Renal Pathology (Warren) - W3 Flashcards
What are the three parts of the glomerular basement membrane?
What makes up the backbone of the GBM?
What gives the GBM its negative charge?
- 3 parts
- lamina rara interna
- lamina dense
- lamina rara externa - by podocytes
- Type IV collagen
- heparin sulfate gives negative charge
What proteins make up the slit diaphragm?
What do you see in the podocytes with nephrotic syndrome?
- nephrin and podocin
- podocyte fusion (flattened and merged) is characteristic of nephrotic syndrome
What part of the kidney tubule system is most sensitive to ischemia & toxins?
- Proximal tubules
How many people does chronic renal disease affect?
11% in US
What is the definition of azotemia?
- biochemical abnormality
- increased BUN and creatinine
- can be…
- pre-renal: hypoperfusion (hemorrhage, shock, dehydration, CHF)
- renal disease
- post-renal
What is the definition of uremia?
- azotemia and clinical symptoms
- gastroenteritis, anemia, peripheral neuropathy, pruritis (horrible itching), pericarditis
Symptoms of nephritic syndrome
- Hematuria - red cells in urine
- mild to moderate proteinuria
- hypertension
What are the clinical symptoms of nephrotic syndrome?
- >3.5gm/day proteinuria
- hypoalbuminemia
- edema
- hyperlipidemia
- lipiduria
What do you see with acute renal failure?
- rapid decline in GFR - rapid onset azotemia
- increased BUN/Cr
- oliguria or anuria
- caused by glomerular, tubulointerstitial or vascular disease
What do you see with chronic renal failure?
- GFR less than 60 ml/min for at least 3 months
- persistent albuminuria
- end result of all renal disease
What are the four stages of renal disease?
- Diminished renal reserve
- GFR 50% of normal
- see in elderly
- normal range BUN/Cr
- Renal insufficiency
- GFR = 20-50% of normal, azotemia, anemia, hypertension
- Renal failure
- GFR 20-25%, edema, metabolic acidosis, uremia
- End stage renal disease
- GFR <5% of normal
- need dialysis or transplant
What is clearance test and equation?
- clearance = approximation of glomerular filtration rate (GFR)
-
clearance = UV/P
- urine concentration x urine volume
What are the issues w/creatinine as measurement?
How does it compare to the true GFR?
- overestimation of true GFR
- secreted by proximal tubule
- related to muscle mass and meat in diet
- may have extrarenal elimation
What is the risk if a GFR is below 60?
When should you see a nephrologist?
- below 60 = high risk for CV disease
- below 30 = see nephrologist
In what situations do we use some clearance measures?
- Unusual body habitus
- severe muscle wasting
- Rapidly changing kidney function
- Patients with GFR of 60 or greater
- kidney donor eval
- research protocols
What is the BUN?
What is normal?
- major end product of protein nitrogen metabolism - liver will make urea from ammonia
- normal = 10-20 mg/dl
- can combine w/serum creatinine to determine cause of azotemia
What can cause a pre-renal increase in BUN?
- Catabolism (burns, fever, stress)
- high protein diet
- GI bleed
- Hemolysis
- Malignancy
-
decreased renal perfusion
- hypotension/shock
- CHF
- dehydration
- renal vein thrombosis
What is BUN sensitive to?
- decreased renal perfusion
- low flow activates renin-angiotensin system that increases water and Na reabsorption
- urea is passivley reabsorbed along with it
- serum BUN increases out of proportion to any change in the GFR
What are 3 diseases cause a renal increase in BUN?
- Glomerular disease
- ATN
- interstitial disease
What factors cause a post-renal increase in BUN?
-
Urinary Tract Obstruction
- benign prostatic hypertrophy
- prostatic carcinoma
- tumor of bladder or ureter
- retroperitoneal mass
- urinary calculi
- basically anything that affects OUTFLOW
What can cause a decrease in BUN?
- decreased synthesis - low protein intake, liver disease
- hemodilution - overhydration, psychogenic polydipsia, diabetes insipidus, pregnancy
- generally not diagnostically useful
How is creatinine formed and what is the normal excretion?
- waste product formed by the spontaneous dehydration of body creatinine
- Normal = 0.7-1.2mg/dL
- BETTER THAN BUN
What can cause a pre-renal increase in creatinine
-
Increased synthesis
- muscle hypertrophy
- muscle necrosis
- anabolic steroid use
- high meat diet
- intense exercise
-
Decreased reanl perfusion
- CHF, hypotension/shock
What can cause a post-renal increase in creatinine
- urinary tract obstruction
What is a normal BUN: Creatinine ratio?
