Pathology: Glomerular Diseases

Front 1

Normal glomerular anatomy:

Back 1

*Interesting things to keep in mind:
1) Vascular pole, or hilum, is the arteriolar/DCT side.
2) Tubular, or urinary, pole is the PCT side.
3) The Macular densa senses [NaCl] and is part of the DCT wall.
4) Renin comes from the JGA, which is b/t the DCT and the glomerulus.

Front 2

ID and discuss the anatomy:

What are the 4 types of nuclei you see?

Back 2

*NORMAL GLOMERULI*
L: H/E stain.
R: PAS stain (the standard). Shows glycogenated material, i.e. the GBM. Bottom is vascular pole. Capillary lumina are patent. GBM is flimsy looking. Mesangial matrix is sparse (only 1 or 2 cells present in peripheral mesangium (right, center).

Nuclei:
1) Endothelial
2) Podocyte (visceral epithelial)
3) Parietal epithelial
4) Mesangial

Front 3

Back 3

*NORMAL GLOMERULUS on EM*

Front 4

Normal glomerular capillary anatomy:

Back 4

Front 5

Normal anatomy of the Filtration Barrier:

Back 5

*Negative charges keep negatively charged molecules in the subendothelial space.
*Positively charged molecules can cross and go to the subepithelial surface.
*This has practical consequences with things like IC deposition.

Front 6

Back 6

Front 7

Discuss what podocytes do:

Back 7

*Visceral epithelial cells.
*Maintain structural conformation of glomerular tuft.
*The largest glomerular cells.
*Largely responsible for synthesis of the GBM.

Front 8

Discuss Glomerular Slit Diaphragm Proteins:

Back 8

*Nephrin and podocin are important; mutations lead to congenital nephrotic syndromes.

Front 9

What's the composition of the GBM?

Back 9

1) Collagen type IV
2) Laminin
3 Polyanionic proteoglycans (heparan sulfate)
4) Fibronectin
5) Entactin

*Adults: alpha 3, 4, and 5 chains are most important--> problems with these lead to disease.

Front 10

What is the role and the importance of the mesangium?

Back 10

*Are of mesenchymal origin.
*Phagocytic.
*Contactile (modified smooth muscle cells).
*Prone to proliferate.
*Mesangial matrix is similar in makeup to GBM.
*Normally there are 2-3 mesangial cells per mesangial area.

Front 11

Why is the mesangium kind of vulnerable?

Back 11

*No GBM between capillary lumen and mesangium.
*Mesangium is continuous with subendothelial space.
*A lot of IC deposition occurs here.

Front 12

What are the problems with understanding the Pathogenesis of Glomerular Disease?

Back 12

*Not well understood. 3 processes we think about:
1) Circulating IC deposition (lupus); subendothelially (-) and subepithelially (+).

2) Anti-GBM a la Goodpasture (Abs against a-3 chain of Collagen IV).

3) Membranous nephritis: in situ antigen in the podocytes (possible against phospholipase A2 receptor).

Front 13

What are other mediators of glomerular disease besides IC deposition?

Back 13

*T cells.

Front 14

What do pathologists look for in kidney biopsies for renal disease?

Back 14

Front 15

Back 15

Front 16

What are the 4 locations where ICs might deposit?

Back 16

1) Subepithelial (“humps”)
2) Subepithelial (“spike and dome”)
3) Subendothelial
4) Mesangial

Front 17

Back 17

Front 18

Back 18

*Subendothelial Deposits on EM.
*Between endothelial cell and the basement membrane.

Front 19

Back 19

*Subepithelial deposits on EM. Deposits are continuous with the podocyte.

Front 20

What is this and what do we do with it?

Back 20

Front 21

Summarize the Patterns of Glomerular Injury:

Back 21

*Left refers to the Population of glomeruli.
*Right refers to a Single glomerulus.

Front 22

What is going on here?

Back 22

Front 23

Back 23

*L: PAS stain, showing extracapillary hypercellularity (cellular crescents).
*R: Same glomerulus on H/E, showing fibrinoid necrosis.

