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Miscellaneous Glomerular Diseases

In addition to the common causes of proteinuric kidney disease in dogs, there are other patterns of glomerular injury that are rare or insufficiently characterized.  With time, we hope to develop standardized criteria for diagnosis for these diseases and better understand their pathogeneses.  Some of these diseases still have clinical features based on what we have gleaned from our database of cases, whereas the rarity of other diseases have precluded our ability to report the relevant clinicopathologic data.


MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS WITH IMMUNE COMPLEXES

  • Glomerular disease characterized by frequent mesangial hypercellularity (>3 nuclei) and associated mesangial matrix expansion secondary to the presence of immune complex deposits that are themselves limited to mesangial zones. Diagnosis requires TEM and IF to verify the presence of the immune complexes.
  • There is often segmental sclerosis observed on histology.
  • Cases with mesangial expansion and / or hypercellularity without identifiable immune complex deposits should be given a descriptive diagnosis of “Glomerulopathy characterized by mesangial cell proliferation.”

    Clinical Features

    • Initial sign is typically moderate to marked proteinuria (UPC > 2), although median UPC is lower than most other categories of glomerular disease, and rare cases can have a UPC as low as 0.5. Dogs with mesangioproliferative GN are unlikely to have a UPC higher than ~15, and they are more likely to have normal serum albumin concentration compared with many of the other categories of glomerular disease.
    • Dogs with mesangioproliferative GN are more likely to be non-azotemic at the time of biopsy than other categories of glomerular disease.
    • While rare cases have been identified in dogs as young as 4 months of age, dogs <1 year of age are unlikely to have mesangioproliferative GN.
    • No breed predisposition is currently recognized.

    FIG.1A (HE): Moderate mesangial cell hypercellularity (greater than 3 nuclei in close apposition) within an expanded mesangial matrix (circled).

    FIG.1B (PAS): Increased numbers of mesangial cells within an expanded matrix (circled).

    FIG.1C (MT): Mild to moderate mesangial cell hyperplasia with matrix expansion.

    FIG.1D (JMS): The GBM is irregularly thickened. Please note that this JMS stain is dark due to prolonged time in silver.

FIG.1E (TEM):  Portions of 3 mesangial cell nuclei in close appostion (mesangial hyperplasia).  Note multiple electron dense deposits withih the mesangial area, often just beneath the GBM (paramesangial).

FIG.1F (TEM): Colorized version of above TEM image with electron dense deposits (black) between the mesangial matrix (blue) and the paramesangial GBM (green).  The podocytes are pink.

 

MINIMAL CHANGE DISEASE (Minimal change glomerulopathy)

  • Minimal change disease is an uncommon (in dogs), acquired, potentially reversible, podocytopathy. May be drug-induced (reported in dogs given the tyrosine kinase inhibitor masitinib), idiopathic, or presumed immune-mediated (steroid responsive MCD in children).
  • Characterized by relatively normal (hence the name) glomeruli via light microscopy and absence of specific tubulointerstitial or vascular lesions. The detection of glomerular changes and final diagnosis require TEM that will show global podocyte foot process effacement.
  • Affected dogs are markedly proteinuric.  Azotemia has been rarely reported due to presumed associated acute tubular necrosis.

FIG.2A (HE): The glomerulus is normocellular.

FIG.2B (PAS): The glomerulus is normocellular and the mesangium and GBM are unremarkable.

FIG.2C (MT): The glomerulus is histologically normal. Fuschinophilic (red) deposits are not osberved. The GBM is thin and uniform, the mesangium is normal, and there is no fibrosis in the surrounding interstitium.

FIG.2D (JMS): Capillary walls are of normal thickness; there is no evidence of GBM remodeling.

FIG.2E (TEM): Ultrastructural evidence of diffuse and global podocyte injury is present. In this case, one podocyte contains large electron dense lysosomes, and although difficult to appreciate at this low magnification, all podocytes exhibit foot process effacement.

FIG.2F (TEM): Severe podocyte injury with foot process effacement, protein resorption droplets, and cell lysis. The endothelium is unremarkable, and neither electron dense deposits nor fibrils are evident.

