High Yield Glomerular Disease Pathology

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

Back 2

*NORMAL GLOMERULUS on EM*

Front 3

Why is the mesangium kind of vulnerable?

Back 3

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

Front 4

Back 4

Front 5

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

Back 5

1) Subepithelial (“humps”) - post strep
2) Subepithelial (“spike and dome”) - Diffuse membranous glomerulopathy
3) Subendothelial - SLE - Diffuse Proliferative Glomerulonephritis
4) Mesangial - IgA

Front 6

Back 6

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

Diffuse Proliferative Glomerulonephritis

Front 7

Back 7

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

Diffuse membranous glomerulopathy

Front 8

What is going on here?

Back 8

IgA // proliferative Glomerulonephritis

Front 9

Back 9

these are both crecentric.

*L: PAS stain, showing extracapillary hypercellularity (cellular crescents). -- goodpasture's, wegner's, microscopic polyarteritis.
*R: Same glomerulus on H/E, showing fibrinoid necrosis.

Front 10

Back 10

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

Front 11

Back 11

*L: Membranous nephropathy, showing Thickened
GBMs. -- Catopril, HBV, SLE, common in adults
*R: Duplicated GBMs (“double contours”). - Tram Track - Type I and 2 MPGN

Front 12

L is normal. Right?

Back 12

L: Normal
R: Minimal change showing podocyte effacement.

Front 13

What is lipoid necrosis?

When is the term used?

Back 13

*Another (older) name for Minimal Change Disease.

*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 14

What is FSGS in general?

Back 14

HIV, young black males, IV drugs
- Primary: APOL1 gene variant increases risk (protects against trypanosomal infection in Africa).

Most common kind in adults.

Front 15

Discuss “Primary” or “idiopathic” FSGS:

Back 15

*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).
-Primary: APOL1 gene variant increases risk (protects against trypanosomal infection in Africa).
- Secondary: HIV, Drug use, obesity.

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

Front 16

Back 16

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

*Most common cause of adult idiopathic nephrotic syndrome (particularly in African-Americans).
-Primary: APOL1 gene variant increases risk (protects against trypanosomal infection in Africa).
- Secondary: HIV, Drug use, obesity.

Front 17

ID and discuss this disease process:

Back 17

*FSGS Classic Variant.

*Most common cause of adult idiopathic nephrotic syndrome (particularly in African-Americans).
-Primary: APOL1 gene variant increases risk (protects against trypanosomal infection in Africa).
- Secondary: HIV, Drug use, obesity.
*Here, there would be podocyte damage, entrapment of plasma proteins (hyalinosis), and increased ECM deposition (sclerosis).
*Hyalinosis comes before sclerosis.

Front 18

Back 18

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

*Most common cause of adult idiopathic nephrotic syndrome (particularly in African-Americans).
-Primary: APOL1 gene variant increases risk (protects against trypanosomal infection in Africa).
- Secondary: HIV, Drug use, obesity.

Front 19

Back 19

*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.

*Most common cause of adult idiopathic nephrotic syndrome (particularly in African-Americans).
-Primary: APOL1 gene variant increases risk (protects against trypanosomal infection in Africa).
- Secondary: HIV, Drug use, obesity.

Front 20

Discuss Membranous Nephropathy:

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

Back 20

*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 21

ID AND DISCUSS:

Back 21

*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.

*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.

Front 22

Back 22

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

Front 23

Back 23

*Granular capillary wall deposits in membranous nephropathy.

*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.

Front 24

Back 24

*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.

*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.

Front 25

Back 25

*Diffuse and nodular mesangial sclerosis in DIABETIC NEPHROPATHY.

Front 26

Back 26

*Kimmelsteil-Wilson nodules IN DIABETIC NEPHROPATHY.

*Lots of GBM and mesangial matrix material, not hypercellularity.

Front 27

ID and discuss. How do you diagnose this disease?

Back 27

*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).

*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.

Front 28

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

Back 28

*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 29

ID and discuss:

Back 29

*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).
*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 30

Back 30

*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.
*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 31

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

Back 31

*Henoch-Schonlein Purpura!!!!!

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

*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 32

Back 32

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

*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 33

Top is normal. bottom?

Back 33

*Top: Normal.

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

*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 34

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

Back 34

*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.

*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.

Front 35

Back 35

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

*Both show "starry sky" pattern.

*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 36

Back 36

*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.

*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 37

Back 37

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

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Back 38

*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.

*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.

Front 39

Back 39

*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.

*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.

Front 40

Back 40

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

*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.

Front 41

Back 41

*EM showing Ruptures of GBM in Crescentic GN.

*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.

Front 42

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

Back 42

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 43

Discuss Goodpasture Syndrome:
AKA?

Back 43

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

Front 44

Back 44

*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.

*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 45

ID and discuss what you are seeing here:

Back 45

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

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 46

Train tracks??

Back 46

*Double Contours of GBM in MPGN.

Front 47

What's the difference between these two?

Back 47

*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 48

Back 48

*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 49

Back 49

*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 50

Back 50

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

Front 51

Back 51

*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).

*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 52

Back 52

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

*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 53

Back 53

*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).

*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 54

Back 54

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

Front 55

Back 55

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

Front 56

Back 56

*These are “Wire loops” seen almost exclusively in lupus nephritis. - Diffuse proliferative glomerulonephritis

Front 57

Back 57

*These are “Wire loops” seen almost exclusively in lupus nephritis. - Diffuse proliferative glomerulonephritis

Front 58

What is the main pathologic feature being shown here?

Back 58

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

- Diffuse proliferative glomerulonephritis.

Front 59

Back 59

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

- Diffuse proliferative glomerulonephritis

Front 60

Back 60

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

- Diffuse proliferative glomerulonephritis

Front 61

Back 61

*Fingerprint pattern in lupus nephritis.

- Diffuse proliferative glomerulonephritis

Front 62

Back 62

*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.

*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.