Front 24

Back 24

*L: Diffuse mesangial sclerosis in early diabetic nephropathy.
*R: Nodular mesangial sclerosis in late diabetic nephropathy (Kimmelstein-Wilson nodules).

Front 25

Back 25

*L: Membranous nephropathy, showing Thickened
GBMs.
*R: Duplicated GBMs (“double contours”).

Front 26

Back 26

*L: Segmental glomerulosclerosis. Proceeds to global.
*R: Global glomerulosclerosis. This glomerulus is occluded totally; it is end-stage.

Front 27

What are the 10 Patterns of glomerular injury I need to know?

Back 27

1) Mesangial Hypercellularity (3+)
2) Endocapillary hypercellularity
3) Extracapillary hypercellularity (cellular crescents)
4) Fibrinoid necrosis
5) Diffuse mesangial sclerosis
6) Nodular mesangial sclerosis
7) Thickened GBMs
8) Duplicated GBMs (“double contours”)
9) Segmental glomerulosclerosis
10) Global glomerulosclerosis

Front 28

What are all the types of nephrotic syndrome?
2 categories, 4 diseases in each.

Back 28

Front 29

Discuss Minimal Change Disease:

Back 29

*The most frequent cause of nephrotic syndrome in children (peak 2-6 yrs).
*Diffuse effacement of foot processes of podocytes.
*Response to corticosteroid therapy; usually completely reversible.

Front 30

What's the pathogenesis of Podocyte Injury in Minimal Change Disease?

Back 30

*Not really understood. Thought to be some kind of hypersensitivity thing (post-vaccine, etc.).

Front 31

Back 31

L: Normal
R: Minimal change showing podocyte effacement.

Front 32

Back 32

Front 33

What is lipoid necrosis?

Why is the term used?

Back 33

*Another (older) name for MCD.

*We see yellowish discoloration of renal cortex from deposits of lipid in MCD.
*There are lipid droplets in proximal tubular cells: fine vacuolization (bubbly cytoplasm), reflecting lipiduria secondary to hyperlipidemia.
*These lipid deposits aren't very specific to MCD.

Front 34

What is FSGS in general?

Back 34

Front 35

Discuss “Primary” or “idiopathic” FSGS:

Back 35

*A true “podocytopathy”
-There has been a recently identified potential circulating factor (suPAR, urokinase receptor) as possible culprit.

*Most common cause of adult idiopathic nephrotic syndrome (particularly in African-Americans).
-APOL1 gene variant increases risk (protects against trypanosomal infection in Africa).

*Less responsive to corticosteroid therapy (than MCD).
*40-60% progress to ESRD within 10-20 years of onset.
*30-50% recurrence in transplants.

Front 36

Discuss Secondary FSGS:

Who do you see this in?

Back 36

*Familial or genetic (podocin and nephrin mutations).
*Virus-associated (HIV nephropathy: collapsing variant).
*Drug associated (heroin).
*Scarring secondary to another glomerular process (like IgA nephropathy).

*It can be adaptive (after nephron loss): like in unilateral renal agenesis, reflux, surgical ablation, systemic HTN, obesity.

Front 37

How quickly can podocytes regenerate?

Back 37

Trick! They can't. Once they've been effaced, they can't come back.

Front 38

Back 38

*FSGS. Note accumulation of matrix in the right glomerulus; no more patent capillaries in this tuft.

Front 39

ID and discuss this disease process:

Back 39

*FSGS Classic Variant.
*Here, there would be podocyte damage, entrapment of plasma proteins (hyalinosis), and increased ECM deposition (sclerosis).
*Hyalinosis comes before sclerosis.

Front 40

Back 40

Top: FSGS. This was idiopathic.
Bottom: FSGS. This was secondary to sickle cell.

Front 41

Back 41

*FSGS Immunofluorescence and EM.
*No IC deposition, but you do see non-specific IgM and complement C3 in areas of sclerosis and hyalinosis (seen on IF).
*On EM, you see effacement of foot processes.

Front 42

ID and discuss this disease process:

Back 42

*HIV nephropathy.
*In 5-10% of patients with HIV, more frequent in African Americans.