FIG.2G (TEM): There is diffuse foot process effacement. Podocytes are hypertrophied, with podocyte cytoplasm filling Bowman’s space.

JUVENILE ONSET/HEREDITARY GLOMERULAR DISEASES

  • Group of non-inflammatory, degenerative or developmental renal diseases affecting young animals and leading to chronic renal disease. Juvenile nephropathies frequently occur in pure breed patients but an hereditary mechanism has been confirmed in few breed.
  • The pathogenesis is unknown: genetic diseases, infections or environmental stresses are possible causes.
  • Light microscopic features are not pathognomonic and are indicative of a primary glomerular disease with secondary involvement of the other renal compartments.
    • Glomeruli are hypercellular, with segmental to global mesangial expansion.
    • Cystic glomerular atrophy is often prominent.
    • Presence of immature glomeruli in variable proportion.
    • Tubulointerstitial changes are fibrosis, tubular atrophy and dilation with intraluminal collection of proteinaceous material.

COLLAGENOFIBROTIC GLOMERULOPATHY (Collagen Type III Glomerulopathy)

  • Rare glomerulopathy characterized by expansion of mesangium and capillary wall by massive accumulations of type III collagen fibrils, less amounts of type V collagen, and fibronectin.
  • It affects all glomeruli and, similar to amyloidosis, it can be mild, moderate, or severe according to the dimension and confluence of the deposits, and the effacement of tuft architecture.
  • With routine histochemical staining, it is somewhat similar to amyloidosis but deposits are not congophilic and they lack the nodular character typical of amyloid. Electron microscopy reveals large cross-banded fibrils within the widened GBM and mesangium. Positive immunostaining for type III collagen further confirms this diagnosis.

FIG.3A (HE): There is global expansion of the mesangium and capillary loops by eosinophilic material with multifocal collapse of capillary lumina. On HE the material closely resembles amyloid and other histochemical staining is necessary to differentiate the two diseases. Segmental to diffuse mesangial hypercellularity is observed (circles). Mineralization of the Bowman’s capsule and small synechiae are also present.

FIG.3B (PAS): The deposited material is weakly positive on PAS. There is expansion of the mesangium and capillary loops with restriction and partial collapse of capillary lumina (circled). Segmental to diffuse mesangial hypercellularity is observed (arrows).

FIG.3C (MT): Non-amyloid fibrillary deposits stain deep blue. Segmental to diffuse mesangial hypercellularity is observed (arrow).

FIG.3D (JMS): Deposits take up silver with the JMS method.

FIG.3E (TEM): The glomerular basement membrane is markedly widened and contains variably sized fibrils and granular material. There is foot process effacement.

FIG.3F (TEM): The fibrils are often curvilinear and measure 10-33 nm in diameter. Prominent cross striations can be appreciated in larger fibrils.

ALPORT SYNDROME-LIKE NEPHROPATHY

  • Alport nephropathy in humans is caused by an inherited defect in type IV collagen, a major component of glomerular basement membrane (GBM). Alport syndrome is caused by mutations in alpha-3 chain (COL4A3), alpha-4 chain (COL4A4), and/or alpha-5 chain (COL4A5) of type IV collagen, resulting in a structurally abnormal GBM and eventual glomerulosclerosis.
  • Juvenile nephropathies due to mutations in type IV collagen have been confirmed in few canine breeds (English cocker spaniel, English springer spaniel, Samoyed).
  • Light microscopic features are not specific for this disease. Glomerulosclerosis is common later in the disease, which may be misdiagnosed as MPGN based on light microscopy alone (hypercellular, synechiae).

