glomerular diseases

Question 1

define glomerulonephritis

Answer 1

This is an immunologically mediated injury that usually resutls in proteinuria and hematuria. If untreated, glomerulonephritis can cause a decrease in renal function.

Question 2

describe normal glomerular structure

Answer 2

from the inside out:
fenestrated capillary endothelium, basement membrane, food processes of podocytes. near the mesangium, the only barrier is the capillary endothelium.
the spaces between the podocytes are called slit diaphragms and serve as the best barrier between the capillary and the space inside the glomerulus.

Question 3

describe the basis of normal glomerular function

Answer 3

the slit diaphragms between the foot processes form the major physical filtration barrier barrier.
However, charge barrier is the most potent barrier to molecular movement from blood to urine:
1. Fenestrated endothelium has spaces that are 42 A (albumin is only 36A) with a negative charge due to heparin sulfate.
2. GBM is made of collagen type IV and heparine sulfate- negative charge again.
3. slit diaphragms also have a negative charge.

Question 4

describe the mesangium

Answer 4

the mesangium is a reticuloendothelial system with 2 kinds of cell populations: intrinsic mesangial cells that respond to angiotensin II and can syntehsize prostaglandins, may release cytokines, and proliferate in response to cytokines. This sets up a dangerous cycle of cytokine release, proliferation, and further cytokine release.
2. macrophages and monocytes that move between the mesangium and blood and can contribute to local inflammation.

Question 5

How does deranged movement of macromolecules in the mesangium lead to mesangial injury?

Answer 5

altered glomerular permeability selectivity leads to an increased traffic of molecules in the mesangium. Some molecules persist in the mesangium, including IgM and C3. These molecules cause mesangial inflammation, which causes injury. Injurey leads to glomerulosclerosis, decreased nephron mass, an alteration in glomerular flow and pressure in other glomeruli, and an altered glomerular permeability- viscous cycle.

Question 6

Normal protein and albumin levels in urine

Answer 6

albumin in urine less than 20 mg/day
total protein less than 150 mg/day
usually we measure protein:creatinine ratio and microalbumin:creatine ratio.

Question 7

Range of immune reactions in the kidney

Answer 7

from immune complexes and inflammation, which are very destructive and punch holes in the GBM and show more hematuria than proteinuria (nephritic) to lymphokines and cytokines, which show more subtle functional damage (nephrotic syndrome)

Question 8

How does indirect immunologic attack work? (hint: proteinuria is damaging- why?)

Answer 8

protienuria is both a symptom and a cause of glomerular injury. Basically, proteinuria promotes the release of angiotensinogen and NFkB. These two feed back on each other and promote cascade of other factors leading to increased matrix protein, the proliferation and differentiation of fibroblasts, and inflammation. Taken together, these three factors cause renal scarring. This cascade also explains why ACE inhibitors, ARBs, and aldosterone blockers are renal protective.

Question 9

What are the major types of glomerulonephritis?

Answer 9

minimal change disease, membranous glomerulonephritis, focal segmental glomerulonephritis, mesangial proliferative, diffuse proliferative (membranoproliferative and mesangiocapillary)

Question 10

What are the nephrotic GNs and what are their common characteristics?

Answer 10

minimal change disease, membranous GN, and focal segmental glomerulosclerosis (FSGS) (occasionally mesangial proliferative disease) They all represent immunologic rather than inflammatory injury with a complex deposition area that is protected from blood-borne factors. urine will show proteinuria and lipidura (oval fat bodies). Few RBCs, WBCs, casts (except hyaline) with a relatively benign prognosis

Question 11

What are the nephritic GNs and what are their common characteristics?

Answer 11

mesangial proliferative (often), diffuse proliferative, (membranoproliferative or mesangiocapillary). All show dysmorphic RBCs and RBC casts. These features are more prominent than proteinuria.

Question 12

Pathophysiology of mesangioproliferative disease

Answer 12

immune complexes depositived in the mesangium- either IgA or IgM/C3. Immune complexes in the mesangium are protected from blood-borne inflammation but ARE exposed to mesangial immune cells and inflammatory mediators. This disorder may be nephritic or nephrotic. It is nephritic when it is mediated by IgA inflammation and is also called Berger’s disease. It is nephrotic when medated by IgM inflammation.

