ICL 2.4: Nephritic Glomerular Diseases Flashcards
what does the mechanism of glomerular injury depend on?
the site of the antigen and pathway of complement activation
what are the different mechanisms of glomerular injury?
- fixed tissue antigens
- immune complex nephritis
- alternate complement pathway
- cell-mediated immune injury (cytotoxic antibodies)
what is the fixed tissue antigen mechanisms of glomerular injury?
type II hypersensitivity reaction where glomerular injury is due to antibodies to antigen
fixed to basement membrane
the antigen is fixed to the basement membrane of the capillaries in the glomeruli and antibodies come bind to the antigen which activates compliment and the compliment activation is chemotactic
antigen = non-collagen domain of collagen type IV**
ex. Goodpasture syndrome = hematuria and hemoptisis
what is the immune complex nephritis mechanism of glomerular injury?
antigen and antibody circulating in the blood and then it deposits in the basement membrane to activate complement
this causes chemotaxis that calls in neutrophils, lysosomal enzymes and causes tissue damage
type III hypersensitivity reaction
ex. post-streptococcal glomerulonephritis
what is the alternate complement pathway mechanism of glomerular injury?
alternate complement pathway activation starts by cleavage of C3 by bacteria or viruses or other agents
then neutrophils, enzymes and tissue damage happen
ex. membranoproliferative nephritis II
what is the cell-mediated immune injury mechanism of glomerular injury?
T-cells damage the processes of the gomerulus
ex. minimal change disease
what is the clinical presentation of nephrotic syndrome glomerular diseases?
- proteinuria (3+gram/24hrs)
- edema: when you lose protein the oncotic pressure goes down and causes edema
- hypoproteinemia
- hyperlipidemia
- lipiduria
lead to thickening of the basement membrane!!
what is the clinical presentation of nephritic syndrome glomerular disease?
- hematuria
- RBC casts* = structures that are molded in the renal tubules
- mild proteinuria
- HTN
- oliguria
- azotemia = high BUN and creatinine
- edema
leads to proliferation of the mesangial cells and necrosis = inflammation
what is the clinical presentation of hematuria syndrome glomerular diseases?
pure hematuria indicates variable changes in the glomeruli so we don’t really know what changes are happening
what is the clinical presentation of chronic renal failure?
hyalinization or sclerosis
how do you diagnose glomerular diseases?
① renal biopsy via light microscopy with the following special stains:
- PAS shows mesangium
- Jones silver stain shows basement membrane (important in nephrotic syndrome)
- trichrome shows fibrosis (important in CKD)
② then you have to save frozen tissue and do immunofluorescence –> if it’s mechanism I vs. II vs. III it’ll all look different!
③ you also need to do electron microscopy to see where the immune complexes were deposited
what are the layers of the glomerulus?
- endothelium
- epithelium
- mesangium
so the basement membrane has 3 parts = central lamina densa sandwiched between two layers called the lamina rara interna and lamina rara externa
on the inside of the glomerulus are epithelial cells and in-between them are fenestrations
then on the outside are the foot processes of the epithelial cells and in-between them are the filtration slits and diaphragm
what are the 2 components of the mesangium?
- cells
they’re contractile and regulate blood flow through the glomerulus and they’re phagocytic – in some disease like post-strep, at the onset of the disease you’ll see deposits at the periphery of the capillaries but later on when the mesangial cells phagocytose the immune complexes they’ll be in the mesangium
- matrix
provides support
a 5 year old was brough tot he ED because the mother noted dark urine. the child had a sore throat 10 days earlier.
PE shows 120/80, urinarylis shows RBCs, RBC casts, 1+ protein
CBC is normal, ESR increased, elevated BUN and creatinine
diagnosis?
what other tests would you order?
post-streptococcal nephritis
something is effecting the kidney after a strep infection so this is an immune complex mechanism of glomerular injury
the antigen is the strep antigen! some strep antigen are still circulating and antibodies formed against it so then the classic complement pathway is activated leading to glomerular damage
ESR is high because of the inflammation happening
high BP, RBC casts, little protein, azotemia = high BUN and creatinine –> nephritic syndrome!! this means you’ll see proliferation of mesangial cells and necrosis
we want to check the complement levels which will be low since they’re being consumed
what is the clinical and lab presentation of post-streptococcal glomerulonephritis?
immune glomerulonephritis (mechanism II) = immune complex mediated nephritic syndrome = mesangial cell proliferation and necrosis
clinical presentation
- hematuria
- HTN
- azotemia
lab findings
- ASO titer increased
- low complement
- RBC in urine
- RBC casts in urine
- elevated BUN
- elevated creatinine
what is the histological, IF and EM morphology of post-streptococcal glomerulonephritis?