When is the ratio ELEVATED?
- NORMAL IS 15:1
- elevated in pre-renal conditions
- BUN is excessively elevated compared to creatinine
What is fraction of excreted sodium used for?
FeNa calcuation?
What do the % mean?
- differential diagnosis of pre-renal vs. renal disease
- FeNa = urineNa xplasmaCr x 100 / urineCrx plasmaNa
- FeNa < 1.0% = pre-renal
-
FeNa > 2.0% = ATN
- tubules fail so urine sodium is high (>40mEq/L)
What is the urine dipstick used for?
What is it sensitive to?
When can it give a false +?
- sensitive to albumin
- used to detect protein in urine
-
False +
- alkaline urine
- gross hematuria
- dilute urine
What is the quantitative protein to creatinine ratio used for?
- estimates if there is significant increase in 24 hour urine protein excretion
- used after + dipstick
What can cause proteinuria without renal disease?
- postural orthostatic (young adults)
- transient
- functional
- heavy exercise, cold exposure, fever
- won’t be a lot - <0.5gm/24hours
- hyaline/granular casts
- CHF - <0.5gm/24hours
- massive obesity
- constrictive pericarditis
- renal vein thrombosis
what is seen with selective proteinuria?
What is seen with nonselective proteinuria?
- albumin and small globulins = nonselective
- post infectious GN
- albumin = selective
- nephrotic syndrome and minimal change disease
- show glomerular pattern
What is seen with renal disease and shows a tubular pattern
beta-2 microglobulin
What is hypoplasia?
What do you see with it?
- failure of development of kidneys to normal size
- no scarring - see decreased number of renal lobes
- 6 or less required for true hypoplasia
- most cases are acquired
What is the most common congential kidney disorder?
Horseshoe kidney
10% upper pole fusion
90% lower pole fusion
What is the kidney trapped behind with horseshoe kidney?
behind the root of the inferior mesenteric artery in the pelvis
What is seen with cystic renal dysplasia?
How do people get it?
- enlarged, mulitcystic gross features
- MICRO: tissue that doesn’t bleong
- cartilage & undifferentiated mesenchyme
- may have other lower tract anomlaies
- sporadic disorder - not inherited
How is adult polycystic kidney disease inherited?
Is it unilateral or bilateral?
when do we see renal failure?
- autosomal dominant
- bilateral - initially only involes part of kidney
- by age 75, 75% have renal failure
What causes adult PCKD?
What are the defects seen with each type?
- multiple expanding cysts destroy renal parenchyma
-
PKD1 - gene on chromo 16p13.3
- POLYCYSTIN 1
-
PKD2 - gene on 4q21
- polycystin 2
- less caes and less severe
What are the gross features of PCKD?
What are the symptoms?
- bilaterally enlarged kidneys (HUGE) - look like bag of cysts
- may be asymptomatic, have pain, or hematuria
What are extra-renal anomalies seen in PKCD?
- Liver cysts
- Intracranial berry aneurysms
- Mitral valve prolapse
How is childhood polycystic kidney disease inherited?
what is seen on gross features?
bilateral or unilateral?
what else can you see?
- autosomal RECESSIVE
- 4 categories
- enlarged, smooth kidneys externally
- cut section shows small cysts in cortex and medulla
- BILATERAL
- liver cyts and duct proliferation
What is potter sequence?
why does it occur?
Features?
- abnormalities in fetal kidneys
- occurs with low amniotic fluid leading to olighydramnios
- findings
- low set ears
- parrot beak nose/flat mid fase
- lung hypoplasia
4 cystic diseases of the medullla
- Medullary sponge kidney
- normal kidney function w/ cysts
- Nephronophthisis
- polyuria or polydipsia
- Acquired cystic disease
- long term dialysis
- simple cysts
- not vascular
What do you see with medullary sponge kidney?
- cystic dilutions of collectin gducts
- disease of ADULTS
- hematuria, infection or stones
- NORMAL KIDNEY FUNCTION
Nephronophthisis - Uremic Medullary Cystic Disease Complex
Presenation?
Onset?
- presents in childhood
- progressive
- see cortical tubular atrophy and interstitial fibrosis - will eventually have small kidneys
- polyuria and polydipsia
What is the major cause of aquired cystic disease?
long term dialysis - up to 50%
What are the features of a simple cyst?