*Direct effect of HIV on the differentiation and proliferation of podocytes; podocytes proliferate.
*Aggressive clinical course.

*AKA Collapsing glomerulopathy.
*You see tubular microcysts with occlusive hyaline casts.
*On EM: Tubuloreticular inclusions.

Front 43

Discuss Membranous Nephropathy:

What does it cause?
What is it characterized by?
What are the two kinds?

Back 43

*Frequent cause of idiopathic nephrotic syndrome in adults (second to FSGS).

*You see diffuse thickening of glomerular capillary walls due to SUBEPITHELIAL immune complex deposits.
*GBM “spike” formation between deposits.

1) Primary (75%):
*Recently discovered phospholipase A2 receptor (on podocytes) as target antigen in a majority of cases.

2) Secondary (25%):
*Malignancy (mostly carcinomas: lung, GI, breast).
*Autoimmune diseases (lupus, RA).
*Hepatitis B > hepatitis C.
*Meds: penicillamine, captopril, NSAIDs.
*TREAT THE UNDERLYING CAUSE!!!

Front 44

ID AND DISCUSS:

Back 44

*Membranous Nephropathy.
*Note thickened GBM; that's what should catch your eye here. In the early stage of the disease, the glomeruli can appear normal.

*Note pattern of IC deposits.
*SEE ROBBINS 922.

Front 45

Back 45

*“Spikes” on the Basement Membrane in membranous nephropathy.
*Silver stain stains GBM material, but NOT the IC deposits.

Front 46

Back 46

*Granular capillary wall deposits in membranous nephropathy.

Front 47

Back 47

*Membranous nephropathy. Discrete deposits that are slightly more electron dense than the GBM. They are on the epithelial, or external, side of the GBM.
*Podocytes show some effacement.

Front 48

*Describe the progression of the stages of this disease process:

Back 48

*MN.
*GBM attempts to resorb the ICs.

Front 49

Discuss Diabetic nephropathy:

How significant is it?
When is biopsy indicated?

Back 49

*Most common cause of ESRD in the US.

*Develops in 50% of patients with both type 1 and type 2 DM (changes are identical).

*Retinopathy, neuropathy, and nephropathy usually develop concurrently.

*Indication for biopsy: if a diabetic patient has proteinuria without retinopathy or neuropathy.

Front 50

What do you see pathologically in diabetic nephropathy?

Back 50

*Excessive synthesis of collagenous proteins and glycoproteins due to abnormal glucose metabolism.
*Glycosylation of basement membrane-type material.

*Glomerular findings:
-Thick GBMs + TBMs
-Nodular and diffuse mesangial sclerosis (“Kimmelstiel-Wilson nodules”)

*Vascular findings:
-Arteriolar hyalinosis
-Arteriosclerosis

Front 51

Back 51

*Diffuse and nodular mesangial sclerosis in DIABETIC NEPHROPATHY.
*SEE ROBBINS 1142.

Front 52

Back 52

*Kimmelsteil-Wilson nodules IN DIABETIC NEPHROPATHY.
*SEE ROBBINS 1142.
*Lots of GBM and mesangial matrix material, not hypercellularity.

Front 53

Discuss kidney involvement in amyloidosis:

Back 53

*The kidney is the most commonly affected organ in amyloidosis.

*Primary AL (light chain) amyloid, usually lambda.
*You see overt myeloma in 20% of patients.

*Secondary (AA) amyloid is associated with chronic infections or inflammatory states (seen in developing countries):
-RA, psoriasis, anklosing spondylitis, Crohn’s.
-TB, osteomyelitis.
-IV drug abuse (skin popping).
-Familial mediterranean fever.

*The injury pattern can be confused with diabetic nephropathy.

Front 54

ID and discuss. How do you diagnose this disease?

Back 54

*AMYLOIDOSIS.
*Amorphous deposits in all compartments (can look like diabetes...MUST RULE THIS OUT WHEN DIAGNOSING DIABETIC NEPHROPATHY).

*Diagnostic feature: Congo red stain (apple-green birefringence on bottom right).

*On EM: randomly oriented fibrils (amyloid fibers are 8-12 nm diameter).

