized. The glomeruli appear enlarged predominately as a result of mesangial expansion. Nevertheless, the light microscopic findings of this condition are rather non-specific with an increase in mesangial matrix (Fig. 1) which shows enhanced argyrophilia and occasional thickening of peripheral capillary walls, especially in early manifestations of the glomerular process. Weak PAS positivity is seen in the expanded mesangial areas and in the expanded subendothelial zones (Fig. 2). Trichrome stain highlights collagen deposition (Fig. 3a) and eventual mesangial nodularity (Fig. 3b). Mesangial hypercellularity may be identified in some cases (Mizuiri et al. 1993; Vogt et al. 1995) (Fig. 4). No glomerular necrosis and no crescents are observed. The expanded mesangial areas may compress the adjacent capillary spaces, and the glomeruli may acquire a somewhat lobulated appearance as the disease process advances and mesangial expansion becomes more pronounced (Fig. 5).

Fig. 1
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Collagenofibrotic glomerulopathy, early stage. Hematoxylin and eosin stain. X750. Segmentally expanded mesangium with increased matrix

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Fig. 2
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Collagenofibrotic glomerulopathy. PAS stain. AX750. Note weak staining in expanded mesangial areas and segmentally expanded subendothelial zones

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Fig. 3
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Collagenofibrotic glomerulopathy. Trichrome stain. AX750, BX750. Note blue mesangial staining with increment from an early case (a) to a well-developed case with distinct mesangial expansion with increased matrix/nodular appearance (b)

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Fig. 4
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Collagenofibrotic glomerulopathy. PAS stain. X750. Mesangial hypercellularity is present in selected cases

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Fig. 5
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Collagenofibrotic glomerulopathy, advanced stage. Hematoxylin and eosin stain. X750. Expanded mesangial areas with increased matrix acquiring a lobulated appearance segmentally

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Immunofluorescence/Immunohistochemistry

The typical immunofluorescence battery of stains is negative in the majority of the cases. Non-specific IgM and C3 deposition in mesangial areas has been reported.

Collagen III Immunohistochemical Stain

Collagen III immunohistochemical stain shows either focal, segmental, or diffuse, generalized mesangial staining (Fig. 6) primarily depending on the stage of the disease process, representing the hallmark of the diagnosis. The deposition of collagen III is impressive and far more than can be seen in other glomerulopathies focally in mesangial areas (Salcedo 1984; Ikeda et al. 1990; Ferreira et al. 2009; Imbasciati et al. 1991; Gubler et al. 1993; Tamura et al. 1996; Yoshioka et al. 1989; Mizuiri et al. 1993; Yasuda et al. 1999; Gubler 2008; Vogt et al. 1995; Striker et al. 1984).

Fig. 6
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Collagenofibrotic glomerulopathy. Immunohistochemical stain for collagen III. Peroxidase anti-peroxidase stain, diaminobenzidine. X750. Intense mesangial staining in expanded mesangial areas and also staining in the interstitium

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Reliable antibodies to collagen III are commercially available. Normal human glomeruli do not have or reveal minimal amounts of collagen III (D’Ardenne et al. 1983; Razzaque et al. 1994), but collagen III may be found in the interstitium, especially when fibrosis is present; however, this finding is of no specific diagnostic importance, as has nothing to do with making a diagnosis of collagenofibrotic glomerulopathy.

One case in the literature documented widespread staining for collagen V in glomeruli as well in a case of collagenofibrotic glomerulopathy (Morita et al. 2003). This may be an isolated incident or a feature of collagenofibrotic glomerulopathy. The significance of this finding is unclear at the present time.

Electron Microscopy

However, the ultrastructural findings are quite characteristic and characteristic enough to make a presumptive diagnosis in most instances. The mesangial areas and affected peripheral capillary walls show a clear to mottled appearance, and phosphotungstic or tannic acid treatment of the electron microscopy sections enhances the collagen fibers making them much easier to identify in areas where they are not abundant (Alchi et al. 2007). The electron microscopic findings will prompt the request for a collagen III stain to confirm the suspected diagnosis (Gubler 2008; Vogt et al. 1995; Striker et al. 1984; Herrera 2016; Iskandar and Herrera 2014). The fibers deposited predominantly in the mesangium and to a lesser extent in the subendothelium reveal unusual features ultrastructurally (Fig. 7a, b). The fibers appear curved, frayed, spiraled, or worm or comma shaped when sectioned transversely and show a distinct periodicity from 43 to 65 nm. The fibers typically arrange in irregular bundles when cut longitudinally. In some cases, the collagen III fibers form peculiar lattices as they arrange in bundles that intersect (Fig. 7c, d). In contrast to nail-patella syndrome, the lamina densa of the glomerular basement membranes almost always remains intact with no collagen fibers deposited in this location (Herrera 2016; Iskandar and Herrera 2014). However, there have been two children with collagenofibrotic glomerulopathy that have exhibited abnormal collagen fibers in the lamina rara interna and externa of glomerular basement membranes, creating some confusion with nail-patella syndrome glomerular lesions (Tamura et al. 1996; Gubler 2008).