- `1-5 cm
- clear fluid inside
- not vascular
what is normally the main cause of glomerulonephritis?
immune mediated disease
what 3 histological patterns of injury are common with glomerulonephritis?
- hypercellularity
- basement membrane thickening
- hyalinization and sclerosis
Define:
Diffuse
Focal
Global
Segmental
- diffuse = all glomeruli involved
- focal = proportion of all glomeruli invovled
- global = entire single glomeruli invovled
- segmental = part of single glomeruli invovled
Immune mechanisms of injury for glomerulus
- Antibody mediated
- insitu immune complex deposition
- circulating immune complex deposition
- cell mediated immune injury
- activation of alternative complement path
What are 3 in situ immune complex depositions?
- Anti-GBM glomerulonephritis
- heymann nephritis
- planted antigens
What is Anti-GBM glomerulonephritis?
- in situ immune complex depositition - antibodies directed against normal GBM components
- homogenous, diffuse, linear pattern
- can cause hemoptysis in lungs - goodpasture syndrome
- antigen component of alpha 3 chain of type IV collagen
- <5% of human GN
Heymann Nephritis
type
antigen
see on EM
- in situ complex deposition
- M type phospholipase A2 receptor (PLA2R)
- granular and interrupted pattern
- deposits on subepithelial aspect of GBM
What are planted antigens?
- non glomerular in origin
- localize to kidneys
- antibodies form against them
- can be DNA, bacterial products, aggregated immunoglobulins
What is this?
Anti - GBM
diffuse.
What occurs with circulating immune complex nephritis?
- glomerular injury caused by trapping circulating complexes within glomerulis - not sepcific for glomerulus
- type III hypersensitivity
- antigens endogenous or exogenous
- can have may types of deposits
At what GFR will you progress to end stage renal disease no matter the enciting event w/glomerulonephritis?
30-50%
What is an adaptive change that occurs with glomerulonephritis?
What is the issue?
how do we treat?
FSGS
- occurs w/loss of functioning nephron
- known as compensatory hypertrophy
- see increased flow, filtration and pressure
- leads to segmental scerlosis - cell injury, protein accumulation
- treat with ACE
What develops with glomerulonephritis over tiem?
What happens to downstream tubules?
- Tubulointersitital fibrosis
- occurs due to proteinuria that is directly toxic to downstream tubular cells - see ischemic tubules downstream from sclerotic glomeruli
- increased acute & chronic inflammation
What do you see with nephritic syndrome?
- Hematuria and red cell casts
- variable proteinuria
- azotemia
- hypertension - signficant
What do you see with nephrotic syndrome?
- proteinuria > 3.5g
- hypoalbuminemia
- edema
- hyperlipidemia
- oval fat bodies
- fusion of podocytes
What can cause acute poststreptococcal glomerulonephritis?
What are some tests for it?
- caused by group A streptococci - 12, 4 and 1
- nephritic syndrome
- serum complement - low
- antistreptolysin O and antiDNAse B
What is seen on IF and EM w/poststreptococcal GN?
Histology?
- large, hypercellular gloomeruli
- infiltration of neutrophils and monocytes
- IF
- granular IgG, IgM, C3 deposits along GBM and mesangium
- EM
- subepithelial humps “camel”
Prognosis and clinical presentation of acute post-streptococcal GN
- nephritic presentation
- malaise, oliguria, hematuria “smoky urine”
- red cell casts
- periorbital edema
- 95% of children recover
- 60% of adults recover
Syndrome that causes SEVERE injury to the glomerulus
Rapidly progressive (Crescentic) GN
What makes up a crescent w/rapidly progressive GN
proliferations of parietal epithelial cells of Bowman’s capusle mixed w/inflammatory cells
What are the 3 types of crescentic gN
- Type 1: anti-GBM glomerulonephritis
- IgG, C3 in GM
- type 2: immune complex mediated
- lumpy bumpy granular pattern
- SLE, IgA nephropathy
- Type 3: Pauci-immune type
- lack of IF staining
- P or c anca
What is the clinical course of crescentric GN?
What is the treatment?
- progressive over weeks w/severe oliguria
- treated w/plasma exchange, steroids and chemo
Describe the pathophysioloy of nephrotic syndrome
- increased permeability to plasma proteins - massive proteinuria - low albumin - reduces colloid osmotic pressure leading to edema
- increased synthesis of lipoproteins
- infections due to Ig and complement loss
- hypercoaguable state due to ATIII loss
Who is membranous GN common in?
