Chapter 20.1: Glomerulonephropathies Flashcards
1
Q
Nephritic Syndrome
Process and Sx
A
2
Q
Nephritic Syndrome
Glomerular diseases presenting with nephritic syndrome are often characterized by ________________ => nephritis, damaging the filtration barrier to __________
- Features: _______, ___________ (<3.5 grams/day), ______, ____; usually sicker/less sick than nephrotic
A
Glomerular diseases presenting with nephritic syndrome are often characterized by inflammation in the glomeruli => nephritis, damaging the filtration barrier to RBC and proteins.
- Features: Hematuria, mild proteinuria (<3.5 grams/day), azotemia, HTN; usually sicker than nephrotic
3
Q
Major causes of Nephritic Syndrome
A
- Acute/Diffuse proliferative (post-streptococcal) glomerulonephritis
- RPGN
- Berger’s IgA nephropathy
- Alport Syndrome
4
Q
Acute (Diffuse) Proliferative Glomerulonephritis is a _______ syndrome and is a __________ hypersensitivity reaction.
A
Nephritic
Type 3 (Immune complex)
5
Q
Acute (Diffuse) Proliferative Glomerulonephritis is what, that typically occurs when, in who?
A
- Inflammation of the glomeruli after group A B-hemolytic strep infection in children and young adults, but may occur after infection with many other organisms. Usually FTER,
- Impetigo (skin)
- Pharyngitis (strep)
6
Q
Strep can lead to rheumatic fever and post-strep GN.
Can patients develop both?
A
No.
- Certain strep bacteria are nephritogenic strains, which are specific types of M protein virulence factor.
- Subtype: lancefield group A.
7
Q
What is the pathology of Acute (Diffuse) Proliferative Glomerulonephritis?
Group A B-Hemolytic Strep causes?
How do lesions form?
A
- 1-4 weeks AFTER Group A B-hemolytic strep => causes diffuse proliferation of glomerular cells and influx of leukocytes in all glomeruli
- Lesions formed when:
- [IgG/M Ab] against [step pyogenic exotoxin B (SpeB)] antigen =>
- in-situ formation of immune-complexes in the subepithelium (with many neutrophils).
- => inflammatory reaction, which involves + compliment (C3) and attracts PMNs, which damage podocytes
- Leads to hypocomplementemia, because it degrades the body of compliment proteins.
8
Q
In acute proliferative glomerulonephritis, in-situ immune complexes that form in _________ spaces will do what?
A
- Subepithelial
- => inflammation => + compliment & attract PMNS =>
9
Q
Acute (Diffuse) Proliferative Glomerulonephritis
- Light microscopy:
- Electron microscopy:
- IF:
A
- Light Microscopy: Hypercellular & enlarged glomeruli (d/t proliferation of endothelial/mesangial cells) and many leukocytes (d/t inflammation)
- Not specific
- Electron Microscopy: Subepithelial humps of immune complexes
- DIAGNOSTIC of POST-STREP GN
- Immuno-Fluorescence: “starry sky”; granular deposits of IgG, IgM and C3 in mesangium and along GBM
10
Q
Acute (Diffuse) Proliferative Glomerulonephritis is most common in who?
A
Children (6-10); more atypical and aggressive in adults
11
Q
How is acute proliferative GN different in children and adults
A
- More atypical and aggressive in adults => causes sudden HTN, edema, high BUN
- Recovery
- 95% recovery in children; 60% recovery in adults
- Takes adults longer to heal
- More progress to chronic glomerulonephritis or RPGN type 2(10%)
12
Q
Acute/diffuse proliferative GN is most likely to occur in children (6-10) ___________ after a strep throat/skin infection (impetigo) due to ab to ________.
A
- 1-4 weeks (thus, pt will have no sx)
- SpeB (streptococcal pyogenic exotoxin B)
13
Q
- How does Acute Proliferative (Poststreptococcal) Glomerulonephritis typically present (signs/sx’s and findings)?
- Urine?
A
- 1-4 weeks AFTER infection, child (6-10 YO) will have fatigue + fever + nasuea + oliguria + hematuria and sx of nephritic syndrome
- Urine: red cell casts, dysmorphic RBCs
*
14
Q
Blood tests of patient with acute proliferative (post-strep) glomerulonephritis will have what findings?
A
- + ASO titers for Strep (Antistreptolyosin O Ab), anti-DNaseB
- low compliment levels
15
Q
What is the outcome of children with Acute (Diffuse) Proliferative Glomerulonephritis d/t strep?
