Pathophysiology: Glomerular Disorders

Front 1

What are the causes of end stage kidney disease?

Back 1

*Glomerular disease: 25%!

Front 2

Review of glomerular anatomy (xs):

Back 2

*Note 3 layers.
*Visceral epithelium = podocytes.

Front 3

Review of the GBM's role in filtration:

Back 3

*GBM has strong negative charge due to polyanionic proteoglycans: heparin sulfate as well as other glycoproteins / Sialoglycoproteins (thromboresistance and anionic charge).

*Thus Negative molecules like albumin do not filter.

*Structural proteins such as Fibronectin, Entactin, and Laminin contribute to “filter.”
*Freely permeable below 2nm, and impermeable above 4 nm.

Front 4

Discuss the role of the Visceral epithelial cell:

Back 4

*AKA podocyte (ultrastructural term).
*Maintain structural conformation of tuft.
*Largely responsible for synthesis of GBM components.

*Foot processes are separated by 20-30 nm filtration slits
*Slit diaphragm presents a size-selective distal diffusion barrier to the filtration of proteins.

*Proteins located in the slit diaphragm control glomerular permeability.

Front 5

What makes up the slit diaphragm of the podocytes?

Back 5

*Podocin and nephrin are most important.

Front 6

Discuss the mesangial cells:

What functions do they have?

Back 6

*Modified Smooth Muscle Cells embedded in a matrix similar to the GBM.

*Functions:
1) Endocrine (renin production).
2) Contractile (structural integrity).
3) Phagocytic.
4) Synthetic.

*Capable of proliferation (2-3 cells per region is normal).

*Diagram notes: No GBM between capillary lumen and mesangium; Mesangium is continuous with the Subendothelial space.

Front 7

Identify all the layers based on color shown here:

Back 7

Front 8

What are the 2 major categories of Glomerular Disorders and what characterizes them?

Back 8

1) NEPHROTIC Syndrome:
***proteinuria (>3.5 g/24 hr)***
+edema
+hypoalbuminemia
+hypercholesterolemia
+/-hematuria
+/-hypertension

2) NEPHRITIC Syndrome:
***hematuria*** +/- casts
+hypertension
+/-edema
+/-proteinuria

Front 9

What is the "spectrum" of glomerular diseases?

Back 9

*Diseases in the middle can present as either nephritic or nephrotic.

Front 10

What is the "spectrum" of glomerular diseases by looking at inflammation?

Back 10

Front 11

Discuss nephritic syndome in general:

What can it be accompanied by?

Back 11

*The nephritic syndrome, or nephritis, refers to inflammatory renal diseases characterized by blood in the urine.

*Nephritis is principally characterized by hematuria and can be accompanied by:
1) Hypertension
2) Edema
3) Reduced GFR
4) Sub-nephrotic proteinuria

Front 12

Discuss Nephrotic Syndrome in general:

What can it be accompanied by?

Back 12

*The nephrotic syndrome (or nephrosis) refers to “non-inflammatory” glomerular diseases marked by heavy proteinuria ( > 3.5 g/day in an adult).

*Nephrosis is principally characterized by heavy proteinura and may be accompanied by:
1) Edema.
2) Hyperlipidemia.
3) Lipiduria.
4) Hypercoagulability.

Front 13

What's the pathophysiology of edema in nephritic syndrome?

Back 13

Front 14

What's the pathophysiology of edema in nephrotic syndrome?

Back 14

Front 15

What are the Complications of Nephrosis?

Back 15

Front 16

What are the primary and systemic Nephritic diseases?

Back 16

*Primary:
1) IgA nephrohathy.
2) Hereditary (thin b.m.).
3) PSGN.
4) MPGN.
5) RPGN.

*Systemic:
1) Vasculitis.
2) Endocarditis.
3) Lupus.
4) Goodpasture’s.
5) Henoch-Schoenlein purpura.

Front 17

What are the primary and systemic Nephrotic diseases?

Back 17

*Primary:
1) Minimal change
2) Idiopathic FSGS
3) Membranous
4) MPGN

*Systemic:
1) Diabetes
2) “Secondary” FSGS
3) Amyloid
4) SLE (membranous)

Front 18

What is the role of circulating immune complexes in kidney disease?

Back 18

*There can be deposition or trapping of pre-formed antigen-Ab (immune) complexes in glomerulus, which can lead to disease.

*Origin of antigens:
Endogenous (SLE = DNA).
Exogenous (streptococci = postinfectious).

*Rarely seen in the epithelial space.

Front 19

Glomerular Pathology: Definitions:
Diffuse--
Focal--
Global--
Segmental--

Back 19

*Diffuse: A lesion involving most (≥50%) of the glomeruli.

*Focal: A lesion involving <50% of the glomeruli.

