Pathology of Podocytopathies Causing Nephrotic Syndrome in Children

Abstract

Nephrotic syndrome (NS) in children includes a diverse group of diseases that range from genetic diseases without any immunological defects to causes that are primarily due to immunological effects. Recent advances in molecular and genomic studies have resulted in a plethora of genetic defects that have been localized to the podocyte, the basic structure that is instrumental in normal filtration process. Although the disease can manifest from birth and into adulthood, the primary focus of this review would be to describe the novel genes and pathology of primary podocyte defects that cause NS in children. This review will restrict itself to the pathology of congenital NS, minimal change disease (MCD), and its variants and focal segmental glomerulosclerosis (FSGS). The two major types of congenital NS are Finnish type characterized by dilated sausage shaped tubules morphologically and diffuse mesangial sclerosis characterized by glomerulosclerosis. MCD has usually normal appearing biopsy features on light microscopy and needs electron microscopy for diagnosis, whereas FSGS in contrast has classic segmental sclerosing lesions identified in different portions of the glomeruli and tubular atrophy. This review summarizes the pathological characteristics of these conditions and also delves into the various genetic defects that have been described as the cause of these primary podocytopathies. Other secondary causes of NS in children, such as membranoproliferative and membranous glomerulonephritis, will not be covered in this review.

Keywords: C1q nephropathy; Finnish type; congenital nephrotic syndrome; diffuse mesangial sclerosis; focal segmental glomerulosclerosis; minimal change disease.

Figure 1

A diagrammatic representation of the basement membrane foot processes with the location of the most common genes implicated in nephrotic syndrome.

Figure 2

Histological panel for congenital nephrotic syndrome of Finnish type. (A) A photomicrograph showing a cluster of normal appearing glomeruli with dilated proximal tubules with proteinaceous contents (H&E 100×). (B) Another area from this resected renal specimen showing the varying shapes of the dilated proximal tubules, a characteristic feature of congenital NS (H&E 100×). (C) Another image from the opposite kidney showing the same morphological features with no segmental sclerosis evident at this time (H&E 100×).

Figure 3

Histological images for diffuse mesangial sclerosis. (A) An image from another nephrectomy specimen showing the numerous dilated tubules with small occasional glomeruli (H&E 40×). (B) Higher magnification of the glomeruli showing a solidified appearance on light microscopy (H&E 200×). (C) A Jones silver stain highlighting the solidified loops with accentuation of the epithelial cells on the surface. No capillary loops are identified (Jones methanamine silver 200×). (D) A trichrome stain showing the mesangial sclerosis characteristic of this disease. Note again the prominent epithelial cells. Progressive disease leads to glomerular obsolescence and interstitial fibrosis seen in this image (Trichrome 200×).

Figure 4

Minimal change disease. (A) A photomicrograph showing normal appearing uniform sized glomeruli in the cortex (H&E 400×). (B) A silver stain showing the normal loops with accentuation of the epithelial cells (Jones 400×). (C) A low magnification image of a trichrome stain showing no glomerular or interstitial fibrosis (Trichrome 40×). (D) A negative immunofluorescence panel for immunoglobulins or C3 (Direct immunofluorescence 400×). (E,F) An electron micrograph image showing open capillary loops with effacement of foot processes better visualized in (F), which shows the diffuse fusion of foot processes [6200× (E) and 46,000× (F)].

Figure 5

Primary focal segmental glomerulosclerosis. (A,B) Photomicrographs showing two glomeruli with a segmental lesion characterized by obliteration of capillary loops with solidification and eosinophilia of the segment due to sclerosis (H&E 200×). (C,D) PAS stained sections showing a focal sclerosing lesion in a segment in (C) and in the perihilar region in (D) close to the vascular pole. Note again the preservation of capillary loops in other segments of the glomeruli (PAS 200×). (E) A trichrome stain showing the perihilar zone of sclerosis as evidenced by the blue staining of that segment. Note also some fibrin deposition in that area (red) (Trichrome 200×). (F) Immunofluorescence showing strong staining for albumin in the tubules, a characteristic feature of nephrotic syndrome in general. Not shown is the associated IgG deposition (DIF 100×). (G,H) Two electron photomicrographs showing collapsed loops in the (H) with effacement of foot processes in both images. Typically, the foot process effacement may be segmental and over the sclerosed segments (EM 3400×).

Figure 6

Secondary FSGS. (A) An image showing a biopsy with interstitial fibrosis, tubular atrophy, and a segmentally sclerosed glomerulus (H&E 100×). (B) PAS stain showing the extensive tubular atrophy (PAS 100×). (C) PAS stain showing two glomeruli, one larger than the other with the smaller one showing an area of sclerosis associated with epithelial cell proliferation in that area (PAS 200×). (D) A silver stain showing the segmental sclerosis in the perihilar region (Jones 200×). (E,F) Electron micrographs showing two images of the basement membranes with variable diameters showing prominent splitting of lamina densa with a basket weave appearance characteristic of hereditary nephritis, proven by collagen studies. Note also the microvillous transformation of foot processes and effacement in this patient with nephrotic range proteinuria (11,500×).

Figure 7

Collapsing glomerulopathy. (A,B) H&E images showing a low power and higher magnification appearance of a glomerulus with prominent epithelial cells and closed capillary loops better visualized on special stains (H&E 100× and 200×). (C) A PAS stain showing the collapsed cords of basement membranes with exuberant epithelial cell proliferation that seems to “choke” the capillary loops (PAS 400×). (D) A silver stain showing another glomerulus with wrinkling of the basement membranes and prominent epithelial cell proliferation (Jones 400×).

Figure 8

C1q nephropathy. (A,B) Light microscopy showing a low and high magnification images of normal appearing glomeruli in this child with nephrotic syndrome. Note one glomerulus in (B) is undergoing normal obsolescence (H&E 100× and 200×). (C) A silver stain showing normal glomeruli with no tubular atrophy (Jones 100×). (D) Immunofluorescence for C1q shows a 2+ staining in a mesangial location within a glomerulus. All other stains were negative, including C3, IgG, and IgM (DIF 100×). (E,F) Electron micrographs showing open capillary loops with mesangial, paramesangial, and even some subendothelial deposits. Note diffuse foot process effacement (3400× and 7100×).