Clinical Manifestations of the Nephrotic Syndrome

Question 1

clinical course of minimal change nephrotic syndrome

Answer 1

initiated by respiratory infection

albuminuria

anasarca (massive swelling)

remitting and relapsing course

pallor

counter-irritant induces relapse

spontaneous remission

Question 2

How does decreased albumin in the blood lead to edema?

Answer 2

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

Question 3

What is the pathogenesis of edema formation in nephrotic syndrome?

Answer 3

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

Question 4

What are the reasons to question a direct role of albumin in nephrotic edema?

Answer 4

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

Question 5

underfill vs. overflow in nephrotic edema

Answer 5

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

Question 6

How do lipid levels change with nephrotic syndrome?

Answer 6

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

Question 7

causes of lipid abnormalities in nephrotic syndrome

Answer 7

increased hepatic lipoprotein synthesis (oncotic/viscosity signal)

defective lipid transport (HDL lost in urine)

decreased LPL and LCAT activity - may reflect urinary albumin loss

Question 8

How does albumin contribute to hypercholesterolemia?

Answer 8

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

Question 9

cause sof hemostasis in neprotic patients

Answer 9

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

Question 10

What are the possible abnormalities that can arise in the face of nephrotic syndrome?

Answer 10

hemostasis

susceptibility to infection

bone disease

thyroid dysfunction

anemia

effects of low albumin

Question 11

How is bone metabolism affected in nephrotic syndrome?

Answer 11

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

Question 12

Why do nephrotic patients become susceptible to infection?

Answer 12

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

Question 13

How does nephrotic syndrome affect the thyroid?

Answer 13

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

Question 14

How does nephrotic syndrome lead to anemia?

Answer 14

loss of iron-binding proteins

Question 15

What consequences for physiology and medical care does loss of albumin itself have?

Answer 15

loss in buffering capacity

decreased tissue perfusion

biochemical effects on metabolism

drug metabolism and efficacy is altered

Question 16

What are some major concenrs of pure nephrotic syndrome?

Answer 16

hemoconcentration - vomiting and diarrhea is worriesome

intrarenal edema -> back pressure leads to decreased filtration -> acute kidney injury

Question 17

What are some major concerns for nephritic-nephrotic patients?

Answer 17

hypertension

may not ahve intravscular volume depletion

Question 18

treatment of nephrotic syndrome

Answer 18

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

Question 19

What are the major categories of diseases that can cause nephrotic syndrome?

Answer 19

podcytopathy

primary renal inflammatory disorders

systemic inflammatory disorders

metabolic disorders

other

Question 20

What are the podocytopathies that can cause nephrotic syndrome?

Answer 20

minimal chance disease (MCD)

focal segmental glomerulosclerosis (FSGS)

diffuse mesangial sclerosis (DMS)

collapsing glomerulopathy

congenital nephrotic syndrome of the finnish type

Question 21

What disease is the following representative of?

Answer 21

Minimal Change Nephropathy

Question 22

What are the main features of minimal change diseaes?

Answer 22

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

Question 23

How might a cold or bee sting lead to nephrotic proteinuria?

Answer 23

“immune system” proteins or peptides that bind to slit diaphragm components and distrupt their assembly

Question 24

What is the hypothetical pathogenesis of minimal change disease?

Answer 24

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

Question 25

treatment of MCD

Answer 25

if steroids are effective, outcome is excellent

Question 26

What disease is in the following image?

Answer 26

Focal Segmental Glomerulosclerosis

Question 27

What are the features of focal segmental glomerulosclerosis?

Answer 27

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

Question 28

idiopathic FSGS

Answer 28

unknown hereditary component

podocyturia

suggests fewer podocytes than capillary surface area

Question 29

secondary FSGS

Answer 29

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

Question 30

treatment of FSGS

Answer 30

relatively corticosteroid-resistant

cyclosporine

mycophenolate mofetil

rituximab

transplant patients have a high incidence of recurrent disease (suggestive of a circulating pathogenic factor)

Question 31

What disease does the following image represent?

Answer 31

Diffuse Mesangial Sclerosis

Question 32

features of DMS

Answer 32

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

Question 33

What disease does the following image represent?

Answer 33

Collapsing Glomerulopathy

Question 34

features of CG

Answer 34

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

Question 35

What are the primary renal inflammatory disorders?

Answer 35

membranoproliferative glomerulonephritis

membranous nephropathy

Question 36

What are the features of membranous nephropathy?

Answer 36

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

Question 37

presentation of membranoproliferative glomerulonephritis

Answer 37

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

Question 38

pathogenesis of MPGN

Answer 38

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

Question 39

What systemic inflammatory disorders can give rise to nephrotic syndrome?

Answer 39

systemic lupus erythamatosus

periarteritis

meixed connective tissue disease

Question 40

What metabolic disorders can give rise to nephrotic syndrome?

Answer 40

diabetes mellitus

amyloidosis