dangles off of arteries by afferent arterioles (afferent and efferent arterioles are NOT morphologically distinguishable)
blood runs at 50-60 mmHg (high) of pressure Þ provides driving pressure for creating ultrafiltrate
glomerular capillary structure is arranged in tufts which are supported by mesangial cells lying between the capillaries
the mesangial matrix forms a meshwork through which the mesangial cells are scattered
these cells, of mesenchymal origin, are contractile, phagocytic, and capable of proliferation, of laying down both matrix and collagen, and of secreting a # of biologically active mediators Þ important players in glomerulonephritis
cross-section of tuft:
endothelium contain fenestrae slits Þ allows blood direct access to the glomerular basement membrane
epithelium gives rise to podocytes
epithelium and endothelium contribute to synthesis of basement membrane which sits in-between
constituents of glomerular basement membrane Þ restricts on basis of size and charge
(1) contains type IV collagen, looks like chicken wire Þ restricts molecular size to 36 Å (i.e. IgG) Þ albumin could fit thru since it is 30 Å;
(2) contains heparin sulfate (negatively charged and repels other negatively charged molecules (i.e. albumin))
Glomerulus Histology
sac of capillaries (glomerular tufts) surrounded by a space (Bowman’s space) where the ultrafiltrate will end up
separating the blood from the ultrafiltrate is a very thin basement membrane
stains used for glomerulus Þ Schiff bases (pale pink when oxidized; magenta when reduced) Þ glycosaminoglycan in basement membrane stains a charateristic color
periodic acid schiff (PAS) stain allows us to identify the basement membrane from the endothelium and epithelium
Jone’s technique Þ silver nitrate solution (produces a mirror effect) Þ basement membranes become black
Direct immunoflourescent staining for IgG
Transmission electron microscopy Þ stain with heavy metals Þ can see all 3 layers Þ fenestrated endothelium, epithelial layer of podocytes, basement memb; mesangial area is mostly extracellular matrix
Definitions
What can happen to these normal structures? look for the following:
based on % of involvement Þ focal (<75% glomeruli involved) vs diffuse (>75% glomeruli involved)
based on localization within a structure Þ global (throughout glomerulus) vs segmental (only part of glomerulus)
Proliferation: refers to an Ý in # of cell nuclei
cellular infiltration, proliferation of indigenous cells, and reduced cell loss all contribute to this process
foci of necrosis within glomeruli is often lumped with proliferative glomerulonephritis because diseases that elicit glomerular necrosis eventually lead to Ý # of glomerular cells
Sclerosis – scarring process in which glycosaminoglycans accumulate in addition to accumulations of collagen
stains strongly with PAS, silver-methenamine, and trichrome stains in contrast to cirrhosis or fibrosis (trichrome only) as a result of the high carbohydrate content
global process where mesangial material is found where empty spaces should be throughout the entire glomerulus
Anti-glomerular basement membrane (anti-GBM) disease(Goodpasture antigen)Þ antibodies (IgG) are directed against intrinsic fixed antigens (collagen type IV) that are normal components of the GBM proper
Antibodies bind along the entire length of the GBM, resulting in a homogeneous, diffuse linear pattern of staining for the antibodies by immunofluorescent techniques
Anti-GBM nephritis is characterized by severe glomerular damage and development of rapidly progressive renal failure
form of extracapillary proliferation
Membranous glomerulonephritis (Heymann antigen)
Characterized by presence of numerous electron dense deposits (made up largely of immune reactants) along the subepithelial aspect of the basement membrane
Pattern of immune deposition by fluorescence microscopy is granular and interrupted, rather than linear
Results from the reaction of antibody (IgG) with an antigen complex (megalin) located on the basal surface of visceral epithelial cells and cross-reacting with brush border antigen
Antibody binding is followed by complement activation and then by patching, capping, and subsequent shedding of the immune aggregates form the cell surface to form the characteristic subepithelial deposits
Circulating Immune Complex Nephritis (resulting from type III hypersensitivity reactions)
Glomerular injury is caused by the trapping of circulating antigen-antibody complexes within glomeruli. The antibodies have no immunologic specificity for glomerular constituents, and the complexes localize within the glomeruli because of their physicochemical properties and the hemodynamic factors peculiar to the glomerulus
The evocative antigen can be of endogenous origin (i.e. SLE, tumor antigens) or of exogenous origin following bacterial infections (i.e. streptococci), viral infections (i.e. Hep B, Hep C)
Antigen-antibody complexes are formed in the circulation, trapped in the glomeruli, then produce injury in large part through the binding of complement
The glomerular lesions usually consist of leukocytic infiltration in glomeruli and proliferation of mesangial and endothelial cells
The immune complexes are seen as granular deposits either along the basement membrane (subendothelial deposits or subepithelial deposits) or in the mesangium, or in both locations
