Renal Pathology Part 2

Question 1

Antibodies can react

Answer 1

Antibodies can react in situ with antigens that are not normally present in the glomerular but are “planted” there
-such antigens may localize in the kidney by interacting with various intrinsic components of the glomerulus

Question 2

Planted antigens include

Answer 2

cationic molecules that bind to anionic components of the glomerulus; DNA, nucleosomes, and other nuclear proteins, which have an affinity for GBM components; bacterial products; large aggregated proteins, which deposit in the mesangium because of size; and immune complexes themselves, since they continue to have reactive sites for further interaction with free antibody, free antigen, or complement

Question 3

In anti-GBM antibody induced glomerulonephritis,

Answer 3

• antibodies bind to intrinsic antigen homogeneously distributed along the entire length of the GBM, resulting in a diffuse linear pattern of staining for the antibodies by immunofluorescence techniques
• often the anti-GBM antibodies cross-react with other basement membranes, especially those in the lung alveoli, resulting in simultaneous lung and kidney lesions (Goodpasture syndrome)
• causes severe necrotizing and crescentic glomerular damage and the clinical syndrome of rapidly progressive glomerulonephritis

Question 4

GBM antigen that is responsible for classic anti-GBM antibody-induced glomerulonephritis and Goodpasture syndrome is

Answer 4

a component of the non collagenous domain (NC1) of the alpha3 chain of type IV collagen that is critical for maintenance of GBM superstructure

Question 5

In glomerulonephritis resulting from deposition of circulating immune complexes,

Answer 5

• injury is caused by 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 physiochemical properties and the hemodynamic factors peculiar to the glomerulus

Question 6

Antigens that trigger formation of circulating immune complexes may be

Answer 6

of endogenous origin, as in the glomerulonephritis associated with SLE or in IgA nephropathy, or they may be exogenous, as may occur in the glomerulonephritis that follows certain infections
-microbial antigens that are implicated include bacterial products (streptococcal proteins), the surface antigen of hepatitis B virus, hepatitis C virus antigens, and antigens of Treponema palladium, Plasmodium falciparum, and several viruses

Question 7

Inflammation and injury following immune complex formation

Answer 7

• binding of complement and also engagement of Fc receptors on leukocytes and perhaps glomerular mesangial or other cells as mediators of injury process
• glomerular lesions may exhibit leukocytic infiltration and proliferation of mesangial and endothelial cells

Question 8

In Immune complex mediated glomerulonephritis, electron microscopy

Answer 8

reveals electron-dense deposits, presumably containing immune complexes, that may lie in the mesangium, between the endothelial cells and the GBM (sub endothelial deposits), or between the outer surface of the GBM and the podocytes (subepithelial deposits)
-deposits may be located at more than one site in a given case

Question 9

By immunfluorescence microscopy the immune complexes are seen

Answer 9

as granular deposits along the basement membrane, in the mesangium, or in both locations

Question 10

Once deposited in the kidney, immune complexes may

Answer 10

eventually be degraded, mostly by infiltrating neutrophils and monocytes/macrophages, mesangial cells, and endogenous proteases, and the inflammatory reaction may then subside
-such a course occurs when the exposure to the inciting antigen is short-lived and limited, as in most cases of post streptococcal glomerulonephritis

Question 11

If immune complexes are deposited for prolonged periods

Answer 11

• as may be seen in SLE or viral hepatitis
• repeated cycles of injury may occur, leading to a more chronic membranous or membranoproliferative type of glomerulonephritis

Question 12

Highly cationic antigens tend to

Answer 12

cross the GBM, and the resultant complexes eventually reside in a sub epithelial location

Question 13

Highly anionic macromolecules are

Answer 13

excluded form the GBM and are trapped subendothelially or are not nephritogenic at all

Question 14

Molecular or neutral charge and immune complexes containing these molecules tend to

Answer 14

accumulate in the mesangium

Question 15

Large circulating complexes are

Answer 15

not usually nephritogenic, because they are cleared by the mononuclear phagocyte system and do not enter the GBM in significant quantities

Question 16

Immune complexes located in sub endothelial portions of capillaries and in mesangial regions are

