Clinical Manifestations of the Nephrotic Syndrome Flashcards
clinical course of minimal change nephrotic syndrome
initiated by respiratory infection
albuminuria
anasarca (massive swelling)
remitting and relapsing course
pallor
counter-irritant induces relapse
spontaneous remission
How does decreased albumin in the blood lead to edema?
decreased albumin leads to decreased oncotic pressures driving fluid back into the blood
fluid accumulates in the interstitial space
decreased venous return to the heart and decreased perfusion pressure leads to RAAS activation and encourages more edema formation
What is the pathogenesis of edema formation in nephrotic syndrome?
albuminuria
hypoalbuminemia
decreased vascular oncotic pressure
capillary fluid loss
edema
vascular volume contraction
decreased glomerular perfusion
renin secretion - thirst - water intake - more edema
aldosterone production
increased sodium reabsorption - even more edema
What are the reasons to question a direct role of albumin in nephrotic edema?
humans with congenital analbuminemia doe not develop nephrosis-like edema
many patients with minimal change disease who respond to corticosteroid treatment begin to diurese before their plasma albumin normalizes
underfill vs. overflow in nephrotic edema
in some cases of nephrotic syndrome, primary sodium retention causes increased plasma volume and circulatory overload
in these cases, renin and aldosterone are decreased (as opposed to underfilling where renin is increased)
this represent the “overfilling or “overflow” theory of sodium retention
in this model, renal tubular sodium retention may be the primary ause
How do lipid levels change with nephrotic syndrome?
increased hepatic synthesis of lipoprotein and impaired catabolism of circulating lipids
VLDL and LDL are disproportionately decreased
increase slowly with relapse and decrease slowly with remission
chages are unresponsive to diet but can be adjusted with lipid-lowering agents
prolonged elevation is atherogenic and may contribute to progressive renal scarring
causes of lipid abnormalities in nephrotic syndrome
increased hepatic lipoprotein synthesis (oncotic/viscosity signal)
defective lipid transport (HDL lost in urine)
decreased LPL and LCAT activity - may reflect urinary albumin loss
How does albumin contribute to hypercholesterolemia?
lecithin + cholesterol <-> lysolecithin + cholesterol ester
mediated by the enzyme LCAT
albumin as a transport protein binds to the products of this reaction and removes them from the equilibrium
thus, hypoalbuminemia may indirectly inhibit the progression of this reaction
cause sof hemostasis in neprotic patients
hemoconcentration from fluid extravation
increased production of certain clotting factors
urinary loss of anticoagulant proteins such as antithrombin III as well as free protein S
hemoconcentration and loss of natural anticoagulants in the urine lead to radicles of renal vein as a likely site for coagulation to cause renal vein thrombosis
when the ambient albumin concentration is decreased, platelets become hyperaggregable
fibrinolysis is altered
glycoprotein charge on platelet and vessel wall
evnironmental factors such as dehydrations or steroid use
What are the possible abnormalities that can arise in the face of nephrotic syndrome?
hemostasis
susceptibility to infection
bone disease
thyroid dysfunction
anemia
effects of low albumin
How is bone metabolism affected in nephrotic syndrome?
vitamine D-binding protein and vitamin D metabolites are lost in the urine (due to megalin overload)
associated with decreased intestinal Ca2+ absorption and increased PTH
exacerbated by steroids
some patients benefit from calcidiol and calcium therapy
Why do nephrotic patients become susceptible to infection?
immuglobulin loss
alternative complement pathway factors B and D are low, sensitive towards Pneumococcus
abdominal ascites is a great growth medium for bacteria
patients with minimal change disease may be poorly responsive to immunizations, which may be a primary manifestation of the disease causing nephrosis rather than a direct manifestation of proteinuria
How does nephrotic syndrome affect the thyroid?
thyrod binding globulin is lost in urine
not clinically significant in most patients with acquired nephrotic syndrome but is very significant in Finnish-type congenital nephrotic syndrome
How does nephrotic syndrome lead to anemia?
loss of iron-binding proteins
What consequences for physiology and medical care does loss of albumin itself have?
loss in buffering capacity
decreased tissue perfusion
biochemical effects on metabolism
drug metabolism and efficacy is altered
What are some major concenrs of pure nephrotic syndrome?
hemoconcentration - vomiting and diarrhea is worriesome
intrarenal edema -> back pressure leads to decreased filtration -> acute kidney injury
What are some major concerns for nephritic-nephrotic patients?
