Renal Path: Glomerular Disease Flashcards
In autosomal recessive polycycstic kidney disease, what do the kidneys lok like
enlarged, but SMOOTH externally. Cut sections show many small cysts in both the cortex and medulla
What are the 4 categories of autosomal recessive polycystic kidney disease?
perinatal, neonatal, infantile and juvenile. Only the last two survive infancy.
For those patients that survive infancy with autosomal recessive PKD, what extra-renal findings do they often show?
liver cysts
bile duct proliferation
congenital hepatic fibrosis (periportal fibrosis)
Describe medullary sponge kidney disease?
it’s an adult disease with multiple cystic dilatations of the collecting ducts in the medulla
What are the symptoms or medullary sponge kidney
relatively normal kidney function!!!
hematuria
How do children with nephronophthisis-uremic medullary cystic disease complex present?
polyuria and polydypsia due to a tubular defect caused by the cysts in the medulla
Many people on dialysis for over 10 years will get cysts which are usually asympomatic. What’s the worry with these cysts?
7% will develop renal cell carcinoma within the cysts
Describe a simple cyst - commonly found on autopsy?
typically cortical in location
1-5 cm in size
filled with clear fluid
single layer of cuboidal or flattened eptihelium lining
NO clinical significance except to differentiate from possible tumor.
On to glomerulonephritis…
What are the three histologic patterns of glomerular injury?
- hypercellularity (increased mesangial, endothelial cells, epithelial cells, WBCs, crescent formation)
- basement membrane thickening (BM material to deposited material)
- Hyalinization and sclerosis
What do these terminology refer to: diffuse focal global segmental
diffuse - all glomeruli are affected
focal - only some glomeruli are affected
global - the entire glomerulus is affected
segmental - only part of the glomerulus is affected
What are the 4 basic histologic methods we use to evaluate renal disease?
- H&E
- Special stains: PAS, Trichrome, silver
- Immunofluorescence
- Electron microscopy
What color is PAS? Trichrome? silver?
PAS is pink - for sclerosis
trichrome is blue - cartilage?
silver - black capillary walls
What are the three general immune mechanisms of glomerular injury?
- antibody-mediated injury
- cell-mediated ijury
- activation of alternative complement pathway
What are the two kinds of antibody-mediated injury?
in situ immune complex deposition (antigen IN the kidney gets bound by antibody and forms a complex)
circulating immune complex deposition (antigen binds antibody elsewhere in the body and then complex gets stuck in kidney)
What happens in Goodpasture syndrome? WHat kind of antibody-mediated injury is this?
You have IgG direced against normal component sof the GBM - specifially the noncollagenous domain of the alpha 3 chain of Type IV collagen
since the antigen is in the kidney, it’s in situ immune complex deposition
What other organ is affected by Goodpasture?
lungs - same type of collagen there in the pulmonary alveoli
What’s the experimental rat version of goodpasture?
masugi
What histological technique can give you a goodpasture diagnosis?
Immunofluorescence = diffuse ribbon deposition
What is another version of in situ immune complex deposition where the antigen is M-type phospholipase A2 receptor? Rat model?
membranous (most membranous anyway)
heymann nephritis in rats
What’s the deposition pattern on IF in membranous?
granular - since the M-type phospholipase A2 receptor isn’t everywhere like GBM material is.
What will EM show in membranous?
electron dense deposits along the subepithelial aspect of the GBM
What is meant by the term “planted antigens”
Antigens are non-glomerular in origin, but localize to eh kidney and then antibodies form against them
What will the IF deposition pattern be for circulating immune complex nephritides?
granular
Describe progression of glomerular disease…Once GFR is reduced to 30-50%….
progression to end stage renal failure will proceed at a steady rate, no matter what the inciting event was
What two histological findings will you see after glomerular disease has progressed to ESRD>
focal segmental glomerulosclerosis
tubulointerstitial fibrosis
Describe how focal segmental glomerulosclerosis is an adaptive change?
