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What are the components of the glomerular filtration barrier, and what selectivity does each confer?
- Endothelium: charge selectivity (negaitve)
- Basement Membrane: size (60kD spaces) and charge selectivity (negative)
- Visceral Epithelium/Podocytes: size and charge selectivity (negative)
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Podocytes synthesize the ________ and have _________ capability.
basement membrane; phagocytic
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3 functions of the mesangium.
structural support, contractile, phagocytic
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The ___________ is an early site of deposition of immune complexes and amyloid fibrils.
mesangium
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Protein losing nephropathy= ____________; two types of PLN are __(2)__.
glomerular disease; glomerulonephritis (GN) and amyloidosis
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What are the most common ways the glomerulus is injured, leading to glomerular disease? (3)
increase glomerular capillary BP (hypertension), immune complex deposition on the endothelium and BM, amyloid deposition
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Glomerular disease eventually leads to... (3)
inflammation, proliferation of extracellular matrix, and fibrosis.
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___________ is the most common cause of glomerular disease; it results from...
Immune complex deposition; nearly equal numbers of antigen and antibody complexes in the circulation.
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Immune complex GN is caused by...
deposition of immunoglobulin or complement in the glomerular capillary wall.
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Factors affecting the localization of deposition of immune complexes include... (4)
size of complexes, charge of complexes, removal of complexes by phagocytosis, and damage to the BM.
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Small immune complexes that are deposited under the foot processes.
Subepithelial complexes
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Large or highly-negatively charged complexes that are under the endothelium (too large to pass the BM).
Subendothelial complexes
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The location of immune complex deposition determines the __(2)__.
histologic changes and severity of glomerular dysfunction
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Subepithelial complexes are associated with __(2)__ histologic changes and ________ proteinuria.
BM thickening, minimal inflammatory cell infiltration; severe
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Subendothelial complexes are associated with __(2)__ histologic changes and _________ proteinuria.
BM thickening, recruitment of inflammatory cells; moderate
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Intramembranous complex deposition is associated with _____________.
anti-glomerular basement membrane disease
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Mesangial complexes are __________.
asymptomatic
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Immune complex deposition in the glomerulus reduces the amount of __________, thus enhancing filtration of ____________, such as _________.
fixed negative charge; negatively-charged circulating macromolecules; albumin
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Complement activation in the glomerulus results in ___(3)___.
membrane damage, proteinuria, and recruitment of inflammatory cells
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Platelet activation occurring secondary to endothelial damage causes __(3)__.
proliferation of mesangium and endothelium, vasospasm, and increased coagulation
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How do mesangial cells contribute to glomerular inflammation?
increased matrix production--> fibrosis and scarring
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3 consequences of immune complex deposition on glomerulus.
reduce negative charge, activate complement, activate platelets
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Neutrophils and macrophages localize in the glomeruli and cause damage by...
releasing mediators that damage and scare the glomerulus.
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Lesion associated with membranous GN.
BM thickening
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Pathogenesis of membranous GN.
subepithelial complexes, minimal inflammation
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Clinical course of membranous GN. (3)
slowly progressive, marked proteinuria, eventual nephrotic syndrome
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Lesion associated with proliferative GN.
hypercellularity
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Pathogenesis of proliferative GN.
mesangial complexes with increase mesangial cells
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Clinical course of proliferative GN.
no clinical disease
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Lesion associated with membranoproliferative GN. (2)
BM thickening and hypercellularity
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Pathogenesis of membranoproliferative GN.
subendothelial complexes with increased inflammatory cell influx
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Clinical course of membranoproliferative GN. (2)
moerate proteinuria, progression to renal failure
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In most cases, GN is classified as ________ because...
idiopathic; antigen source or underlying disease is not identified.
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The primary target for immune-mediated glomerular disease is the ___________; the primary target for non-immune mediated appears to be the ___________.
filtration barrier; endothelial cell
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Damaged endothelial cells release factors that have __(3)__ effects, stimulating __________.
vasoactive, proliferative, and pro-inflammatory; coagulation
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Factors that damage endothelial cells... (3)
hemodynamic factors (hypertension), coagulation followed by platelet release, hyperlipemia
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Glomerular disease may induce __________ and progress to ____________.
tubulointerstitial disease; end-stage kidney disease
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Obstruction of glomerular capillaries may result in ________ of the tubules and ___________.
ischemia; tubulointerstitial disease
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Proteinuria leads to _____________ and _________ disease.
interstitial immune response; tubulointerstitial disease
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Inflammatory mediators from damaged glomeruli may lead to ___(2)___ damage.
tubular and interstitial
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GN may resolve by... (3)
solubilization of complexes by complement, phagocytosis of complexes by macs, degradation of complexes by proteases
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Removal of ___________ may result in resolution of GN.
causative agent
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When a large amount of protein is consumed, ___________ occurs; the _______ increases, which worsens permselectivity; this also leads to __(2)__.
hyperfiltration; SNGFR; inflammation and injury to tubules and BM
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GN is classified morphologically according to the presence of... (3)
BM thickening, hypercellularity, or both.