- mesangial cell prolifeartion and necrosis = lots of cells and neutrophils on the histology
- IF will show lumpy bumpby coarse granular peripheral deposits of IgG and C3 = necklace made of rocks
this is because immune complexes circulating and then they deposit in capillary membrane basement membrane
- EM will show subepithelial electron dense humps
what is the prognosis of post-streptococcal glomerulonephritis?
in children 90% resolve
in adults 70% resolve and the remainder become hypertensive and develop renal failure
35 year old male went to doctor for annual physical. he was found to have microscopic hematuria that wasn’t visible to the eye
CBC and Chem20 were normal
differential diagnosis?
other tests?
renal biopsy findings?
IgA nephropathy
but it could also be many other things like familial nephritis, stones in the kidney that just haven’t caused pain yet, tumor, etc.
what is IgA nephropathy?
sometimes there’s a preceding illness like URI/GI since IgA is the mucosal antibody but there’s also familial IgA nephropathy
thought to be due to activation of alternative complement pathway by IgA
clinical findings can be either gross or microscopic hematuria
if you have hematuria the morphology can be variable so we don’t know what we’re going to see…
what is the histological, IF and EM morphology of IgA nephropathy?
light microscopy histology is variable because since it’s just hematuria we don’t have a hallmark thing we’re going to see –> might see crescent shape
IF will show diffuse mesangial IgA! so the deposits aren’t in the periphery, they’re in the mesangium
there is no specific EM picture
how do you treat IgA nephropathy?
- steroids
2. fish oil
what is the prognosis of IgA nephropathy?
benign in children
in adults 19% have renal failure and 32% become hypertensive –> it recurs in renal transplants**
12 year old girl presents with a palpable red rash on her buttocks, arthralgia, abdominal pain and hematuria
UA: RBCs and RBC cell casts with increased BUN and creatinine
serum IgA
Henoch-Schonlein purpura
purpura = thrombocytopenia –> this is a misnomer, it’s actually a vasculitis!! there’s no thrombocytopenia
a nephritic syndrome that is a systemic disease which effects the skin, GI and kidney
palpable rash
pain without inflammation = arthralgia while arthritis is actual inflammation of the joints
IgA mediated so high serum IgA**
what is Henoch-Schonlein purpura?
usually there is a preceding illness, usually a URI
- diffuse vasculitis
- transient immune complex reaction
- possible alternate pathway activation
- nephritic syndrome
- GI and cutaneous manifestations
- gross and microhematuria
- IgA in the kidney and skin!
- palpable rash**
main systems involved are the skin, GI and kidney
what are the lab findings associated with Henoch-Schonlein purpura?
- normal platelet count and bleeding time
2. increased IgA levels in the serum
what is the morphology associated with Henoch-Schonlein purpura?
LM is variable but you can have proliferation, necrosis or crescents –> proliferation can be diffuse or focal
IF will show IgA, IgG, C3, mesangial deposits, IgA deposits in the skin
a 25 year old male presents with profuse hemoptysis following a flu-like illness a week prior
PE shows pale, tired young man
urinalysis shows many RBCs, RBC casts
CBC shows Hb of 11
differential diagnosis?
biopsy findings?
other tests?
Goodpasture syndrome
anemic from from coughing up blood and also blood in urine
fixed antigen to the basement membrane and then complement comes and binds to the fixed antigen which attracts neutrophils that release enzymes that cause damage
biopsy finding: the entire basement membrane is antigenic so the whole basement membrane will fluoresce!!
other tests = serologic tests to test anti-globular basement membrane antibodies
what is Goodpasture’s syndrome?
fixed antigen to the kidney basement membrane
presents in the 3rd and 4th decade
often there is a preceding illness; specifically URI
clinically there will be hematuria and hemoptysis –> hematuria can precede hemoptysis or vice versa
what is the morphology of Goodpasture’s syndrome?
LM shows necrosis and crescents –> Bowman’s space is obliterated and there are adhesions between the capsule and the glomerulus
IF shows linear* peripheral IgG deposits along the basement membrane of the glomerulus and the alveolar septa in the lungs
EM is not diagnostic
what are the lab findings associated with Goodpasture’s syndrome?
serum anti-glomerular basement membrane (anti-GBM)
the antigen is the alpha-3 chain of type IV collagen**
what is crescentic glomerulonephritis?
leakage of fibrin in Bowman’s space
so you can’t see Bowman’s space at all because it’s filled with fibrin and proliferating cells of the Bowman’s capsule = crescents!
crescents signify aggressive glomerular disease and poor prognosis = rapidly progressive –> not specifally diagnostic for any specific disease it just means a rapidly progressive renal disease
if you do IF, you’ll see an actual crescent that stains for fibrin and fibrinogen
which disease are asccoaited with crescents?