Once deposited, immune complexes are degraded by phagocytic infiltrating monocytes and mesangial cells and the inflammatory changes may then subside
occurs when exposure to inciting antigen is short-lived and limited (i.e. poststreptococcal glomerulonephritis)
If continuous exposure to antigens is provided (i.e. SLE, viral Hep B, Hep C), repeated cycles of immune complex formation, deposition, and injury may occur Þ chronic membranoproliferative glomerulonephritis
Cytotoxic antibodies
In addition to causing immune deposits, antibodies directed to glomerular cell antigens may react with cellular components and cause injury by cytotoxic or other mechanisms
(2) Cell-Mediated Immune Injury
Although antibody-mediated mechanisms may initiate many forms of glomerulonephritis, there is now considerable evidence that sensitized T cells, as a reflection of cell-mediated immune reactions, cause some forms of glomerular injury and are involved in the progression of many glomerulonephritides
(3) Activation of Alternative Complement Pathway
alternative complement pathway activation occurs in membranoproliferative glomerulonephritis (MPGN type II)
Glomerular Diseases
(1) Primary Glomerulopathies
(a) Acute diffuse proliferative (poststreptococcal, postinfectious) glomerulonephritis – diffuse proliferation of glomerular cells associated with influx of leukocytes; lesions typically caused by immune complexes
(1) Poststreptococcal Glomerulonephritis Þ immune complex-mediated mechanism with granular immune deposits in the glomeruli
Enlarged, hyercellular glomeruli caused by (1) diffuse infiltration by leukocytes (neutrophils, monocytes); (2)diffuse endocapillary proliferation of endothelial and mesangial cells
Small deposits of fibrin within capilllary lumens and mesangium in most cases
Immunofluorescence Þ focal and sparse granular deposits of IgG, IgM, and C3 in the mesangium and along the basement membrane
Electron microscopy Þ discrete, amorphous, electron-dense deposits on epithelial side of memb, often having the appearance of "humps" Þ represent the Ag-Ab complexes at the epithelial cell surface
(2) Nonstreptococcal Acute Glomerulonephritis Þ occurs sporadically in association with other bacterial infections, viral disease (i.e. Hep B, Hep C, HIV), and parasitic infections
Characterized by rapid and progressive loss of renal function associated with severe oliguria and death from renal failure within weeks to months Þ all 3 types of RPGN have severe glomerular injury
Regardless of the cause, characterized by presence of crescents in most of the glomeruli
Crescents produced by proliferation of the parietal epithelial cells and Bowman capsule and in part by infiltration of monocytes and macrophages
Fibrin strands are prominent between the cellular layers in the crescents Þ most crescents undergo sclerosis
we see interuptions of GBM due to polymerized fibrin (result of a reparative process following an explosive attack Þ explosive fibrin necrosis)
50% of the disorders are idiopathic Þ ¼ type I; ¼ type II; ½ type III
Type I RPGN – anti-GBM disease
Linear deposits of IgG and C3 in the basement membrane (see anti-GBM disease above)
Type II RPGN – immune complex-mediated disease Þ postinfectious glomerulonephritis (see above), SLE, IgA nephropathy and Hech-Schonlein purpura
Immunofluorescence Þ "lumpy bumpy" granular pattern of staining
Type III RPGN – pauci immune type
lack of anti-GBM antibodies or immune complexes by immunofluorescence and electron microscopy
90% of patients have antineutrophil cytoplasmic antibody (ANCA) in the serum Þ plays a role in vasculitides
In many cases, pauci-immune crescentic gllomerulonephritis is isolated and hence idiopathic
(c) Nephrotic Syndrome Þ massive proteinuria, hypoalbuminemia, generalized edema, and hyperlipidemia and lipiduria
Initial event is derangement in glomerular capillary walls resulting in Ý permeability to the plasma proteins Þ massive proteinuria Þ leads to depletion of serum albumin levels Þ hypoalbuminemia Þ loss of colloid osmotic pressure of the blood Þ generalized edema
(1) Membranous Glomerulonephritis (Membranous Nephropathy) – non-proliferative glomerular disease Þ most common cause of nephrotic syndrome in adults
Characterized by diffuse thickening of the glomerular capillary wall and accumulation of electron-dense, immunoglobulin-containing deposits along the epithelial (subepithelial) side of the basement membrane
Glomeruli exhibit uniform, diffuse thickening of the glomerular capillary wall caused by irregular dense deposits between the basement membrane and the overlying epithelial cells (which have lost their foot processes)
Basement membrane material is laid down between these deposits, appearing as irregular spikes protruding from the GBM Þ these spikes thicken to produce domelike protrusions and eventually close over the immune deposits
As the disease advances, the membrane thickening encroaches on the capillary lumens and sclerosis of the mesangium may occur Þ glomeruli become totally hyalinized
(2) Minimal Change Disease (Lipoid Nephrosis) – non-proliferative glomerulare disease – abnormalities in BM Þ most frequent cause of nephrotic syndrome in children