A
- 95% recover w/ conservative therapy (water and salt restriction) (<1% progress to RPGN Type II)
16
Q
- Acute proliferative GN does not have to occur d/t strep => Acute proliferative glomerulonephritis (post-infectious and non-streptococcal) can occur d/t what else?
A
- 1. Bacteria
- 2. Viral
- 3. Parasites (toxoplasmosis and malaria)
17
Q
How do the immune deposits found in postinfectious GN due to staphylococcal infection differ from that of strep?
A
- immune deposits have IgA, not IgG
18
Q
- NOTE: Distractor! if there is a current complaint of sore throat and dry cough it is what can we exclude
A
PSGN: happens 1-4 weeks after an untreated case
19
Q
Rapidly Progressive Glomerulonephritis (RPGN) is a _______ syndrome and a __________ hypersensitivity reaction.
A
Nephritic
Type 2 (immune complex)
20
Q
What is Rapidly Progressive Glomerulonephritis (RPGN)?
A
- A severe form of glomerulonephritis where inflammation can lead to renal failure in weeks - months
- Caused by:
-
Cell-mediated immune response and MO cause BM to tear
- RBC, inflammatory mediatorys (=> inflammation) plasma proteins, fibrin, monocyte/MO & parietal epithelial cells leak out into Bowmans space =>
-
Parietal epithelial cells, MO/monocytes, fibrin & thrombin** => formation of **crescents in Bowmans space (causing normally thin epithlial layer to thicken and necrosis.
*
-
Cell-mediated immune response and MO cause BM to tear
21
Q
What makes up crescents in RPGN?
How do we view them?
A
- Proliferation of parietal epithelial cells that line Bowman’s capsule, monocytes, MO, and fibrin
- PAS stain on LM
22
Q
What occurs due to the damage induced in RPGN?
A
- Rapid obliteration of urinary space => rapid and progressive loss of renal function,
- Severe oligaria
- Tears in BM => cause RBCs to squeeze throuhh and NTR urinary space => hematuria
- Renal failure in weeks to months
23
Q
What symptoms can we see in a patient that we suspect has RPGN before conducting a renal biopsy?
A
1. Nephritic urine (RBC in urine)
2. Fatigue and anorexia
3. Acute renal failure
24
Q
Causes of RPGN are distinguished based on what?
A
IMMUNOFLUORESCNCE
25
What do we see on **LM**, **EM** in a patient with **_RPGN_**?
* **Light microscopy**: _Crescents_ & _MO/leukocyte infiltration_
* **Electron microscopy:** _wrinkling/tearing of GBM_ and _RBC_ can often be seen scooting into urinary space
26
**Causes of RPGN** are distinguished based on **immunofluorescence**.
## Footnote
**How do we do so?**
1. **RPGN** **Type 1:** _Linear_ IF
2. **RPGN** **Type 2:** _Granular_ IF
3. **RPGN** **Type 3:** _Negative_ IF
27
**RPGN Type 1** (\_\_\_\_\_\_)
**RPGN Type 2** (\_\_\_\_\_\_)
**RPGN Type 3** (\_\_\_\_\_\_)
**RPGN Type 1** (anti-GBM)
**RPGN Type 2 (**Immune complex)
**RPGN Type 3** (Pausi-immune)
28
**Type I RPGN (anti-GMB Ab)** disease is characterized by what kind of deposits?
Why this pattern?
* **Linear deposits** of **anti-GM antibodies (_IgG_ and _C3_)** in the **GBM** of _kidney_ and _lung._
* Linear bc binds to intrinsic Ag *along ENTIRE length of GBM*
29
* **RPGN Type I (Anti-GBM Antibody)** occurs when...
* **anti-GBM antibodies** against GBM antigens deposit in the **_BM_**
30
\_\_\_\_\_\_\_ is an example of a disorder than can cause RPGN Type I (anti-GBM Ab).
**Goodpastures**
31
**Goodpastures syndrome** can cause **RPGM Type 1 (anti-GBM Abs).**
What antigen will the **anti-GBM Abs** attack?