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Disease characterized primarily by fibrosis of the glomeruli.
glomerulosclerosis
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Chronic changes associated with glomerular disease eventually lead to _________; _________ glomeruli are not functional.
sclerosis; sclerotic
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The presence of _________ on US is suggestive of glomerular disease.
tubular protein casts
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Chronic GN is accompanied by...
tubular dilatation and atrophy, interstitial lymphplasmacytic inflammation, and interstitial fibrosis.
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Gross changes of glomerular disease are ________.
rare
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Group of diseases characterized by extracellular deposition of fibrils formed by polymerization of protein subunits with a beta-pleated sheet.
amyloidosis
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Amyloid deposits are detrimental due to their __(2)__.
insolubility and resistance to proteolysis
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What is the clinical diagnosis of amyloidosis based upon?
green birefringence after Congo red staining when viewed under polarized light
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Renal amyloidosis in dogs and cats is... (3)
systemic, reactive, and involves AA amyloid.
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Familial amyloid syndromes in __(6)__ are examples of reactive, systemic amyloidosis.
Abyssinian, Siamese, and Oriental shorthaired cats and Shar Pei, Beagle, and English Foxhound dogs
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Amyloid A protein is an animal terminal fragment of ___________.
serum amyloid A (acute phase reactant)
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__(2)__ are necessary pre-requisites for development of reactive amyloidosis.
Chronic inflammation and a prolonged increase in SAA conc
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In the dog, AA amyloid deposits are most common in the __________ and clinical signs are due to __(2)__.
kidney; renal failure and uremia
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Signalment for animals with glomerular disease.
middle aged to older; no sex predilection in dogs, 75% male in cats
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__________ with a ________ and __________ is a hallmark of glomerular disease.
Proteinuria; urine protein:cre >0.5; inactive sediment
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What are the 6 ways glomerular disease can present?
proteinuria as an incidental finding during wellness exam, underlying infectious/inflammatory/neoplastic disease, chronic renal failure (anorexia,weight loss, lethargy, PU/PD, vomiting), classical nephrotic syndrome (ascites, edema), thromboembolism (dyspnea, paraparesis), sudden blindness from retinal detachment due to hypertension
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What is Shar Pei fever?
episodic joint swelling (tibotarsal) and high fever that resolves within a few days
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What physical findings are associated with severe protein loss? (4)
ascites, edema, poor body condition, poor haircoat
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What physical findings are associated with systemic hypertension? (3)
retinal hemorrhages, vascular tortuosity, and retinal detachment
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Damage to the glomerulus leads to ____(2)____ loss.
albumin (NOT globulin, as with PLE) and antithrombin III
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You must interpret proteinuria in light of ___________.
urine specific gravity
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Isosthenuria occurs with _________ of the nephron population is non-functional; early loss of conc ability may occur in animals with ______________.
>66%; medullary amyloid deposition (Abyssinians, etc)
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Biochem abnormalities with glomerular disease. (3)
hypoalbuminemia, hypercholesterolemia, azotemia (end-stage)
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Why does hypercholesterolemia occur in patients with glomerular disease?
increased hepatic synthesis secondary to chronic hypoalbuminemia
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___________ can lead to chronic renal failure with the expected biochem abnormalities.
Either GN or amyloidosis
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A _________ is essential in order to diagnose glomerular disease.
urine protein:cre
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The presence of __(2)__ makes the urine protein:cre unreliable.
hematuria or pyuria
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What is the only way to differentiate amyloidosis from GN from primary interstitial disease?
renal biopsy
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___________ and ___________ will lead to effusion into body cavities and/or peripheral edema.
Decreased oncotic pressure in the vessels; increased hydrostatic pressure
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Measurement of _________ activity may help identify animals at risk for thromboembolism.
antithrombin III
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The effusion seen with patients with GN/PLN is a ___________ with ______ cell count and _______ total protein conc.
pure transudate; low; low
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Complications that can occur with glomerular disease. (6)
hypoalbuminemia, hypertension, sodium retention, thromboembolism, muscle wasting, hyperlipidemia
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4 major reasons for hypoalbuminemia.
impaired liver synthesis, GI loss, renal loss, large volume blood loss
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Hepatic albumin synthesis is ________ with nephrotic syndrome, but...
increase; it's insufficient to compensate for hypoalbuminemia.