Characterized by diffuse loss of foot processes of epithelial cells in glomeruli that appear virtually normal by light microscopy Þ most characteristic is its dramatic response to corticosteroid therapy
Principal lesion is in the visceral epithelial cells, which show a uniform and diffuse effacement of foot processes Þ "fusion" of foot processes
Cells of the proximal tubules are laden with lipid hence lipoid nephrosis
Characterized by sclerosis of some glomeruli (focal), and in the affected glomeruli, only a portion of the capillary tuft is involved (segmental)
Frequently accompanied by nephrotic syndrome and heavy proteinuria
Electron microscopy: Pronounced, focal detachment of the epithelial cells with denudation of the underlying GBM
Immunofluorescence: IgM and C3 are present within hyaline masses in the sclerotic areas
It is the epithelial damage that is the hallmark of focal segmental glomerulosclerosis
The hyalinosis and sclerosis represent entrapment of plasma proteins in extremely hyperpermeable glomeruli with Ý ECM deposition
HIV-associated Nephropathy Þ most commonly leads to a severe form of focal segmental glomerulosclerosis
(d) Membranoproliferative Glomerulonephritis (MPGN) – including Hep C
Characterized by alterations in the basement membrane, proliferation of glomerular cells (predominately of mesangium), and leukocyte infiltration
Glomeruli are enlarged and hypercellular (by endocapillaryproliferation of mesangial cells)
Infiltrating leukocytes and parietal epithelial crescents are present in many cases
The glomerular capillary wall often shows a "double-contour" or "tram-track" appearance caused by "duplication" of the GBM and mesangial and monocyte interposition
Type I MPGN Þ characterized by presence of subendothelial electron dense deposits
Immune complexes in the glomerulus and activation of both classic and alternative complement pathways
Type II MPGN Þ GBM is transformed into an irregular, ribbon-like, extremely electron-dense structure because of the deposition of dense material of unknown composition Þ dense deposit disease; IgG is usually absent
Abnormalities suggest activation of the alternative complement pathway only
(e) IgA Nephropathy (Berger Disease) – mesangial membranoproliferative nephritis
Characterized by presence of prominent IgA deposits in the mesangial regions, detected by immunofluorescence
Is a frequent cause of recurrent gross or microscopic hematuria
(f) Focal Proliferative and Necrotizing Glomerulonephritis (Focal Glomerulonephritis) Þ glomerular proliferation is restricted to segments of individual glomeruli and commonly involves only a certain proportion of glomeruli
Lesions are predominately proliferative; focal necrosis and fibrin deposition within the lesions often occur
(g) Chronic Glomerulonephritis Þ considered an end stage pool of glomerular disease fed by a number of streams of specific types of glomerulonephritis
Kidneys become symmetrically contracted and have diffuse granular, cortical surfaces
Hyaline obliteration of glomeruli; most patients are hypertensive
(2) Systemic Diseases
Systemic Lupus Erythematosus Þ recurrent microscopic or gross hematuria, acute nephritis, the nephrotic syndrome, chronic renal failure, and hypertension
Henoch-Schonlein Purpura Þ purpuric skin lesions involving the extensor surfaces of arms and legs as well as buttocks; abdominal manifestations include pain, vomiting, intestinal bleeding; nonmigratory arthralgia; renal abnormalities (IgA is deposited in the glomerular mesangium in a distribution similar to that if IgA nephropathy)
Amyloidosis – abnormalities in matrix structure Þ deposits of amyloid within the glomeruli
Congo red amyloid-positive fibrillary deposits are present within the mesangium and subendothelium Þ eventually obliterate the glomerulus completely
(3) Hereditary Disorders
Alport Syndrome – nephritis accompanied by nerve deafness and various eye disorders
Thin membrane Disease (benign familial hematuria) – familial asymptomatic hematuria and diffuse thinning of GBM
Tubulointerstitial Disease
inflammation which traverses the cortico-medullary junction – pyelonephritis
Pyelonephritis Þ renal disorder affecting tubules, interstitium, and renal pelvis Þ one of most common diseases of the kidney
Acute pyelonephritis – caused by bacterial infection; associated with urinary tract infections; acute suppurative inflammation of the kidney; associated with vesicoureteral reflux
Hallmarks – patchy interstitial suppurative inflammation and tubular necrosis
Chronic pyelonephritis – bacterial infection plays a dominant role, but other factors (vesicoureteral reflux, obstruction) are involved in its pathogenesis
Chronic tubulointerstitial inflammation and renal scarring are associated with pathologic involvement of the calyces and pelvis
Chronic obstructive pyelonephritis Þ recurrent bouts of renal inflammation and scarring; results in renal insufficiency
Reflux nephropathy Þ occurs early in childhood
inflammation confined to the cortex
pyelonephritis (rich in neutrophils) – see above
allergic interstitial nephritis (edematous, predominantly lymphocytes and macrophages, rich in eosinophils and plasma cells) Þ actually type IV hypersensitivity
other causes Þ malformations/developmental defects; metabolic errors; ischemia; tumors