*Global: A lesion involving more than half of the glomerular tuft.

*Segmental: A lesion involving less than half of the glomerular tuft (i.e., at least half of the glomerular tuft is spared).

Front 20

Discuss Post-streptococcal or Post-infectious Glomerulonephritis:

When does it occur? What causes it?
Symptoms?

Back 20

*7-14 days after exposure to nephritogenic (e.g. Group A ß-hemolytic strep) antigen:

*Symptoms:
1) hematuria
2) edema + hypertension
3) renal insufficiency
4) Hypocomplementemia

*Usually reversible with spontaneous recovery.
*Photos: top shows inflammatory cells. Bottom is EM, showing capillary surrounded by lumpy hump-looking structures that represent ICs.

Front 21

Discuss IgA Nephropathy:

Back 21

*Gross or µscopic hematuria; often accompanies URI (hematuria may not lag behind the infection like in post-strep nephritis).
*Associated with abnormalities of IgA (secretory).
*May progress to advanced CKD or ESRD (20-50%).

*Pic: Green corresponds to the mesangium; lighting up with an IgA antibody.

Front 22

What are the Mechanisms underlying glomerular deposition of IgA and progression of renal disease in IgA nephropathy?

Back 22

*Defective glycosylation leads to deposition.
*Cytokines lead to localization of IgA in mesangium.

Front 23

Discuss Rapidly Progressive GN:

Back 23

*AKA "Crescentic."
*Rapid onset of renal failure (days-weeks).
*LM shows >50% of glomeruli with crescents.

*3 types (distinguished by immunofluorescence):
1) Pauci-immune (vasculitis).
2) Anti-GBM disease (e.g. Goodpasture’s; shown in bottom pic. You can tell this is anti-GBM because the green is so complete, as compared the the lumpy fluorescence in IC-mediated).
3) Immune complex (lupus).

*May occur as unusual presentation for OTHER diseases, e.g IgAN or PSGN. THIS IS A PATHOLOGICAL PATTERN, NOT A SPECIFIC DISORDER.

Front 24

Describe the 6 classes of lupus:

Back 24

Class I: minimal mesangial lupus nephritis.
Class II: mesangial proliferative lupus nephritis.
Class III: focal lupus nephritis (a).
Class IV: diffuse segmental (IV-S) or global (IV-G) lupus nephritis (b).
Class V: membranous lupus nephritis (c).
Class VI: advanced sclerosing lupus nephritis.

*3, 4, and 5 we try to treat; these may progress to end-stage renal disease.

Front 25

Back 25

TL: Normal.
TR: Mesangial lupus (class II).
BL: Proliferative lupus (class III or IV)
BR: Proliferative; IF. Lumpy bumpy appearance of ICs.

Front 26

What are the 4 main types of Nephrotic syndrome?

Back 26

Minimal change nephropathy
Focal segmental glomerulosclerosis
Membranous glomerulopathy
Diabetic nephropathy

Front 27

Discuss Minimal Change Nephropathy:
How common?
When does it occur?
What do you see on histology?

Back 27

*AKA Lipoid Nephrosis.
*Most common form of nephrotic syndrome in childhood.
*Often rapid onset.
*Spontaneous remission or rapid response to steroids.

*Histopathology:
-Totally normal light microscopy.
-Epithelial foot process loss (effacement) on EM.

*Pics: Top is normal; bottom shows minimal change.

Front 28

Back 28

L: Normal
R: Minimal change disease.. Loss of podocyte foot processes.

Front 29

Back 29

Loss of podocytes in minimal change? I think yes, but this image was skipped in class.

Front 30

Discuss Focal Segmental Glomerulosclerosis:
How does it progress?
How common? Who gets it?
What are the subtypes?

Back 30

*Progressive proteinuria with progression to renal failure.
*Most common NS among adults, particularly young adults and African-Americans.

*Steroid dependence or resistance.

*Histologic subtypes:
1) Tip lesion.
2) Collapsing (HIV).

*May be idiopathic “secondary” to other conditions, such as reflux nephropathy, obesity, HIV. There is high recurrence of idiopathic lesions in transplant recipients.

*Pics: Top is normal; bottom is FSGS.

Front 31

What is the Pathogenesis of Secondary FSGS?

Back 31

*Multiple pathways of progression to the same end result:
1) Glomerular HTN/Hyperfiltration
*Increased body mass (obesity) or decreased renal mass (nephron loss).
2) Glomerular Hypertrophy.
3) Podocyte Injury.

Front 32

What's the pathogenesis of "Podocytopathies"?

Back 32

Front 33

What genetic associations make African-Americans more likely to get certain glomerular diseases?

Back 33

*ApoL1 gene is associated with higher risk among African-Americans. Risk may be 20x higher than population at large.
*This mutation ALSO may confer resistance to trypanosomiasis (malaria)!