What are the assciations?
- adults - caucasian population
- assocations
- drugs; peenicillamine, captopril, gold, NSAIDs
- lung, colon cancer, melanoma
- SLE
- HBV, HCV, syphillis, shcistosomiasis malaria
- DM, thyroiditis
What is the pathogenesis of membranous GN?
- chronic antigen-antibody medaited disease - phospholipase A2 is autoantigen in many adult cases
- damage to GBM is complement mediated
What is seen on pathology of membranous GN?
Silver stain?
EM?
IF?
- DIFFUSE process
- thickening of capillary wall - looks like cheeros
- silver stain - spikes - GBM laid down between deposits
- Subepithelial deposits - may also see effacement of podocytes
- IF: lumpy, bumpy pattern
What is the clinical course of membranous GN?
- chronic proteinuria and slow deteriation
- 40% develop renal insufficiency
- 10% die
- HIGHLY VARIABLE
What is the most common nephrotic disease in children
What are the associations?
- minimal change disease (lipoid nephrosis)
- associations
- atopy
- respiratory infection, immunization
- Hodgkin lymphoma
What is the pathogenesis of minimal change disease?
- possible T cell dysfunction and release of cytokines that damages visceral epithelial cells - may lose charge barrier
- slit diaphragm loses architecture
what is seen clinically with minimal change disease?
What is the treatment?
- massive proteinuria
- highly selective - mostly albumin
- no renal failure or hypertension
- corticosteroids - reverse the damage.
What is the pathology of minimal change disease?
M:
IF:
EM
- normal under light micrscope
- IF shows no staining
- EM - effacement of foot processes - no deposits
What population is focal segmenal glomerulosclerosis (FSGS) common in?
Associations?
- most common cause of nephrotic syndrome in adults
- Associations
- HIV
- heroin addiction
- sickle cell disease
- OBESITY - making it more common
What is seen with pathology of FSGS?
- M: see focal necrosis - need a good biospy
- may see collapse of GBM, hyalinization, increased matrix
- EM: effacement of foot processes
- IF: not helpful
look for damage to visceral epithelial cells
What is shown in the image?
Membranous gN
what is shown in the picture
Focal segmental glomerulosclerosis (FSGS)
What is the clinical course of FSGS?
- nephrotic syndrome w/hypertension
- poor response ot steroids
- 50% have ESRD in 10 years
What is associated w/FSGS and has a worse prognosis?
HIV Nephropathy
- most common renal complication is FSGS
- common in african americans
- see tubuloreticular inclusions in ENDOTHELIAL CELLS
What can be a mixed nephrotic and nephritic syndrome and is common in YOUNG ADULTS or children
membranoproliferative GN
What is shown in the picture?
membranoproliferative GN
What is seen on pathology of membranoproliferative GN?
Associations?
- see proliferation of glomerular cells, leukocyte infiltration and changes in the GBM
- Assoc.
- SLE
- Hep B
- Hep C
- endocarditis
- infected ventricle shunts
- partial lipodystrophy
- alpha 1 antitrypsin def.
- malignancy (CLL, lymphoma, melanoma)
What is seen under the microscope for membranoproliferative GN
- thickened GBM
- silver stain: shows tram-track or dobule contour due to mesangial cell interposition into the GBM
What is seen with type I membranoproliferative GN
- 2/3 of cases
- granular C3, IgG, C1q, C4
- subendothelial deposits
- immune complex disease + complement activation
What is seen with type II membranoproliferative GN
- granular C3 only
- dense deposit disease
- lamina dense of GBM is ribbon-like and extremely dense due to deposits of unknown material
- excess activation of alternative complement
- may have C3 nephritic autoantibody
What is the course of membranoproliferative GN
- 50% have renal failure in 10 years
- steroids NOT helpful
- very common post transplant
- esp. type II
What is the most common nephropathy worldwide and causes recurrent hematuria with or without proteinuria
Berger Disease (IgA nephropathY)
What is Berger Disease (IgA nephropathY) associated with?
- Henoch-Schnolein purpura
- Celiac sprue patients
- liver disease
How does Berger Disease (IgA nephropathY) occur?
What is seen on IF?
- plasma polymeric IgA is increased - may be glycosylated.
- IF: shows mesangial deposition of IgA
- microscope: mesangial widening
- EM: mesangial deposits
What presents with hematuria following respiratory, GI or urinary tract infection?
IgA Nephropathy