When you start to lose function of the nephron, an adaptive change ocurs in the glomerulus called compensatory hypertrophy to make up for it
this leads to hemodynamic changes in individual gomeruli (including increaseed pressure)
this leads to segmental sclerosis over time with cell injury, epithelial cell loss and accumulation of proteins
What class of drugs can be given to hoepfully slow down the progression of focal segmental glomerulosclerosis?
ACE inhibitors or ARBs
WHy does tubulointerstitial fibrosis develop with glomerulonephritides over time?
As the glomeruli sclerose in FSGS, the tubule downstream from these glomeruli become ischemic
the ischemia and proteinuria are toxic to the tubule and they undergo both acute and chronic inflammation leading to scarring and fibrosis
Again, what are the characteristics of nephritis glomerulonephritis?
hamaturia with RBC cases
variable proteinuria, less than 3.5 g/d
azotemia
hypertension
What are the characteristics of nephrotic syndrome?
proteinuria over 2.5 g/d hypoalbuminemia Edema hyperlipidemia hyperlipiduria
Why do you have increased infection risk in nephrotic syndrome?
loss of gammaglobulins in proteinuria
Why are you procoagulable in nephrotic syndrome?
loss of antithrombin III in proteinuria
What is the common finding in all nephrotic glomerulonephritides
severe damage to the podocytes
When does acute poststreptococcal glomerulonephritis typicall occur?
1-4 weeks post a strep pharyngeal or skin infection
most commonly in children, but present in all ages
What lab tests can help you make the diagnosis of acute poststreptococcal glomerulonephritis without doing a kidney biopsy?
serum C3 will be low
serum antistreptolysin O present
antiDNase B high
What will acute postreptococcal GN look like on plain histology?
large, hypercellular glomeruli with proliferation of endothelial and mesangial cells
infiltration of neutrophils and monocytes
What will acute poststreptococcal GN look like on IF?
EM?
IF will show granular IGG, IgM or C3 deposits in the mesangium and along the GBM
EM will show subepithelial humps
What will the clinical presentation be in acute poststreptococcal GN?
malaise, oliguria hematuria (smoky urine!)
RBC cases, mild proteinuria, periorbital edema, mild HTN
If you see crescents in most of the glomeruli on a slide, what does that mean?
rapidly progressive glomerulonephritis = bad news!
not caused by a specific entity
What are the crescents made of?
proliferations of parietal epithelial cells of Bowman’s capsule mixed with inflammatory cells - obliterate the urinay space in the capsule and squish the glomerular tuft
also fibrin
What are the classifications of rapidly proliferative GN?
type 1 = anti-GBM GN
Type 2 = immune complex mediated
Type 3 = pauci-immune type
What will you see on the gross anatomy in rapidly proliferative GN?
large, pale kidneys with petechiae
What will you see on microscopic evaluation in rapidly proliferative GN? EM? IF?
micro = screscent formation with fibrin strands
EM: ruptures in the GBM with or without depostis
IF: depends on type - positive in type 1 and 2, but negative in 3
What is the clinical presentation of rapidly proliferative GN?
nephritic syndrome with hematuria with RBC casts, moderate proteinuria, HTN, edema
progressive over WEEKs instead of yers with ultimlately severe oliguria
What is the most common cause of nephrotic syndrome in kids?
minimal change disease
What is the most common cause of nephrotic syndrome in adults?
FSGS
followed closely by membranous
What is the most common cause of membranous GN?
trick question!
85% are idiopathic
What are the common associations/secondary causes of membranous GN?
drugs (penicillamine, captopril, gold, NSAIDS)
malignancy (lung, colon, melanoma)
SLE
Infections: HBV, HCV, syphilis, schistosomiasis, malaria
Metabolic disorders like DM or thyroiditis
Describe the pathogenesis of membranous GN?
you get chronic antigen-antibody mediated idsease against the phospholipase A2 receptor
this leds to complement-mediated damage of the GBM
What will you see on microscopy with HE> silver?