Front 55

Discuss IgA nephropathy:
How significant? Who do you see it in?
What is it associated with?
What is the systemic form?

Back 55

*Most common glomerulonephritis worldwide.
*Often in southeast Asians, Hispanics.

*Associations: URIs, cirrhosis, celiac disease.

*You see microscopic hematuria and mild proteinuria.

*Systemic form: Henoch-Schonlein purpura:
1) Skin, joint, and intestinal involvement:
-Lower extremity purpura, arthralgias, abdominal pain.
-Vascular IgA deposition on skin biopsy.
2) Children >>> adults.

Front 56

ID and discuss:

Back 56

*The most common glomerular disease revealed by renal biopsies worldwide.

*Mesangial proliferation and matrix increase.

*Mesangial deposition of IgA (IgA1), less IgG or IgM.

*Activation of alternative complement pathway (C3 in deposits).

*SEE ROBBINS 929.

Front 57

Back 57

*IgA nephropathy on EM.
*Arrows indicate IgA deposits in the mesangial matrix; they are more dense than the GBM material. They classically accumulate right under the GBM in the mesangium.

Front 58

WTF is wrong with this fool? Elaborate. 4 systems will be jacked up.

Back 58

*Henoch-Schonlein Purpura!!!!! HEeeeeeeyyyyy!!!!

*Systemic syndrome associated with IgA nephropathy:
1) Skin (purpuric rash)
2) GI tract (abdominal pain)
3) Joints (arthritis)
4) Kidneys (hematuria, mesangial IgA deposits)

Front 59

Discuss the old fashioned Classic postinfectious GN:

Back 59

*God, those were the days, right?

*Post-streptococcal GN usually seen in children after pharynx or skin infection:
-Abrupt onset, latent period of 7-21 days.
-Self-limited (complete recovery in >90%).
-Low C3/C4, returns to normal within 6 weeks.
-Hematuria lasts months, proteinuria even longer.
-Nephritogenic Group A b-hemolytic strep.

Front 60

Back 60

*Poststreptococcal GN.
*Gross Findings
1) Swelling of the kidney.
2) A “flea-bitten” appearance caused by the RBCs.

Front 61

Back 61

*Top: Normal.

*Bottom: Poststreptococcal GN.
*Diffuse and global glomerular proliferation.
*Glomeruli are:
-Enlarged
-Hypercellular (leukocytes...mainly NEUTROPHILS, endothelial, mesangial, crescents in severe cases).

Front 62

What do you see on IF in post-strep GN?

Back 62

*Immunofluorescence microscopy of post-strep GN.
*Coarsely granular deposits of IgG, IgM, and C3 in in the mesangium and along the GBM.
*Bottom left shows IgG.
*Top right shows C3.
*Both show "Starry sky" appearance.

*Compare to MN, which has a finely granular pattern.

Front 63

Back 63

*Immunofluorescence microscopy of post-strep GN.
*L: IgG deposition.
*R: C3 deposition.

*Both show "starry sky" pattern.

Front 64

Back 64

*EM of Post-infectious GN (usually strep).
*EM shows Subepithelial humps (no GBM spikes); they are usually sparse, but obvious, and project out into the urinary space.

Front 65

Discuss Rapidly Progressive (Crescentic) GN:

Back 65

*Severe glomerular injury.

*Macroscopic hematuria with RBC casts.
*Moderate proteinuria.
*Serologic studies: serum anti-GBM Abs, ANAs, ANCAs.
*Severe oliguria.

*If untreated, death of renal failure in weeks to months.

*ROBBINS 920.

Front 66

Back 66

*Gross image of kidney in RP (crescentic) GN.

Front 67

*ID and describe what you are seeing here.

Back 67

*Crescentic GN.

*Diffuse proliferation (most glomeruli are involved).
*Parietal epithelial cells in Bowman’s space:
-Monocytes, macrophages, lymphs, neutrophils in the urinary space.
-These proliferating cells start in Bowman's capsule, move in the urinary space, and compress the tuft.

Front 68

Back 68

*Crescentic GN.
*L: H/E. Shows fibrinoid necrosis in the middle, tuft to the left, and the crescent of proliferation to the right.
*R: PAS. Crescent is on the top.