* [**non-collagen portion** of **a-3 chain** of **type 4 collagen**] in the ***GBM*** and ***alveoli***
32
**RPGN Type 1** that occurs in **Goodpastures syndrome** causes what symptoms?
1. **Hemoptysis** due to pulmonary hemorrhage
2. **Hematuria**
3. **Nephritic syndrome**
33
Which **_HLA subtype_** is associated an increased liklihood of getting **RPGN (i.e., Goodpasture Syndrome)?**
**_HLA-DRB1_**
34
What is used in the **treatment** for **Type I RPGN** (anti-GBM Ab disease)?
How effective?
* **Plasmapheresis** + **immunosupressive** **therapy**
* Can reverse pulmonary hemoorhage and renal failure
35
* **Type 2 RPGN (immune complex mediated)** disease is characterized what pattern of IF?
* **Where do the immune complexes deposit?**
**_Subendothelial_ _Granular_** due to deposition of immune complex
## Footnote
**& cell proliferation**
36
Major causes of **Type II (immune complex) RPGN?**
Occurs due to the progression of
1. **Post-infection GN (post-strep acute proliferative GN)**
2. **SLE**
3. **IgA Nephropathy**
37
RPGN Type 2 (Immune complex) is a type ____ hypersensitivity reaction.
ignore until further notice.
**3**
38
Can **Type II RPGN** be treated by **plasmapheresis**?
**No; treat underlying disease**
39
**Type 3 RPGN disease** is characterized by what kind of deposits?
* **_NO_ [anti-GBM Ab** & **immune complexes] because** of a **_pausi-immune response._**
40
Presence of what in the serum is virtually diagnostic of **Type III (Pauci-Immune) RPGN?**
**_p/c-ANCA (anti-neutrophil cytoplasmic Ab)_**
41
**Type III (Pauci-Immune) RPGN** may occur due to underlying disorders?
* **Vasculitis syndromes**, such as
* 1. Wegener (c-ANCA)
* 2. Microscopic Polyangiitis and Churg Strauss (pANCA)
42
In **RPGN** what is commonly seen in prominent amounts between the cellular layers in crescents?
**Fibrin**
43
**Rapidly progressive glomerulonephritis** can evolve into _________ or lead to what?
* **Chronic glomerulo**_sclerosis_****
* **Renal failure** in *weeks* =\> *months*
44
In **nephrotic syndrome,** what barrier is lost?
**Barrier to proteins (podocytes/epithlielial cells);** RBC filtration barrier (endothelium) is intact.
45
* Most causes of **nephrotic syndrome** are related to damage of what?
* **Podocytes (epithelial cells) =\> protein loss only**
* **Endothelial cells (RBC barrier) are intact**
46
Does inflammation occur in **nephrotic** syndromes?
**_NO_**
47
What causes **nephrotic syndrome, resulting in** **proteinuria?**
And if indicated**, what are they due to?**
1. **Primary**
1. **Minimal change disease:** cytokines
2. **Focal segmental glomerulosclerosis (FSGS):** podocyte damage
3. **Membranous nephropathy**: immune complexes
1. Diabetic: glucose
2. **Systemic causes**
1. 2. **Membranoproliferative glomerulonephritis**
48
**_Nephrotic_** **syndrome** in US **kids less than 17YO** is due to what?
**To primary lesion of the kidney**
49
What ***primary lesion*** is most common in children?
**Minimal change disease** (75% of cases in children)
50
How does the cause of **nephrotic syndrome** in **children \<17 yo diffe**r from **adults**?
* - **Children** = almost always caused by a lesion **primary** to the kidney
* - **Adults** = often associated with a ***_systemic disease_***
51
What are the 3 most common primary glomerular lesions responsible for the development of **nephrotic syndrome**?
Which is most common in children and which in adults?
1. **Minimal change disease** = most common in children (75%)
2. **Membranous glomerulopathy** = most common in older adults
3. **Focal segmental glomerulosclerosis** = occurs at all ages
52
What are the most frequent **systemic** **causes** of **_nephrotic_ syndrome**?
1. **- Diabetes**
2. **- Amyloidosis**
3. **- SLE**
4. - Drugs
5. - Infections
6. - Malignant dz (carcinoma, lymphoma)
53
How should we treat **nephrotic syndrome** in **children**?
* Nephrotic syndrome in children is **_minimal change disease**_ until proven otherwise; _**don't biopsy_** -- **tx with steroids** and **see if condition improves** because MCD responds to steroids.