Answer 16

accessible to the circulation and more likely to be involved in inflammatory processes that require interaction and activation of circulating leukocytes

Question 17

Diseases in which immune complexes are confined to the sub epithelial locations and for which the capillary basement membranes may be a barrier to interaction with circulating leukocytes

Answer 17

• membranous nephropathy

- typically noninflammatory pathology

Question 18

Alternative complement pathway activation occurs in

Answer 18

dense-deposit disease

Question 19

Infiltrate the glomerulus in certain types of glomerulonephritis

Answer 19

neutrophils and monocytes
-largely as a result of activation of complement, resulting in generation of chemotactic agents (mainly C5a), but also by Fc-mediated adherence and activation

Question 20

Neutrophils release

Answer 20

proteases, which cause GBM degradation; oxygen-derived free radicals, which cause cell damage; and arachidonic acid metabolites, which contribute to the reductions in GFR

Question 21

Macrophages and T-lymphocytes

Answer 21

• infiltrate the glomerulus in antibody- and cell-mediated reactions
• when activated release a vast number of biologically active molecules.

Question 22

Platelets

Answer 22

• may aggregate in the glomerulus during immune-mediated injury
• their release of eicosanoids, growth factors and other mediators may contribute to vascular injury and proliferation of glomerular cells

Question 23

Resident glomerular cells, particularly mesangial cells, can be stimulated to produce

Answer 23

several inflammatory mediators, including ROS, cytokines, chemokines, growth factors, eicosanoids, NO, and endothelin

Question 24

Complement activation leads to

Answer 24

the generation of chemotactic products that induce leukocyte influx (complement-neutrophil-dependent injury) and the formation of C5b-C9, the MAC.

• MAC causes cell lysis, and stimulates mesangial cells to produce oxidants, proteases, and other mediators
• even in the absence of neutrophils, MAC can cause proteinuria

Question 25

Cytokines, particularly IL-1 and TNF

Answer 25

• may be produced by infiltrating leukocytes and resident glomerular cells
• induce leukocyte adhesion and a variety of other effects

Question 26

Chemokines such as monocyte chemoattractant protein 1 promote

Answer 26

monocyte and lymphocyte influx

Question 27

Seem to be critical in the ECM deposition and hyalinization leading to glomerulosclerosis in chronic injury

Answer 27

TGF-B, connective tissue growth factor, and fibroblast growth factor

Question 28

Fibrin

Answer 28

-frequently present in the glomeruli and Bowman space in glomerulonephritis, indicative of coagulation cascade activation, and activated coagulation factors, particularly thrombin, may be a stimulus for crescent formation

Question 29

Podocytopathy

Answer 29

-can be induced by antibodies to podocyte antigens; by toxins, as in an experimental model of proteinuria induced by puromycin amino nucleoside; conceivably by certain cytokines; by certain viral infections such as HIV or by still inadequately characterized circulating factors, as in some cases of focal segmental glomerulosclerosis

Question 30

Podocyte injury causes changes in podocytes

Answer 30

-effacement of foot processes, vacuolization, and retraction and detachment of cells from the GBM, and functionally by proteinuria

Question 31

Loss of podocytes may be a feature of

Answer 31

multiple types of glomerular injury including focal and segmental glomeruloscleorsis and diabetic nephropathy

Question 32

In most forms of glomerular injury, loss of normal slit diaphragms is

Answer 32

a key event in the development of proteinuria

Question 33

Once any renal disease destroys functioning nephrons and reduces the GFR to about

Answer 33

30-50% of normal, progression to end-stage renal failure proceeds at a steady rate, independent of the original stimulus or activity of the underlying disease.