- IgA nephropathy
- Henoch-Schonlein purpura
- Goodpasture syndrome
- Wegner’s
a 45 year old female with a 3 month history of epistaxis presents with cough and hematuria?
cANCA + ve
diagnosis?
granulomatous polyangiitis = Wegner’s granulomatosus
with cANCA the antigen is proteinase 3 and in pANCA the antigen is myloperoxidase –> Churg Strauss (eosinophilic vasculitis)is associated with pANCA
what is granulomatous polyangiitis?
previously known as Wegner’s granulomatosus
clinical findings = triad of sinusitis, pneumonitis, glomerulonephritis
bleeding from nose, lungs and kidneys
presents from 30-75 years and more in males than females
pathogenesis we don’t understand but it could be hypersensitivity or immune deficiency
what is the morphology of granulomatous polyangiitis?
LM focal necrotizing lesions in the glomeruli with crescents = rapidly progressive and aggressive
IF is variable
EM shows necrosis but isn’t diagnostic
50 year old executive presents with recurrent abdominal pain and skin rash, he has had a low grade fever for 3 months.
PE shows 140/90 BP, 100 F
urinalysis shows RBCs, RBC casts, 1+ protein
CHEM 20 shows BUN 50, creatinine 3, eosinophilia
diagnosis?
other tests?
biopsy findings?
polyarthritis nodosa (PAN)
could be Henoch-Schonlein purpura since there is a rash with abdominal pain BUT the rash isn’t palpable and there’s no arthralgia and this has been going on for 3 months whereas HSP is acute!
what is polyarthritis nodosa (PAN)?
caused by chronic immune complex that effects kidney, GI, MSK, CNS, and skin but lungs are NOT involved***
clinical presentation depends on location, number and size of involved in vessels but most patients have fever
way more common in males than females and presents in the 4th and 6th decades
preceding illness is Hepatitis B**
what are the lab findings associated with polyarthritis nodosa?
- ANA normal
- 30% will have HepB
- transient or persistent antigenemia from HepB
- positive pANC in small % of patients
- involves large and medium sized vessels and also the glomeruli!
what is a crescent made of?
- fibrin
- parietal cells
reminds us of ARDS in the lungs which is also caused by fibrin
platelet count in Henoch-Schonlein purpura
normal
it’s a vasculitis and not thrombocytopenia purpura
IgA deposits in the skin
HSP
linear deposits of IgG on IF
Goodpasture syndrome
3 year old boy presents to ER with lethargy, hematuria and bloody diarrhea for 2 days following a birthday party where he ate a grilled hamburger
CBC shows Hb of 7, elevated BUN, low platelets, elevated creatinine
schistocytes on peripheral smear
diagnosis?
hemolytic uremic syndrome (HUS)
this is a microangiopathic hemolytic anemia!
other diseases associated with microangiopathic hemolytic anemia and renal failure are DIC and TTP –> TTP doesn’t have GI symptoms it’s just transient neurologic manifestations, microangiopathic hemolytic anemia, renal failure, thrombocytopenia and low grade fever –> DIC patients are usually septic
what is hemolytic uremic syndrome?
it’s a disease where microthrombi occlude the arterioles and capillaries, which results in microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury
incidence is usually postpartum and in children under 1 year
preceding illness is almost always a gastroenteritis; specifically the toxins of E. coli
clinical presentation:
1. oliguria
- renal failure
- hemolytic anemia
- thrombocytopenia
- e. coli 0157 toxins
which diseases are secondary glomerular diseases?
- SLE
how is SLE a secondary glomerular disease?
mean age is 29 and more common females
caused by immune complexes
kidney effect = hematuria, proteinuria, casts, nephritic syndrome!!!
systemic disease that shows butterfly rash, photosensitivity,
what are lab findings associated with SLE?
- increased ANA (screening test)
- anti-DNA
- decreased complement
what is the morphology of SLE?
LM is variable
IF is full house so in the basement membrane and mesangial – you’ll also see deposits in the tubular basement membrane
EM will show subendothelial deposits** and mesangial deposits
what are the 5 patterns of SLE?
- normal by light, electron, and immunofluorescent microscopy (class 1), which is quite rare
- mesangial lupus glomerulonephritis (class II)
- focal proliferative glomerulonephritis (class III)
- diffuse proliferative glomerulonephritis (class IV
- membranous glomerulonephritis (class V)
sclerosing changes
none of these patterns is specific for lupus
a 45-year-old female with hypertension and pulmonary fibrosis and Raynaud’s phenomenon for 5 years presents with renal failure
ANA 1:20,000 speckled anti SCL70 +ve
she has thin leathery skin on her hands and face
diagnosis?
scleroderma aka progressive systemic sclerosis
progressive = doesn’t stop, it keeps progressing
systemic = kidney, blood vessels, lung, GI, skin
sclerosis = scars everywhere
cANCA
Wegner granulomatis
full house
SLE
microangiopathic hemolytic anemia
- HUS
- DIC
- TTP
HepB
polyarthritis nodosa = PAN
low C3
- post-streptococcal glomerulonephritis
2. SLE