54
In one word, what is the cause of
* **1. Minimal Change Disease**
* **2. Focal Segmental Glomerulosclerosis**
* **3. Membranous Nephropathy**
* 1. Minimal Change Disease
* **Cytokines**
* 2. Focal Segmental Glomerulosclerosis
* **Podocyte damage**
* 3. Membranous Nephropathy
* **Immune complexes**
55
What does the term "**nephrotic range proteinuria"** refer to?
**Loss of 3 grams or more/day in the urine**
56
* ___________ is the **2nd most common** cause of **_nephrotic_** **syndrome** in **adults** (30%)
**Membranous Glomerulopathy** (nephropathy)
FSGS (35%) is most common.
57
What is **membranous nephropathy?**
* _Chronic_ **immune-complex mediated** disease that causes ***diffuse*** **thickening** of the glomerular BM (**without hypercellarity**) due to deposits of IgG on **subepithelial** side of the BM.
58
Most causes of **membranous glomerulopathy** are _primary/secondary_
**Primary (75% of cases)**
59
**Primary membranous glomerulopathy** is now considered an **autoimmune disease** and linked to which HLA allele?
**HLA-DQA1**
60
**_Primary membranous glomerulopathy_** is a diffuse thickening of the glomerular BM (without hypercellarity). How does this happen?
* **_IMMUNE COMPLEXES:_**
1. **autoAB** to **phospholipase A2 receptor (PLA2R) antigens** (or neutral endopeptidase in secondary) on the **podocytes =\> form subepithelial immune complex deposits (primarily IgG4)**
2. **=\> Leukocyte infiltration and activate compliment =\>**
1. **MAC** causes capillary wall to **become leaky** =\> proteins leave
2. Damage to podocytes and mesengial cells =\> effacement
3. Overtime, **podocytes lay extra BM** =\> thickening of BM (but no hypercellularity) between immune complexes=\> creating a **spike and dome** appearance
61
How is **Membranous Glomerulopathy** different from **Minimal Change Disease?**
* **Membranous Glomerulopathy** **does NOT respond** to steroid therapy.
* MCD does.
62
What appearance does **membranous glomeruleropathy** create**?**
* **Spike and dome appearance** due to thickening of glomerular BM (but no hypercellularity).
63
If **thickening of the BM** occured + **hypercellularity**, what nephropathy would this be?
**_Membranoproliferative glomerulonephritis_**
64
**_Membranous glomerulonephropathy_**
* 1. LM
* 2. EM
* 3. Immunoflourescence
1. **_LM_**: **Uniform**, **diffuse thickening** (no hypercellularity) of BM on PAS stain
2. **_EM_**:
* **[Spike and dome pattern]:** subepithelial deposits of IgG4 on silver stain
* **[Effaced (Flattened) foot processes]**
3. **_IF_**: **"Lumpy bumpy"** **IgG4** **_granular_** deposits
65
What are some of the secondary causes of **Membranous Nephropathy?**
**_“TUMOR, HEPATITIS, RHEUMATOID ARTHRITIS”_**
* **1. Drugs** used to tx RA
* **2. Malignancies**
* **3. Infections (hepB/C)**
* **4. SLE, Autoimmine disorders**
66
**Secondary membranous glomerulonephritis** is more likely to experience \_\_\_\_\_\_\_.
**Hematuria**
67
Describe the proteinuria experienced in **membranous glomerulopathy**
**Non-selective**
68
**Recurrence of Membranous Nephropathy** is a common feature in which patients?
**1. Transplant pts for end-stage renal disease**
2. **Women** have spontaneous remissions and more benign outcome
69
What is the prognosis of **membranous glomerulonephropathy** in **children**?
What can **MGN r**esult in?
* **Good** prognosis in **children**
* **60%** of pts =\> **proteinuria persists**
* **40%** =\> **renal insufficiency**
* **10%** =\> **ESRD**
70
How is **minimal change disease** different from **membranous glomerulonephropathy** in regards to the proteins that leak out?
* **Minimal change disease:** _selective_ proteinuria (only albumin)
* **Membranous glomerulonephropathy**: _non-selective_ proteinuria (albumin AND Ig)
71
**Minimal change disease** is also called \_\_\_\_\_\_\_\_\_.
**Nil disease.**
72
What is **minimal change disease?**
## Footnote
**How does it occur?**
**Nephrotic syndrome where foot processes of the podocytes are damaged, allowing albumin to leak out of the capillary =\> urinary space.**
* **MOA:**
* 1. T-cells release **cytokines**,
* 2. Damage
* damage the (-) charge on podocytes
* effacement (flatten & fusion of) foot processes
* 3. Selective proteinuria
* 4. (-) charged albumin leaks out =\> ↑ albumin in the urine =\> nephrotic syndrome
73
**_Minimal Change Disease_**
## Footnote
1. LM
2. EM
3. Immunoflourescence
**_FINDING ONLY ON EM!_**
* 1. **_LM_**: NL
* 2. **_Immunofluorescence_**: NL bc damage is d/t cytokines
* 3. **_EM_**: Effacement (flatten and fusion) of foot processes, but **glomeruli is NL**.