Question 34

Two major histologic characteristics of progressive renal damage are

Answer 34

-focal segmental glomerulosclerosis (FSGS) and tubulointerstitial fibrosis

Question 35

Progressive fibrosis involving portions of some glomeruli develops

Answer 35

after many types of renal injury and leads to proteinuria and increasing functional impairment

Question 36

FSGS may be seen

Answer 36

• even in cases in which the primary disease was nonglomerular
• the glomerulosclerosis seems to be initiated by the adaptive change that occurs in the relatively unaffected glomeruli of diseased kidneys
• compensatory hypertrophy of the remaining glomeruli initially maintains renal function in these animal models, but proteinuria and segmental glomerulosclerosis soon develop, leading eventually to total glomerular sclerosis and uremia

Question 37

Glomerular hypertrophy is associated with

Answer 37

hemodynamic changes, including increases in glomerular blood flow, filtration, and transcapillary pressure (glomerular hypertension), and often with systemic hypertension

Question 38

Sequence of events that is thought to lead to sclerosis in FSGS entails

Answer 38

• endothelial and visceral epithelial cell injury, visceral epithelial cell loss leading to segments of GBM denuded of overlying foot processes and consequently increased glomerular permeability to proteins, and accumulation of proteins in the mesangial matrix
• this is followed by proliferation of mesangial cells, infiltration by macrophages, increased accumulation of extracellular matrix, and segmental and eventually global sclerosis of glomeruli.
• With increasing reductions in nephron mass and ongoing compensatory changes, a vicious cycle of continuing glomerulosclerosis sets in

Question 39

Most of the mediators of chronic inflammation and fibrosis, particularly TGF-B,

Answer 39

play a role in the induction of sclerosis

Question 40

Tubulointerstitial injury

Answer 40

• manifested by tubular damage and interstitial inflammation
• a component of many acute and chronic glomerulnephritides
• many factors lead to injury, including ischemia of tubule segments downstream from sclerotic glomeruli, acute and chronic inflammation in the adjacent interstitium, and damage or loss of the peritubular capillary blood supply

Question 41

Tubulointerstitial fibrosis contributes to

Answer 41

progression in both immune and nominate glomerular diseases

Question 42

Proteinuria can cause

Answer 42

direct injury to and activation of tubular cells

Question 43

Activated tubular cells in turn

Answer 43

express adhesion molecules and elaborate pro-inflammatory cytokines, chemokines, and growth factors that contribute to interstitial fibrosis

Question 44

Filtered proteins that map produce tubular effects include

Answer 44

cytokines, complement products, the iron in hemoglobin, immunoglobulins, lipid moieties, and oxidatively modified plasma proteins

Question 45

Nephritic syndrome

Answer 45

• inflammation in glomeruli
• hematuria, red cell casts in urine, azotemia, oliguria, and mild to moderate hypertension
• proteinuria and edema common but not as severe as those in nephrotic syndrome

Question 46

Acute Proliferative Glomerulonephritis

Answer 46

• diffuse proliferation of glomerular cells associated with influx (exudation) of leukocytes
• typically caused by immune complexes
• prototypic exogenous antigen-induced disease pattern is post infectious glomerulonephritis
• endogenous antigen example is in SLE

Question 47

Poststreptococcal Glomerulonephritis usually appears

Answer 47

1-4 weeks after a streptococcal infection of the pharynx or skin

• occurs most frequently in children age 6-10 but can occur in any age
• caused by immune complexes containing streptococcal antigens and specific antibodies, which are formed in situ
• strains 12, 4, and 1
• usually elevated titers of antibodies against strep antigens
• low serum complement levels
• granular immune deposits in the glomeruli

Question 48

Poststreptococcal Glomerulonephritis histology

Answer 48

• enlarged, hypercellular glomeruli
• hypercellularity caused by infiltration by leukocytes, both neutrophils and monocytes; proliferation of endothelial and mesangial cells; and in severe cases by crescent formation
• also swelling of endothelial cells, and combination of proliferation, swelling, and leukocyte infiltration obliterates capillary lumens
• may be interstitial edema and inflammation, and tubules often contain red cell casts

Question 49

Proliferation and leukocyte infiltration in poststreptococcal glomerulonephritis are typically

Answer 49

global and diffuse

Question 50

Poststreptococcal glomerulonephritis Immunofluorescence microscopy

Answer 50

• granular deposits of IgG and C3, and sometimes IgM in the mesangium and along the GBM
• immune complex deposits often focal and sparse