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What is the primary stimulus for increased hepatic synthesis of albumin in nephrotic syndrome?
low plasma oncotic pressure
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_____________ is increased in nephrotic syndrome due to increased resorption of filtered protein.
Renal catabolism of albumin
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The ___________ pool of albumin is more depleted than the ___________ pool with nephrotic syndrome.
extravascular; intravascular
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An increase in dietary protein dietary protein stimulates __________ and increases __________.
hepatic albumin synthesis; urinary loss of protein
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Hypoalbuminemia is treated with ___________ to reduce intraglomerular pressure.
ACE inhibitors
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Systemic hypertension occurs due to... (3)
sodium retention, activation of the RAAS system, and impaired release of normal renal vasodilator substances.
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Systemic hypertension has been associated with __(3)__.
GN, glomerulosclerosis, and amyloidosis
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___________ measurements should be obtained in all dogs and cats with suspected glomerular disease because control can slow its progression.
Blood pressure
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What is the mainstay of hypertensive treatment b/c is it an arteriovasodilator.
Ca2+ channel blocker Amlodipine
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The underfill hypothesis is premised on the fact that hypoalbuminemia leads to decreased ___________; decreased circulating volume leads to __________; both of these cause ___________.
oncotic pressure; activation of RAAS; sodium and water retention
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The overfill hypothesis states that the primary intrarenal sodium retention in nephrotic syndrome occurs in the ________ and contributes to ___________.
distal tubule; extracellular fluid volume/edema
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In patients with adequate serum albumin conc and intravascular oncotic pressure, intrarenal sodium retention leads to...
expansion of circulating volume and suppression of RAAS.
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In patients with severe hypoalbuminemia and low circulating volume, intrarenal sodium retention leads to...
activation of RAAS.
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_________ is the most common site for thromboembolism.
Pulmonary artery
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Dogs with pulmonary thromboembolism are __(2)__.
dyspneic and hypoxic
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Hypoalbuminemia causes ________ and ________, which result in increased platelet adhesion and aggregation (and can contribute to thromboembolism).
mild thrombocytosis; platelet hypersensitivity
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Loss of _________ in the urine contributes to hypercoagulability, contributing to thromboembolism risk.
Antithrombin III
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Increased ________ conc and decreased _________ contribute to hypercoagulability; animals with _________ conc greater than _______ and __________ conc less than ________ of normal are considered at risk for thromboembolism and should be treated as such.
fibrinogen; fibrinolysis; fibrinogen; 300 mg/dL; Antithrombin III; 70%
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____________ lead to cachexia, which involves __(3)__.
Inflammatory mediators; reduced food intake, muscle wasting, and suppressed muscle regeneration
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In nephrotic patients, plasma albumin concs are inversely correlated with plasma ____________ conc; and ___________ tends to increase as albumin decreases.
cholesterol/TG; cholesterol/lipid
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How can you slow the progression of glomerular damage?
add Omega-3 fatty acids to suppress glomerular inflammation and coagulation by interfering with production of pro-inflammatory prostanoids
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Goals of treatment of glomerular disease. (6)
slow progression, reduce proteinuria, manage hypertension, ID/treat underlying conditions, consider immunosuppression, prevent thromboembolism
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How do you reduce proteinuria? (3)
ACE inhibitors (Enalapril or benasepril), Ang receptor blockers (Telmisartan)
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ACE inhibitors decrease protein by partially blocking _______ and _________ the ________ arteriole, thus reducing __________.
RAAS; dilating; efferent; intraglomerular pressure
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How do you manage hypertension? (2)
Ca2+ channel blockers (Amlodipine), ACE inhibitors
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Ca2+ channel blockers reduce hypertension by _____________.
vasodilation of arterioles
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ACE inhibitors aid in management of hypertension by...
decreasing sodium and water retention.
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When managing hypertension and proteinuria, monitor for __(2)__.
reduction in GFR and increase in K+
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If the decision is made not to biopsy, immunosuppressive therapy can be started if... (3)
standard therapy is already being given AND Cre>3mg/dL, azotemia is rapidly progressive, or hypoalbuminemia is severe
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If the decision is made to start immunosuppressive therapy, give ________ at the __________ dose; ___________ is an immunosuppressive drug used in dogs.
glucocorticoids; immunosuppressive; Mycophenalate
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How do you prevent thromboembolism in animals that are determined to be at risk?
low-dose aspirin (prevents platelet aggregation)
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Drug that blockades ADP-mediated platelet activation.
Clopidogrel (Plavix)
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Treatment of amyloidosis.
no treatment has shown to be beneficial
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Amyloidosis prognosis.
progressive disease with poor prognosis; less than 1 year
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Prognosis of GN.
variable course; can end with: spontaneous remission, stable course with ongoing proteinuria for months to years, or progression to chronic renal failure over months to years
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