74
**Minimal Change Disease** is most offten seen in who?
What condition is it often a cause of?
* **Children 2-6**
* **Hodgkins Lymphoma** and **lymphoreticular disorders, w**hich release MASSIVE amounts of cytokines.
75
What is main presenting sign in **MCD**?
What sx RARELY develops?
1. **Edema**
2. **Rarely** develop HTN
76
**Minimal change disease** often has a \_\_\_\_\_\_\_\_\_\_, which causes the release of cytokines.
**_Immunological trigger_**
1. Viral infection (URI)
2. Allergic reaction
3. Recent immunization
77
How do we treat **MCD**?
* **_Corticosteroids_** and **_immunosuppressants_** – _very_ responsive (90% of children)
78
What are 5 features of **minimal-change disease** which point to an i**mmunologic basis** for its development?
Increased incidence in pts with what conditions and cancer?
1. Occur after: **URI and immunizations**
2. Responds to **corticosteroids**
**_3. Assoc. w/ atopic disorders (i.e., eczema, rhinitis)_**
4. **Increased prevalence of certain HLA haplotypes**
5. Increased incidence in pts w/ **Hodgkin lymphoma**
79
What is the **SEVERE** **version** of **minimal change disease?**
**Focal Segmental Glomerulosclerosis (FSGS)\*\*\***
80
What is the **most common cause of nephrotic syndrome in _adults_** **U.S. AND WESTERN SOCIETY** (35%)?
_**Focal Segmental Glomerulosclerosis (FSGS)\*\*\***_
81
**_FSGS_** is usually _primary/secondary,_ but there are many ______ causes.
Often, it is a adaptive response to what?
FSGS is usually **primary (idiopathic**) but there are many **secondary** causes.
Often, a response to a **loss of renal mass**
82
What are the secondary causes of **FSGS**?
* **1. HIV (****collapsing variant of FSGS):**
* African Americans \> Caucasians
* **2. SS (Sickle Cell)**
* **3. Heroin**
* **4. Massive obesity**
83
What is **FSGS** and how does it occur?
1. Unknown causes (idiopathic) **damage podocyte =\>** **proteinuria**.
2. Overtime, proteins and lipids get trapped & build-up in the glomerulus =\> resulting in **hyalinosis** =\> **sclerosis**
3. Sclerosis =\> **collapse of the BM** _in a segment_ _of some glomeruli_ (_focal_) in the _kidney_
84
Where does the damasge occur in **FSGS**?
**Segments of SOME glomeruli,** not all are affected.
85
**_FSGS_**
## Footnote
1. LM
2. EM
3. Immunoflourescence
1. **LM**: Hylanosis and sclerosis of a segment of a glomeruli in SOME glomeruli
2. **EM**: Effacement of foot processes; sclerosis
3. **Immunoflourescence**: sometimes focal deposits of **_IgM_** and **_compliment_**
86
What is the ONLY way to dx **FSGS**?
**BIOPSY**
87
Which populations have a higher incidence of **primary** **Focal Segmental Glomerulosclerosis (FSGS)?**
**1. African Americans**
**2. Hispanics**
88
The clinical signs of **FSGS** differ from **Minimal Change disease** in what 4 ways?
1. Higher incidence of **hematuria**, **reduced GFR** and **HTN**
2. **Proteinuria** is often **nonselective**
3. **Doesn't respond well to steroids**
4. Poor prognosis: can progress to **_CKD_** ==\> 50% developing **_ESRD_** within 10 years
89
What is the most characteristic lesion (i.e, morphological variant of **FSGS**) seen in **HIV-associated nephropathy, a type of FSGS.**
**Collapsing glomerulopathy** = severe form of FSGS
90
What is the prognosis of **FSGS** in _children_ vs. _adults_?