HE - normocellular gloms with uniform, diffuse thickening of capillary wall = cheerios!!
Silver stain will show “spikes” of basement membrane material laid down between deposits
over time, deposits just become part of a very thickened GBM
late, mesangial sclerosis and glomerular hyalinization
What will IF show in membranous GN? EM?
IF will have granular deposits along the GBM containing IgG and C3
EM will have subepithelial deposits with spikes of basement membrane between the spikes. Eventually the deposits are resorbed and you just get a thickened GBM
also effacement of foot processes
What is the typical course for membranous GN?
chronic proteinuria and slow deterioration - only 40% will develop chronic renal insufficiency and only 10 % will have renal failure and death
What are the associations with minimal change disease?
atopy
may follow a respiratory infection or routine immunization
increased incidence in Hodgkin lymphoma
What does minimal change disease respond to?
corticosteroids - amazing improvement!
Describe the pathogenesis of minimal change disease?
it’s likely T cell dysfunction with release of cytokines that damage the viasceral epithelial cells (podocytes) leading to loss of charge barrier or adhesin between the podocytes and the GBM = effacement
What will you see microscopically in MCD? on IF/ EM?
microscopid - normal glomeruli, proximal tubules may be filled with lipid
IF - no staining
EM - diffuse effacement of foot processes of the ivsceral epithelial cells, but no deposits
What’s the clinical presentation and course of MCD?
MASSIVE proteinuria, which is highly selective for albumin
no renal failure and often no HTN
most respond to corticosteroid therapy rapidly but some can recur
Back to FSGS…what are some important associations?
HIV infeciton Heroin addiction sickle cell disease morbid obesity more common in african americans
What are some ideas of why FSGS happens
- due to adaptive change in response to loss of kidney function
- idiopathic probably related to minimal change disease
- genetic abnormalities of proteins like nephrin and podocin leading to issues with slit diaphragm
What will you see microscopically in FSGS?
. collapse of the GBM
increased mesangial matrix
hyalinization
with or wihtout foam cells
What will you see on IF in FSGS? EM?
IF with mesangial deposits of IgM and C3 in sclerotic area
EM with diffuse effacement of foot processes and focal detachment of epithelial cells from GBM
WHat is the clinical presentation and course of FSGS?
Steroids work?
How many will have ESRD in 10 years?
Does transplant work?
What association has the worst prognosis?
nephrotic syndrome
HTN and reduced GFR
poor response to corticosteroids
at least 50% will have ESRD in 10 years!
It often recurs post transplant
HIV nephropathy has worst prognosis
What are the two things that characterize membranoproliferative GN?
Just read the name!
- proliferation of glomerular cells and leukocyte infiltration
2 damage to the basement membrane
What is the main association with membranoproliferative?
chronic immun complex disease: SLE, HBV, HCV, endocarditis, infected ventriculoatrial shunts
but also partial lipodystrophy, alpha-1 antitrypsin deficiency and malignancies like CLL, lymphoma and melanoma
Describe the type 1 of membranoproliferative
- type 1 more common - granular deposition of C3, IgG, c1q, and C4 as subendothelial deposits
(immune complex disease with activation of both classic and alternative complement pathway
Describe type II membranoproliferative? What’s the other name?
dense deposit disease -
granular C3 deposit only!! (not IgG, C1q or C4 as in type I)
lamina densa of the GBM is ribbon-like and extremely electrno dense due to deposits of unknown material
excess activation of the alternativecompletment pathway (but not the classic!)
What do the glomeruli look likein both Type 1 and type 2 membranoproliferative? What will silver stain do for both?
like flowers - super hypercellular
silver stain will show “tramtrack” or “doubl coutner” of the GBM due to mesangial icell interposition into the GBM
What percentage will develop chornic renal fialure within 10 years with membranoproliferative?
steroids helpful? transplant?