Front 69

Back 69

*Fibrin Staining in Crescentic GN.
*Fibrin has leaked out AROUND the dull capillary tuft in the middle.

Front 70

Back 70

*EM showing Ruptures of GBM in Crescentic GN.

Front 71

ID and discuss these 3 entities:

Back 71

*Three Groups of Crescentic GN by IF/EM.

1) Top: Type I Anti-GBM antibody disease with LINEAR IgG or C3 fluorescence staining.
*12% of crescentic GNs.
*Worst prognosis of all of them.

2) Middle: Type II IC-mediated with GRANULAR IF staining:
*Poststreptococcal, MPGN, SLE, IgA/HSP.
*44% of crescentic GNs. These immune-mediated ones fall into this category only if they show crescents.

3) Bottom: Type III Pauci-immune with negative or week IF staining. Circulating ANCA. This is a type of vasculitis.
*44% of crescentic GNs.

Front 72

Discuss anti-GBM diseases. What are the 3 types?

Back 72

1) Anti-GBM GN (50%).
2) Anti-GBM pulmonary capillaritis (5%).
3) Goodpasture syndrome: Pulmonary-renal vasculitic syndrome caused by anti-GBM (45%).

TL: Lung.
BL: Kidney.
R: Lungs.

Front 73

Discuss Goodpasture Syndrome:
AKA?

Back 73

*Type IV Collagen Disease.
*Immune disorder
*Goodpasture Antigen is the NC1 domain within a3 chain of collagen IV.

Front 74

Discuss Pauci-immune GN:

What are 4 types?

Back 74

*You see ANCAs in ~80-90% of cases.

*Signs of extrarenal vasculitis in 75%:
1) Granulomatosis with polyangiitis (Wegener’s) (c-ANCA):
-Granulomatous and necrotizing inflammation of lungs and nasal sinuses.

2) Churg-Strauss (p-ANCA):
-Asthma, peripheral eosinophilia.

3) Microscopic polyangiitis (p-ANCA):
-Necrotizing vasculitis in multiple sites (dx of exclusion).

*Renal-limited involvement accounts for 25%.

Front 75

ID/discuss:

Back 75

*Pauci-immune GN.
*Slide shows Arteritis with fibrinoid necrosis.

*Findings:
-Minimal immune complex deposition by IF and EM.
-Occasional fibrinoid necrosis or vasculitis involving the arteries and/or arterioles.

Front 76

Discuss Membranoproliferative GN:

What's the etiology?

Back 76

1) A pattern of glomerular injury which usually has a detectable underying etiology:
*Hepatitis C >> hep B.
*Infected ventriculoatrial shunts.
*Subacute bacterial endocarditis.
*Cryoglobulinemia.

2) “Idiopathic” MPGN:
*Seen in older children and adults.
*Hypocomplementemia (abnormalities of the classical complement pathway).

Front 77

ID and discuss what you are seeing here:

Back 77

*The pattern of injury in MPGN.
-Enhanced lobulation of the capillary tufts (left).
-Endocapillary and mesangial hypercellularity (right).
-Double contours with cellular interposition (right).
*ROBBINS 928.

Front 78

What are double contours? What do you see them in?

Back 78

*Double Contours of GBM in MPGN.

Front 79

What's the difference between these two?

Back 79

*Membranoproliferative GN (Mesangiocapillary):

1) Type I (80% of cases):
*Immune complexes activate classical complement pathway.

2) Dense deposit disease (Type II):
*Aberrant activation of the alternative complement pathway.

Front 80

Back 80

*The 2 types of idiopathic MPGN on IF staining:
L: MPGN type I. IgG and C3 (may be C4, C1q, IgM, IgA).

R: DDD. C3 only (no activation of classic pathway).

Front 81

ID/discuss.

Back 81

*Electron Microscopy in Type I MPGN:
L: Subendothelial and mesangial deposits. Arrow points to the second layer of BM; first layer is right on top of the capillary. This is a double contour.

R: Split membranes and mesangial deposits. Complex pattern of deposition. Started out subendothelial, but became incorporated into the BM. This is also a double contour.