- **Children** generally have **better prognosis** than adults
91
**FSGS** is nephritic/nephrotic?
Can be considered **MIXED; nephrotic sydrome w nephritic characteristics**
92
The **collapsing variant** of **FSGS** in **HIV patients** is most common in what population?
**African American**
93
Is **Membranoproliferative Glomerulonephritis (MPGN)** a disease?
No, it is a **type of injury** d/t **immunity**.
94
* **Membranoproliferative glomerulonephritis (MPGN)** is a group of rare glomerular disorders that can cause _________ syndrome. What occurs?
**_Nephritic or nephrotic syndrome_**
1. **Infiltration of acute inflamm cells (neutrophils)**
2. **Thickening of BM**
3. **Hypercellularity:** mainly mesangial, but can also be capillary
* _Capillary loops_
mesangial: **mesangial interpositio**n occurs, where mesangial cells proliferate & extend into the thickened BM =\> splits BM (producing "double countour"), forming a “tram track appearance” on LM
* _Increases mesangial matrix_
95
**MPGN** causes varying degrees of renal dysfunction, such as:
* **1. Renal failure (high BUN and creatinine)**
* **2. Proteinuria**
* **3. Hematuria**
* **4. Thick BM, hyperceullarity**
96
In **MPGN**, how will the architecture of the lobules change?
They will become **more accentuated.**
97
**Membranoproliferative Glomerulonephritis (MPGN)** is also called ___________ glomerulonephritis.
**_Mesangiocapillary_**
98
What is the difference in the pathology of **MPGN Type 1** and **MPGN Type 2?**
* MPGN Type 1: **subendothelial immune complexes deposits** that contain **IgG** and **compliment**
* MPGN Type 2: **electron dense deposits of C3 (compliment)** in the **BM,** not subendothelium
99
What are the differences between **Type 1** and **Type 2 Membranoproliferative Glomerulonephritis?**
* Only difference (in terms of pathology) is where deposits are:
* **MPGN Type 1 (most common):** Deposition of I**gG/compliment immune complexes** in the **subendothelium**
* _tram-track appearance_
* **MPGN Type 2 (Dense Deposit Disease):** deposition of **C3a/C3b deposits** in the **BM** (not subendothelium) and decreases levels of C3
100
What causes the C3 deposits in the BM in **MPGN Type 2 (dense deposit disease)?**
1. **C3 nephritic factor** (C3NeF, an IgG autoAb)) inapprop activates the alternative compliment pathway
1. Binds to C3 convertase =\> stabilizes =\> prolong activation =\> **increase C3a and C3b**
2. **=\> deposit in BM**
3. **=\> inflammation in BM and low levels of C3**
101
Which causes tram track appearance **MPGN Type 1** or **Type 2**?
**Both**
102
When do most cases of **primary** MPGN Type I present?
How do they present?
- MC in **children** or **young adults mostly,** but can **affect all ages**
- **Nephrotic syndrome** & **nephritic component** manifested by:
* **_Proteinuria_**, microscopic hematuria, **HTN (~30)**, oliguria, some edema, and renal insufficiency
103
About **50%** of patients with **MPGN Type I** will develop what?
Response to immunosuppressant therapy?
* **_Chronic renal failure_ in 10 years**
* Not proven to be beneficial
104
Who does **_secondary_** **MPGN Type I** present in?
Arises in which settings and with what associated disorders?
- Almost exclusively in **adults**
- Arises d/t **chronic antigenemia** (from infection, autoimmune dz or neoplasia), which causes **immune complex deposition**
1. - SLE, **HBV**, **HCV** **(w/ cryoglobulinemia)**, endocarditis, HIV, and schistosomiasis
2. **- α1- antitrypsin deficiency**
3. - Malignancies (**CLL**, **lymphomas**, **melanomas**)
105
Most patients w/ dense deposit disease (aka type II MPGN) have abnormalities reulting in excessive activation of?
**Alternative complement pathway**
106
**Dense deposit dz (MPGN type II)** primarily affects whom?
Only occurs as what kind of disease?
- **Children**
- Only occurs as a **primary renal disease**; **no secondary form**
107
What is the dominant clinical finding in **Dense Deposit disease** vs. **MPGN type I**?
Prognosis of **MPGN II** vs. MPGN I?
- MPGN type 1: proteinuria
- MPGN type 2: hematuria
* - **50% of patient**s will also have **nephritic** syndrome and **50%** will get **ESRD** in 10 years
* - **Poorer prognosis** than MGPN I due to most pts having severe renal dz.