Front 34

What are the 4 types of Membranous Nephropathy?

Back 34

*Idiopathic, or in association with other illnesses:
2) SLE (WHO Class V).
3) Hepatitis B, C.
4) Drugs.

*20-30% have spontaneous complete or partial remission.
*~50% have progressive renal failure.

*Pics: Top is normal; bottom shows thickening of the capillary loop.

Front 35

Back 35

*Membranous Nephropathy*
TL: Silver stain; black corresponds to GBM. Note pink "holes" where there are subepithelial immune deposits.

TR: Immunofluorescence shows granular deposits that array along the capillary loop, not so much in the mesangium.

BL: EM in early stage of disease dark deposits (D) subepithelially.

BR: Later on in the disease; deposits have degenerated and are absorbed. "Holes" have appeared where they used to be.

Front 36

What is the pathogenesis of subepithelial deposit formation in membranous nephropathy?

Back 36

*ICs are not circulating, but FORMED in the subepithelial space (in reaction to the M-type phospholipase A2 receptor).

Front 37

Discuss Diabetic Nephropathy:
How common is it? What makes it worse?
What symptoms are there?
What meds help?

Back 37

*Most common cause of kidney disease leading to End-stage renal disease (ESRD).

*Co-existing hypertension is an accelerent.
*Usually signified by low grade proteinuria, occasionally by nephrotic range proteinuria.

*Ameliorated by ACE-I and ARBs. May be reversed by normalization of glycemic control as with pancreatic transplantation.

*Pics: Top is normal, bottom is Diabetic Glomerulosclerosis; note expansion of mesangial matrix. May coalesce into nodules.

Front 38

What is the course of diabetic nephropathy?

Back 38

*Best appreciated with DM1, because the DM diagnosis is made early.
*GFR is higher than normal early on; kidney and glomeruli become large.
*10-20 years later, you see larger amounts of PRO excretion, accompanied by a drop in GFR. In 2-5 years, patients reach ESRD.

Front 39

Describe the pathogenesis of Diabetic Glomerulosclerosis:

Back 39

Front 40

In evaluating patients with glomerular disorders, what are you looking for in the history?

Back 40

*Presence of gross hematuria or “foamy urine” (could mean proteinuria).

*Description of the hematuria (gross, bloody, clots, tea- or coca-cola colored).

*Associated symptoms (flank pain, edema). Edema is most common.

*Multisystem features (arthritis, upper or lower respiratory tract disease, skin eruption).

Front 41

In evaluating patients with glomerular disorders, what are you looking for on PE?

Back 41

*Blood pressure
*CVA or abdominal tenderness
*Skin eruptions
*Edema
*Joint effusions
*Pulmonary rales, etc
*Other

Front 42

In evaluating patients with glomerular disorders, what are you looking for on labs?

Back 42

*Urine analysis.
*Serum creatinine, BUN.
*CBC.
*May do Serologic tests (ANA, ANCA, C3, C4, Anti-Strep Abs).
*May do Imaging studies. Seldomly help.
*You should only get serology and imaging if you suspect a specific syndrome!

Front 43

When you see blood in the urine, how do you know if it's glomerular or not?

Back 43

Front 44

Back 44

*Dysmorphic RBCs. "Mickey Mouse ear" projecting from the RBC.

Front 45

Back 45

FATTY CASTS IN THE URINARY SEDIMENT

Front 46

Back 46

FATTY CASTS IN THE URINARY SEDIMENT, under polarized light. Showing "Maltese cross" sign.

Front 47

*A 38 year-old man is referred to you because on pre-employment testing, he is found to have "asymptomatic” microscopic hematuria.

*Further history reveals no manifestations of systemic illness.
*Physical Examination: BP 160/90, otherwise normal.

*Urine analysis: Numerous rbcs, some dysmorphic and rbc casts. “2+ proteinuria.”
*Serum creatinine 1.6 mg/dl.
*ANA negative, ANCA negative.
*Serum complement levels, normal.

*Any further workup? If so, what test?

Back 47

*The pt has nephritis (blood in urine, not much protein).

*If you wanted to explore this more, the next step would be a biopsy.

Front 48

What are the general Indications for renal biopsy?

Back 48

A renal biopsy is indicated in any parenchymal renal disease in which histopathology is essential for either diagnosis or management.

Front 49

What are the specific Indications for renal biopsy? 4

Back 49

*Acute or subacute decline in GFR.

*Heavy or nephrotic proteinuria.

*Multisystem illness (e.g. pulmonary-renal syndrome).

*Assessment of treatment (e.g. lupus nephritis) or prognosis.

Front 50

Back 50

*Mesangial involvement.
*This is IgA nephropathy.

Front 51

Back 51

*Mesangial deposits in IgA nephropathy.