Clinical Features

  • Alport syndrome-like nephropathy is initially characterized by marked proteinuria prior to 6 months of age (Lees 2013 ).
  • An increase in UPC is typically first observed between 4-6 months of age; if the dog is monitored closely, microalbuminuria can be identified prior to an increase in UPC (as early as 2 months of age in some dogs).
  • The UPC typically reaches as high as 10-20. Hypoalbuminemia is commonly observed, but subcutaneous edema and/or ascites is not expected.
  • Mild microscopic hematuria may be observed.
  • Males with X-linked hereditary nephropathy (XLHN) and both males and females homozygous for autosomal recessive hereditary nephropathy (ARHN) demonstrate a progressive decline in GFR, typically reaching end-stage renal disease by one year of age (range 6-24 months of age). Dogs >2 years of age are unlikely to have XLHN or homozygous ARHN (Lees 1999) .
  • Clinical signs are generally absent until moderate azotemia is present, after which a rapid clinical decline (usually within 1-2 months) is often observed.
  • Hypertension is not a common feature of the disease.
  • Carrier females with XLHN typically develop proteinuria by 6 months of age, but their proteinuria is less severe (UPC usually <5), and they demonstrate a more slowly progressive disease. The majority of carrier females have a normal lifespan, often succumbing to a non-renal disease.
  • XLHN and ARHN have been identified in English Cocker Spaniels, English Springer Spaniels, Samoyeds, and mixed breed dogs. Of these, it has been identified as a breed-wide problem only in English Cocker Spaniels, and a genetic test has largely eliminated the disease in that breed (Lees 1998; Jansen 1987)
  • A similar GBM lesion has been identified in Bull Terriers and Dalmatians (largely in Australia), but mutations in Type IV collagen have not been found. Similarly, reports of Doberman Pinschers, Beagles, and Rottweilers with the GBM lesion typical for HN are available in the literature (Hood 1995).

 

FIG.4A (HE): There is moderate to marked mesangial cell hypercellularity. A large portion of the capillary tuft is adhered to the thickened Bowman’s capsule. The surrounding interstitium is fibrotic.

FIG.4B (PAS): There is segmental sclerosis of the capillary tuft, with adhesion of this portion to Bowman’s capsule (synechia). Note thickening, wrinkling, and cellular proliferation in area of synechia. There is podocyte hypertrophy and parietal epithelial cell hyperplasia.

FIG.4C (MT): Segmental sclerosis with an extensive adhesion, wrinkling, and thickening of Bowman’s capsule, and fibrosis and mild inflammation in the adjacent interstitium.

FIG.4D (JMS): Segmental sclerosis with an extensive adhesion, wrinkling, and thickening of Bowman’s capsule, and fibrosis and mild inflammation in the adjacent interstitium.

FIG.4E (TEM): Electron microscopy demonstrates the characteristic ultrastructural lesion of irregular GBM thickening and splitting. Other nonspecific changes include diffuse severe foot process effacement, reorganization of actin filaments (long arrow), and irregularity of the abluminal GBM (ellipse).

FIG.4F (TEM): The distinctive splitting, multilamination, and fragmentation of the lamina densa of the GBM is evident.

GLOMERULAR LIPIDOSIS

  • Presence of large “foamy” cells found in one or multiple lobules of the glomerular tufts. The foamy appearance is given by the presence of intracytoplasmic vacuole that are sudanophilic (lipid material) but are clear with other routine staining (HE, PAS, MT and JMS).
  • The origin of the cells is unknown but mesangial and endothelial origin has been proposed.
  • Historically thought to be an incidental finding not affecting the glomerular function. A more severe disease is presumed if the lesion is detected in many glomeruli and if the glomerular architecture is severely effaced.
  • Sometimes detected as sole lesion in proteinuric dogs.

FIG.5A (HE): The glomerular tuft architecture is segmentally distorted and effaced with large “foamy” cells.

FIG.5B (PAS): The glomerular tuft architecture is segmentally distorted and effaced with large “foamy” cells.  the remainder of the tuft appears fairly normal but compressed.

FIG.5C (MT): The glomerular tuft architecture is segmentally distorted and effaced with large “foamy” cells.

FIG.5D (JMS): The glomerular tuft architecture is segmentally distorted and effaced with large “foamy” cells.  The capillary walls of the remaining portion of the glomerulus are of normal thickness and have a smooth contour.

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