108
High incidence of recurrence of **MPGN II** in which patients?
**Transplant patients,** indicating importance of a circulating factor
109
In **MPGN 1 & 2,** on **LM** we see (**hypercellularity**, **GBM splitting**, **leukocyte infiltratio**n and **tram-track appearance**)
What do we see on EM and IF for each?
Type 1
* EM: subendothelial deposits of immune complexes
* IF: IgG, C3; C1q and C4
Type 2
* EM: electron dense deposits in BM that look like ribons (seen in pic)
* IF: C3 and properidin (no IgG, C1q or C4)
*
110
What is the most common type of **glomerulonephritis** **_worldwide?_**
What about in the US?
* **IgA nephropathy:** worldwide
* **FSGS**: USA
111
What is **_IgA nephropathy (Berger Disease)?_**
* a overactive immune system that causes an **↑ IgA production**, forming of **IgA-IgG immune complexes** in response to triggers such as:
* Respiratory infection
* GI infection
112
IgA nephropathy is an overactive immune system that produces excessive IgA, due to what?
**Viral** (MC) infections
* **Respiratory infection**
* **GI infection**
113
**IgA-IgG immune complexes** cause pathology and inflammation where?
**Where they deposit (mesangium)**
114
**IgA-IgG immune complexes** form in the mesangium. What happens next?
1. =\> **Light + of compliment pathway** via alternative and lectin pathway (no hypocomplementemia)
2. =\> **Inflammation** due to release pro-inflammatory cytokines and MO =\> **damage of glomerulus**
115
Will a person with **IgA nephropathy** develop hypocomplantemia? Why
No because compliment is **LIGHLTY activated**
116
**IgA nephropathy** is primarily a disease seen in whom?
Which **ethnicities** more affected?
Which **sex**?
- Older **children** and young adults (20s-30s)
- **White ppl and Asians** \> African Americans
- **Male** predominance: 2:1 or higher (N. America and Europe)
117
What are the MAIN pattern of of **IgA nephropathy (Berger disease)?**
IgA1-IgG **immune complex deposition** in **mesangium** (_GLOBAL_) with only **recurrent microscropic/gross hematuria for a long time (20 years),** before developing into **chronic renal failure.**
118
**_IgA Nephropathy (Berger Disease)_**
* LM
* EM
* IF
* LM: **Focal** proliferation and widening of the mesangium
* EM: Mesangial and paramasangial **dense deposits**
* IF**: Granular IgA-IgG immune complexes, IgM** and **C3** in the mesangium
* No C1q or C4 bc altenrative path was +
119
Due to increased synthesis of abnormal IgA, there is an **increased incidence of IgA nephropathy** seen in which 2 conditions?
1. **Celiac disease** (gluten enteropahty)
2. **Liver disease** (defective hepatobiliary clearance of IgA) --\> **secondary** IgA nephropathy
120
Pts with **IgA nephropathy** commonly present with **hematuria** following what?
How long does it last?
- R**espiratory infection** or, less commonly the GI/GU tracts
- Hematuria **lasts several days**, then **subsides**, only to **return every few months** since childhood
121
What clinical outcome occurs in a majority of patients with **IgA nephropathy?**
- Recurrent episodes of hematuria **w/o progression of renal disease**
122
What are the clinical outcomes of **IgA nephropathy** progressing to a renal disease?
- **5-10%** of patients will progress to **acute nephritic syndrome w/ HTN**
- **15-40%** will progress to **chronic renal failure** over 20 year period
123
* **Post-strep GN:** occurs _____ after infection
* **Minimal change:** occurs:
* **IgA Nephropathy:** occurs:
* **weeks**
* **nephrotic** syndrome after URI
* recurrent episodes of gross/microscopic hematuria **since childhood**, URI, diarrhea
124
IgA nephropathy **without extra renal involvement** is called \_\_\_\_\_\_\_\_\_\_.
What about if there is **extra-renal involvement?**
1. Berger Disease
2. Henoch-Scholein Purpra (HSP
125
What is **Henoch-Schonlein purpura (HSP)?**
Typical clinical presentation?
- IgA nephropathy associated w/ systemic disease --\> onset following **URI**
- Presents w/ **cramping & pain** + **hematuria** and **proteinuria**
126
What is an **isolated glomerular abnormality?**
**IgA Nephropathy**, because patient can be **asymx** for a **LONG TIME**
127
If a pt presents with **glomerulonephritis syndrome** with **hypocomplimentemia**, what is the most common dx?