Question 13

Pathology associated with mesangial proliferative disease:

Answer 13

EM: big excited angry mesangial cells.
LM: hypercellualrity and congestion in the mesangium
Immunofluorescence for IgA shows deposition in the mesangium.

Question 14

What is the clinical picture for Berger’s disease?

Answer 14

Child or young adult with gross hematuria that presents a few days after a non-specific URI. This may last several days, subside, and then return in a few months. This is one of the most common causes of recurrent hematuria in the world. IgA immunoglobulins aren’t properly eliminated or are over produced. Once in the mesangium, they activate the alternative complement pathway.

Question 15

types of mesangial proliferative disease (primary and secondary)

Answer 15

Primary: Berger (IgA deposition), IgM, IgG deposition
secodnary: Henoch-scholein purpura, which also shows diffuse vasculitis in the GI tract and skin; HIV, Hep C, SLE

Question 16

diffuse proliferative GN

Answer 16

2 types: mesangiocapillary or membranoproliferative. This causes immune complex deposition in the subendothelial area and is nephritic. This will have an AGGRESSIVE course of declining kidney function. Examples include post-strep GN.

Question 17

Pathology of diffuse proliferative GN

Answer 17

in cases like post-strep GN, you will see diffuse proliferation and swelling of glomerular cells and inflammatory infiltration with many PMNs (LM). On EM, immune complexes deposited as subendothelial humps are seen nested against the GBM. IF shows granular IgG and complement deposits.

Question 18

focal segmental glomerulosclerosis. pathology and pathophysiology

Answer 18

podocyte injury that begins deep in the kidney caused by circulating lymphokines. This casues scarring deep in the kidney. This syndrome is more nephritic than minimal change disease is (HTN or some RBCs possible). Mesangial trafficking of macromolecules occurs- thwi causes glomerulosclerosis, decreased nephron mass, altered glomerular flow and pressure, changes in gomerular permeability, increased traffic in the mesangium, entrapped macromolecules, inflammation, and mesangial injury.

Question 19

Primary and secondary casues of FSGS

Answer 19

primary: idopathic or familial
secondary: reflux nephropathy, HIV, heroin, obesity, sickle cell, meds

Question 20

In what what is FSGS the final common pathway of decreased nephron mass?

Answer 20

decreased nephrons number may be due to other chronic kidney disease, congenitally low nephron numbers, reflux nephropathy. This decreased number of nephrons can cause glomerular HTN and hyperfiltration, increased mesangial macromolecule trafficking, and progressive glomerular sclerosis and fibrosis.

Question 21

membranous GN

Answer 21

immune complexes deposited in the GBM/subepithelial area cause a charge problem. lM shows no hypercellularity but lots of membranous growth. EM shows grossly abnormal GBM with subeptihelial immune complexes.

Question 22

Primary and secondary membranous GN

Answer 22

primary: idiopathic
secondary: part of CT disease like rheumatoid arthritis or, especially, SLe.
may also be related to non-hodgkins tumors, soldi tumors, NSAIDs and penicllamines, Hep B (and, to a lessor extent, Hep C), syphilis, malaria. focus on tumors, hep, drugs, SLE. You MUST rule out tumors when you see this pathology.

Question 23

Minimal change GN

Answer 23

No changes seen on LM. foot process effacement seen on EM. mediated by lymphokines and cytokines that affect pdopcytes and change the barrier. No hematuria on urinalysis- if you see an RBC cast, you don’t have minimal change disease.

Question 24

Minimal change GN: primary and secondary

Answer 24

may be idiopathic

if secondary may be from allergy, NSAIDs, Hodgekins lymphoma, (IFN-b, sle).

Question 25

Rapidly progressive crescenti glomerulonephritis

Answer 25

involves renal failure over dayst to weeks anc can cause proteinuria and hematuria. This may be associated with generalized vasculitis. Histologically, you will see necrotizing crescentic GN. Basically, the GBM rupture is so severe that we see FIBRIN deposition in Bowman’s space.

Question 26

Primary and secondary causes of crescentic GN

Answer 26

1. Anti-GBM abs (primary) or goodpasture’s (secondary)
2. Immune complex deposition (primary) or rare post-strep, SLE, cryoglobulemia (secondary)
3. Pauci-immune (primary) or Wegener’s (secondary)