Front 82

Back 82

*EM in DDD (type 2 idiopathic MPGN). BM is expanded by these hyperdense deposits. This is totally complement-mediated.

Front 83

Discuss lupus nephritis:

What do you see on pathology?

Back 83

*70% of lupus patients will have renal involvement, with an OVERLAP b/t nephritic and nephrotic syndrome...Hematuria AND proteinuria.

*Serology shows ANA+, dsDNA+.

-Lupus can MIMIC anything:
*Glomerular AND extraglomerular deposits.
*“Wire loops:” large, confluent subendothelial deposits.
*“Full house” IF staining (IgG, IgA, IgM, C3, C1q).
*Endothelial tubuloreticular INCLUSIONS.
*EM deposits with “fingerprint” substructure.

Front 84

Back 84

*Mesangial Lupus GN. Early stage lupus nephritis (class I/II).
*Increased mesangial matrix.
*> 3 mesangial cells/mesangial area.
*Immune deposits (“full house”-IgG,M,A C3,C1q).

Front 85

Back 85

*Focal Proliferative lupus GN (Class III). Less than half of the glomeruli are affected.

Front 86

Back 86

*Diffuse Proliferative lupus GN (class IV).
*More than half of glomeruli are affected; nearly all of them.
*Top left looks kind of like post-strep GN.
*Top right shows crescent formation.
*Bottom right shows "wire loop" structure with a pseudothrombus (all precipitated ICs).

Front 87

Back 87

*Diffuse Proliferative lupus GN (class IV).
*IF here shows capillary wall and mesangial staining. Deposits can be situated ANYWHERE.

Front 88

Back 88

*Membranous lupus GN. Class V. Diffuse thickening of capillary walls.
*IF shows granular staining.
*EM shows subepithelial deposits and a few mesangial deposits.

Front 89

What is the main pathologic feature being shown here?

Back 89

*These are “Wire loops” seen almost exclusively in lupus nephritis.

Front 90

What is the main pathologic feature being shown here?

Back 90

*These are “Wire loops” seen almost exclusively in lupus nephritis.

Front 91

What is the main pathologic feature being shown here?

Back 91

*Hyaline “pseudo-thrombi” in lupus nephritis. You see the thrombi precipitating out within the glomerular capillaries.

Front 92

Back 92

*Extraglomerular immune complex deposition in lupus nephritis. This image just shows that there is deposition in the glomerulus and also outside it. Note some vasculitis going on. Also staining on BM and interstitially.

Front 93

Back 93

*Full house staining in lupus nephritis. All 3 heavy chains, both complements, and kappa/lambda light chains.

Front 94

Back 94

*These are “Wire loops” seen almost exclusively in lupus nephritis. These are subendothelial deposits.

Front 95

Back 95

*Fingerprint pattern in lupus nephritis.

Front 96

Discuss Alport’s (hereditary nephritis):
What's the defect?
Genetics?
Symptoms?

Back 96

*Defective synthesis of collagen IV.

*X-linked: Most common inheritance; mutation is in COL4A5 (a-5 chain of col IV); affects GBM and cochlea.

*Young males:
1) Sensorineural hearing loss.
2) Hematuria.
3) Progressive development of renal failure as adults.

*EM shows Irregular GBM:
*Thickening and thinning, splitting, lamellation, “basket-weave” appearance.

Front 97

Back 97

*EM in Alport’s.
*Left: EARLY--Thick BM, alternating with a thin BM.
*Right: LATE--Lamina dense has been split into two. Alternating, weaving pattern.

Front 98

What diseases tend to lead to Chronic Glomerulonephritis?

Back 98

*Crescentic GN, FSGS, MPGN are the big 3, but anything can lead to it.

Front 99

Back 99

Gross kidney in Chronic Glomerulonephritis, nearing ESRD. Cortical scars lead to a granular surface.

Front 100

Back 100

*Chronic Sclerosing Glomerulonephritis; nearing end stage. Trichrome stain on right shows abundant collagen. There's only one remaining glomerulus here.

Front 101

This slide is a FREAKING JOKE:

Back 101