hypertension
may not ahve intravscular volume depletion
treatment of nephrotic syndrome
diuretics
albumin infusion - may help acutely but may cause hypertension, worsened edema, or prolonged glomerular disease
given the appropriate response of the kidney to an abnormal stimulus, the kidney may oppose many of these treatments
specific treatment of pathophysiology
diet is ineffective to correct for protein or lipid abnormalities
What are the major categories of diseases that can cause nephrotic syndrome?
podcytopathy
primary renal inflammatory disorders
systemic inflammatory disorders
metabolic disorders
other
What are the podocytopathies that can cause nephrotic syndrome?
minimal chance disease (MCD)
focal segmental glomerulosclerosis (FSGS)
diffuse mesangial sclerosis (DMS)
collapsing glomerulopathy
congenital nephrotic syndrome of the finnish type
What disease is the following representative of?
Minimal Change Nephropathy
What are the main features of minimal change diseaes?
no changes observable by light microscopy
podocyte effacement on electron microscopy
appears at all ages but particulalry common in childhood
often triggered by immune stimulus
most cases are responsive to corticosteroid treatment
massive proteinuria
How might a cold or bee sting lead to nephrotic proteinuria?
“immune system” proteins or peptides that bind to slit diaphragm components and distrupt their assembly
What is the hypothetical pathogenesis of minimal change disease?
infection/inflammation
genetic predisposition to excessive or extended response
immune system activation
parallel expression of “disruptive proteins int he podocyte
podocyte cytoskeletal chages/efacement
secondary loss of glomerular charge selectivity
treatment of MCD
if steroids are effective, outcome is excellent
What disease is in the following image?
Focal Segmental Glomerulosclerosis
What are the features of focal segmental glomerulosclerosis?
podocyte effacement
solidification of glomerular tuft
congenital cause - ITGB4
many other genes identified
can be acquired and results from loss of podocytes or increase in capillary mass so that the podocyte cannot fully cover the capillary surface area in the glomerulus
idiopathic FSGS
unknown hereditary component
podocyturia
suggests fewer podocytes than capillary surface area
secondary FSGS
adaptive changes to reduce nephron mass and increased metabolic needs or circulation
common event is glomerular “overload”
hilar predominance, less podocyte effacement
glomerulomegaly
suggests fewer podocytes than necessary for the given capillary surface area
treatment of FSGS
relatively corticosteroid-resistant
cyclosporine
mycophenolate mofetil
rituximab
transplant patients have a high incidence of recurrent disease (suggestive of a circulating pathogenic factor)
What disease does the following image represent?
Diffuse Mesangial Sclerosis
features of DMS
podocyte effacement
proliferative changes and fibrosis in mesangium
hereditary - congenital LAMB2 (Pierson’s syndrome) and childhood WT1 (Denys-Drash, isloated DMS)
typically resistant to treatment, often leads to CKD and dialysis/transplantation
What disease does the following image represent?
Collapsing Glomerulopathy
features of CG
rapid progression
associated with HIV, other infections, idiopathic, some drugs
increased markers of podocyte proliferation
loss of podocyte-related differentiation markers
re-expression of developmental markers
What are the primary renal inflammatory disorders?
membranoproliferative glomerulonephritis
membranous nephropathy
What are the features of membranous nephropathy?
decreased to low-normal cellular elements, thickening of GBM
animal models involve immune-complex disease
secondary causes include hepatitis B infection
high incidence (as much as 35%) of thrombotic complications, often in renal vein thrombosis
presentation of membranoproliferative glomerulonephritis
presents as nephritis, nephrotic syndrome, or rapidly progressive glomerulonephritis
usually associated with complement consumption
increased cellular elements and thickened GBM
pathologic picture may be idiopathic or associated with inflammatory diseases
MPGN II or dense-deposit disease associated with defects in complement system regulation
pathogenesis of MPGN
immune complex disease activating classical complement pathway
secondary causes include hepatitis C, autoimmune disease (lupus), and monoclonal gammopathy
complement disease - activation of C3 convertase -> alternative pathway, mutation in, or antibodies to, factors H, I, B, membrane cofactor or C3 itself
nephrosis and nephritis may represent different processes in the same patient
What systemic inflammatory disorders can give rise to nephrotic syndrome?
systemic lupus erythamatosus
periarteritis
meixed connective tissue disease
What metabolic disorders can give rise to nephrotic syndrome?
diabetes mellitus
amyloidosis