1. **Membranoproliferative GN Type 2**
128
**MPGN Type 1 and 2**: which is more a nepritic/nephrotic syndrome
* **Type 1:** nephrotic syndrome w nephritic findings
* **Type 2:** nephritic
129
Is **Chronic Glomerulonephritis** a diagnosis?
Yes
130
**Chronic Glomerulonephritis** causes what?
* **Chronic renal failure/ chronic kidney disease**
131
What stain is used to view **Chronic Glomerulonephritis** and what is seen?
_**Trichome stain** (_stains blue) shows **_obliteration and replacement of all glomeruli_** with **_acellular eosinophillic masses._**
132
Do we always know what causes **chronic glomerulonephritis?**
**NO**. Many cases arise **mysteriosly** due to the **end-result** of relatively **asymptomatic** forms of **glomerulonephritis** that **progress to uremia.**
133
What PRIMARY glomerular disease most commonly become **chronic glomerulonephritis (CGN)?**
1. **90% of Cresenteric GN**
2. 50-80% of FSGS
3. 50% of membranoproliferative
4. 30-50% of IgAN and membranous nephropathy
5. 1-2% of post-strep GN
134
What are the 2 **hereditary nephritis?**
1. **Alport syndrome**
2. **Thin Basement Membrane Disease (Benign Familial Hematuria)**
135
**80%** of patients with a **family history of hematuria** or r**ecurrent hematuria during childhood** have either
1. **Alport**
2. **Thin Basement Membrane Disease (more likely).**
136
Alport & Thin Basement Membrane Disease are both **isolated glomerular abnormalities** and associated with mutations in in what gene?
Where in the kidney do we see the problem?
* **Collagen gene** that effect collagen
* Reflected by **abnormalities of the BM.**
137
What is **Alport syndrome?**
* A **multi-system disease** that produces a nephritic syndrome: **hematuria** that progresses into **chronic renal failure.**
138
What symptoms are associated with **Alport**?
* Triad (cant pee, cant see, cant hear a bee)
* **1. Hematuria** that progresses into **chronic renal failure.**
* 2. **Hearing loss**
* 3. **Eye disturbance**
139
What is the major inheritance pattern of **Alport Syndrome?**
How does this effect the presentation in men and women?
**X-linked** (more common in **Males**)
140
**Alport Disease** is due to mutations in genes encoding subunits of which molecule?
**COL4A5** (type 4 collagen, alpha5 chain)
141
**Alport Syndrome**
* LM
* EM:
* Immunohistochemistry:
* **LM**: NL (until late in the disease)
* **EM**: Basket weave appearance
* Irregular thickening of BM with alternating attenuation (thinning)
* Splitting/lamination of the lamina densa, and foci of rarefaction
* **IF**: *absence* of a3, a4, and a5 staining
142
Symptoms of **Alport Syndrome** typically manifest btw what ages?
Frequent presentation?
**- 5-20 yo** w/ onset of **overt renal failure btw ages 20-50**
- Present w/ **hematuria** with **red cell casts**
143
What is **_Thin Basement Membrane Disease?_**
Hereditary disorder that causes **asymptomatic microscopic hematuria** due to a **thin** BM (150-250 nm, compared to 300-400 nm) and **rarely** leads end-stage disease
144
What is renal function like and the prognosis for **TBM Disease?**
**NL kidney function** and **excellent prognosis**
145
Which is more likely to lead to c**hronic renal failure/ESRD: Alport or TBMD?**
* **Alport.**
* TBMD rarely leads to ESRD.
146
The thin BM's in Thinned BM Disease is due to mutations in genes encoding what?
Most patients are what type of carriers?
* **Type IV Collagen** – **a3** or **a4** chain gene mutations
* **Heterozygous carriers**
147
**Homozygotes** with Thinned BM Disease resemble what other hereditary nephritis?
**AR Alport**
148
Which stain is used to view **Chronic Glomerulonephritis?**
What's seen?
* **Trichrome stain**
* Shows:
* **replacement** of almost all **glomeruli** w **collagen**
* **obliteration of glomeruli** with acellular **masses of eosinophils**
*
149
As glomeruli progressively become obliterated in chronic GN, what happens to GFR and protein loss?
**- GFR decreases**
- **Protein loss in urine diminshes**
150