Fig. 7
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(a–f) Collagenofibrotic glomerulopathy. (a, b, c, d) Collagen III in mesangium and along peripheral capillary walls. Collagen IV with different ultrastructural appearances. (e) Nonimmune complex-mediated glomerulopathy and (f) IgA nephropathy. AX12 500, BX 155000, CX9500, DX 27700. Transmission electron microscopy. Uranyl acetate and lead citrate. In (a and b), the collagen fibers are located subendothelially and display curved, frayed appearance. In (c and d), they are in an expanded mesangium and display a peculiar lattice arrangement. Compare with well-aligned collagen fibers (not collagen III) in nonimmune complex (e) and immune complex-mediated glomerulopathies (f) (a and b, courtesy of Kensuke Joh, MD)

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Differential Diagnosis

Making a definitive diagnosis of collagenofibrotic glomerulopathy on the basis of light microscopic findings is impossible. Mesangial expansion, either focal, segmental (early), or diffuse and generalized (far more common), is the most characteristic finding. The expanded mesangium displays increased argyrophilia. Due to the expansion of subendothelial spaces and even double-contoured basement membranes, some cases may be confused with thrombotic microangiopathy.

Demonstration of abundant collagen III in the expanded mesangial areas is imperative to confirm the diagnosis (Herrera 2016; Cohen 2013). It is also common to find collagen III in the interstitium, but this is of no diagnostic significance. Immunohistochemistry or immunofluorescence stains are available for testing.

In some cases, membranoproliferative glomerulonephritis is also in the differential diagnosis, as well as diabetic nephropathy and even amyloidosis. Differential diagnosis in selected cases includes distinction of collagen III deposition in mesangium from other fibrillary collagens at the ultrastructural level that can also be identified in the same location. Non-collagen III fibrillary collagen generally appears composed of straight fibrils with periodicity at 65 nm when sectioned longitudinally and circular when cut transversely. These collagen fibers typically dispose themselves in an organized parallel arrangement and, in rare cases, represent the main extracellular material in the mesangium. This type of fibrillary collagen is most commonly observed in focal, segmental glomerulosclerosis in segmentally sclerosed glomerular areas and in diabetic glomerulosclerosis in mesangial nodules (Fig. 7e). It is unusual to see fibrillary collagen in subendothelial zones, unless glomerular remodeling has occurred, but it is not uncommon to identify it in collagenofibrotic glomerulopathy. Rarely, in immune complex-mediated glomerular processes, there can be focal mesangial deposition of fibrillary collagen (Fig. 7f) in expanded mesangial areas.

Differentiation from nail-patella syndrome is also important in some instances (Salcedo 1984). The clinical manifestations of the latter disorder are rather specific in the great majority of the cases, but skeletal manifestations may be absent in selected cases. Ultrastructurally, the collagen fibrils are of the classical type with the usual periodicity and are found along the glomerular basement membranes rather than in the mesangium.

Pathogenesis

The pathogenesis of this disorder remains unclear. Mesangial cells appear to be the most reasonable candidates for the overproduction of collagen III, but systemic overproduction of collagen III has also been suggested as an etiologic factor. Serum procollagen III is usually significantly elevated in these patients and could be considered a marker for this disease when interpreted in the proper clinicopathologic context (Vogt et al. 1995).

Collagen III glomerulopathy has been documented to occur in monkeys, dogs, pigs, and cats (Adachi et al. 2005; Fujisama-Imura et al. 2004; Kamiie et al. 2009; Kobayashi et al. 2009; Shirota et al. 1995; Nakamura et al. 1996). A naturally occurring autosomal recessive model of collagen III glomerulopathy has been published. This model displays morphologic features similar to those seen in humans with this condition. This animal model has shown that the canine Col3A gene is not involved in the pathogenesis of this disorder. It also demonstrated with the use of in situ hybridization analysis that mesangial cells are engaged in the production of de novo collagen III in this disease (Rorveit et al. 2012).

Therapeutics: Treatment and Prognosis

There is no specific treatment for this disorder. Renal failure was reported within 3 years of diagnosis in one patient (Ikeda et al. 1990). In other patients, symptomatology has progressed steadily to an increase in clinical manifestations, renal insufficiency, and, eventually, failure (Imbasciati et al. 1991; Yasuda et al. 1999; Kurasawa et al. 1984). The severity of the disease at presentation is highly variable and its pace of progression unpredictable. However, progression appears to be more severe when the first symptoms occur in early childhood (Salcedo 1984; Gubler 2008; Vogt et al. 1995). In some cases, abrupt deterioration of renal function may be a result of hemolytic uremic syndrome (Gubler 2008). Successful renal transplantation has been reported with no recurrence 3 years later (Suzuki et al. 2004).