Question 51

Poststreptococcal glomerulonephritis electron microscopy

Answer 51

• discrete, amorphous, electron-dense deposits on the epithelial side of the membrane, often having the appearance of “humps,” presumably representing the antigen-antibody complexes at the sub epithelial cell surface
• subendothelial deposits also commonly seen, typically early in disease course, and mesangial and intramembranous deposits may be present

Question 52

In the typical case of post streptococcal glomerulonephritis

Answer 52

• a young child abruptly develops malaise, feel, oliguria, and hematuria (cola-colored urine) 1-2 weeks after recovery form a sore throat
• patients have dysmorphic red cells or red cell casts in the urine, mild proteinuria (usually less than 1 gm/day), periorbital edema, and mild to moderate hypertension
• in adults onset more atypical, such as sudden appearance of hypertension or edema, frequently with elevation of BUN

Question 53

Non streptococcal Acute Glomerulonephritis

Answer 53

• occurs sporadically in association with other infections that aren’t streptococcal
• granular immunfluorescent deposits and subepithelial humps characteristic of immune complex nephritis are present
• when due to staph infection, differ by sometimes producing immune deposits containing IgA rather than IgG

Question 54

Rapidly progressive (crescentic) glomerulonephritis

Answer 54

• a syndrome associated with severe glomerular injury
• characterized by rapid and progressive loss of renal function associated with severe oliguria and signs of nephritic syndrome; if untreated, death from renal failure occurs within weeks to months
• presence of crescents in most of the glomeruli

Question 55

Anti-GBM antibody-mediated RPGN

Answer 55

• characterized by linear deposits of IgG and, in many cases, C3 in the GBM
• in some patients, the antibodies cross-react with pulmonary alveolar basement membranes to produce the clinical picture of pulmonary hemorrhage associated with renal failure (Goodpasture syndrome)

Question 56

RPGN caused by immune complex deposition

Answer 56

• can be a complication of any of the immune complex nephritides, including post infectious glomerulonehpritis, lupus nephritis, IgA nephropathy, and Henoch-Schonlein purport
• in all cases, there is a granular pattern of staining characteristic of immune complex deposition
• frequently demonstrates cellular proliferation and influx of leukocytes within the glomerular tuft, in addition to crescent formation

Question 57

Pauci-immune RPGN

Answer 57

• lack of detectable anti-GBM antibodies or immune complexes by immunofluorescence and electron microscopy
• most patients with this type have circulating antineutrophil cytoplasmic antibodies (ANCAs) that produce cytoplasmic c or perinuclear p staining pattern and are known to play a role in some vasculitides

Question 58

In RPGN, the kidneys are

Answer 58

enlarged and pale, often with petechial hemorrhages on the cortical surfaces

• depending on underlying cause, the glomeruli often show focal and segmental necrosis, and variably show diffuse or focal endothelial proliferation, and mesangial proliferation
• segmental glomerular necrosis adjacent to glomerular segments uninvolved by inflammatory or proliferative changes is the feature most typical of pauci-immune RPGN.
• histological picture dominated by distinctive crescents

Question 59

In RPGN, crescents are formed by

Answer 59

proliferation of parietal cells and by migration of monocytes and macrophages into the urinary space

• neutrophils and lymphocytes may be present
• crescents may obliterate the urinary space and compress the glomerular tuft
• Fibrin strands are frequently prominent between cellular layers in the crescents
• the escape of procoagulant factors, fibrin and cytokines into Bowman space may contribute to crescent formation

Question 60

RPGN immunofluorescence microscopy

Answer 60

• immune complex-mediated cases show granular immune deposits
• Goodpasture syndrome cases show linear GBM fluorescence for Ig and complement
• Pauci-immune cases have little or no deposition of immune reactants

Question 61

RPGN electron microscopy

Answer 61

• discloses deposits in those cases due to immune complex deposition (type II)
• regardless of type, may show ruptures in the GBM, a severe injury that allows leukocytes, plasma proteins such as coagulation factors and complement, and inflammatory mediators to reach the urinary space, where they trigger crescent formation
• in time, most crescents undergo organization and foci of segmental necrosis resolve as segmental scars (a type of segmental sclerosis), but restoration of normal glomerular architecture may be achieved with early aggressive therapy