50%
steroids not helpful
recurs after transplant
What is another name for IgA nephropathy? What’s the systemic disease with overlapping features?
Berger Disease
Henoch-Schonlein purpura
What is the main symptom of Berger disease?
recurrent hematuria - with or without proteinuria
relatively mild
What is IgA nephropathy associated with?
gluten enteropathy (celiac sprue) liver disease (due to ineffective clearance of IgA complexes)
What is the pathogenesis of IgA nephropathy?
IgA is the secretory Ig. For some reason in these people the plasma polymeric IgA is increased (unusual)
the increase leads to abberant glycosylation
the glycosylation leads to IgA immune complex formation - these complexes are deposited in the mesangium
What will you see microscopically in IgA nephropathy?If? EM?
micro: variable appearance, but likely mesangial widening and proliferation
IF: mesangial deposition of IgA
EM: paramesangial and mesangial deposits
Describe the clinical course of IgA nephropathy?
present with hematuria folllowing a respiratoyr, GI or urinary infection
hematuria lasta a few days, stops and recurs
variable course after presentation with 15-40% progressing to chronic renal failure over a long course - like 20 years
What are the two major kidns of hereditary nephritides?
Alport syndrome
Thin membrane disease
Describe what happens in Alport syndrome?
nephritis nerve deafness (may be mild) eye disorders (lens dislocation, cataracts, corenal dystrophy)
Which gender is more ofen affected by alport syndrome and why?
men - the most common form is x-liked dominant
but there are also autosomal recessive and autosomal dominant reported
What is the pathology of alport syndrome in the kidney?
micro: glomeruli with segmental proliferation or sclerosis, persistence of fetal-like glomeruli, foam cells
EM: irregular THICK and thin GBM with splitting of the lamina densa
What is the pathogenesis of alport syndrome?
AKA…what’s the mutation
defective GBM synthesis due to a mutation in the gene encoding the alpha 5 chain of type IV collagen! COL4A5
Describe the clinical course of alport syndrome?
presents with hematuria in childhood or teens
iwth or without proteinuria
renal failture by age 20-50
What is the cause of thin membrane disease?
abnormal genes encoding collagen chains
What do you see on EM in thin membrane disease?
diffuse thinning of the GBM
What does thin membrane disease present with? Course?
hematuria - almost always stays mile with an excellent prognosis
(except for hemoxygous patients - they can proress to renal failure)
Chonric GN is the end result of specific types of GN. What will you see on the gross anatomy?
small, diffusely granular kidneys
What will you see microcopically in chronic GN?
globally hyalinized glomeruli with atrophy and fibrosis of the tubules and interstitium
What GN are more likely to progress to chronic GN?
In decreasing order….
rapidly progressive (duh) focal glomerulosclerosis membranous membranoproliferative IgA poststreptococcal
Nearly all lupus patients will show kidney involvement on IF how? EM?
IF with “full house” - stains with everything
EM with “wire loop” lesions - thickening of capillary wall by subendothelial deposits
What age group gets henoch schonlein purpora more often? Which age group has renal abnormalitis with the HSP more often?
children ges 3-8 get it more often, but adults are more likely to have associated renal abnormlalities
What percentages of diabetics will eventually has ESRD?
up tto 40%
What are the general microscopid findings of diabetic nephropathy?
- capillary basement membrane thickening (hyalinization)
- Diffuse mesangial sclerosis
- Nodular glomerulosclerosis
What happens to the GFR early in diabetes and why? What does this result in over time?
Because of the hyalinization of the blood vessel, hydrostatic in the glomerular capillaries increases so you actually get increased GFR early on
unfortunately this leads to glomerular hypertrophy and ultimately glomerulosclerosis
What is a nother term for the nodular glomerulosclerosis you see with diabetic nephropathy?
Kimmelstiel-Wilson disease - you get hyaline masses at the periphery of the glomerulus
(associated with renal failure)
