SM_212a: Pathophysiology and Clinical Aspects of Nephrotic Syndrome

Question 1

_____ filtration facilitates filtration of small molecules

Answer 1

Permissive filtration facilitates filtration of small molecules

Question 2

_____ filtration resists or prevents the passage of larger molecules and solid elements of the blood

Answer 2

Restrictive filtration resists or prevents the passage of larger molecules and solid elements of the blood

Question 3

Describe normal proteinuria

Answer 3

Normal proteinuria

• 50-60% plasma proteins: albumin (40%), alpha-1 globulins (9%), alpha-2 globulins (2%), others
• 40-50% proteins of tissue origin: uromucoid, glycoproteins, etc

Question 4

Small macromolecules have ____ % clearance, while larger macromolecules have ____ % clearance

Answer 4

Small macromolecules have high % clearance, while larger macromolecules have low % clearance

Question 5

The glomerular filtration barrier is composed of _____, _____, _____, and _____

Answer 5

The glomerular filtration barrier is composed of fenestrated endothelium, glomerular basement membrane, podocyte, and slit pores

• Fenestrated endothelium: coated by a glycocalyx
• GBM: trilaminar structure derived from both endothelial and epithelial cells, restrictive capacity (35% of restriction, functions like gel electrophoresis)
• Podocyte: post-mitotic cell w/ highly specialized structure and function, regulates permselectivity, structural support for capillary, remodeling GBM, endocytosis of filtered protein

Question 6

Slit diaphragm is composed of _____

Answer 6

Slit diaphragm is composed of protein (nephrin) that has multiple immunoglobulin-like repeats that interdigitate

Question 7

Permselectivity curve is _____ in shape due to _____

Answer 7

Permselectivity curve is sigmoidal in shape due to steric hindrance

• Small molecules get through
• Large molecules do not get through
• Medium sized molecules are large enough to interact with the slit pore but not too large so can get through sometimes

Question 8

Albumin does not pass through the filtration barrier because it is ______

Answer 8

Albumin does not pass through the filtration barrier because it is negatively charged

Question 9

_____ charged molecules are preferentially filtered, while _____ charged molecules are repelled by the filtration barrier

Answer 9

Positively charged molecules are preferentially filtered, while negatively charged molecules are repelled by the filtration barrier

Question 10

Glomerular polyanion is ______

Answer 10

Glomerular polyanion is a negatively charged glycoprotein that coats foot processes of podocytes and basement membrane

(allows for charge selectively of filtration barrier)

Question 11

In streaming potential for glomerular filtration, _____

Answer 11

In streaming potential for glomerular filtration, more negative charges get through filtration barrier into urinary space

Question 12

Diffusion is _____

Answer 12

Diffusion is equilibration of concentration gradients

Question 13

Convection is _____

Answer 13

Convection is “solvent drag” that takes solute particles across the partitioning membrane

Question 14

If there is a differnece between hydrostatic pressure and oncotic pressure, there is _____ flow, _____, and _____

Answer 14

If there is a differnece between hydrostatic pressure and oncotic pressure, there is high flow, filtration, and disequilibrium

Question 15

Autoregulation is ______

Answer 15

Autoregulation is ability to control blood pressure over a narrow range

• Mediated by vessel distension from tissue pressure, metabolic (buildup of vasoactive metabolites), diversion of flow into shunt vessels, neural control, vascular remodeling (long-term), RAAS system
• RAAS system: differential resistance of afferent and efferent arterioles, moderate activity causes increased efferent resistance (increased GFR and filtration fraction), high activity causes constriction of both arterioles (decreased GFR)

Question 16

Hypertension leads to _____ filtration pressure, unless _____

Answer 16

Hypertension leads to excessive filtration pressure, unless protected by autoregulation

Question 17

Fluid overload prevents _____, so convection _____

Answer 17

Fluid overload prevents filtration equilibrium from being reached, so convection drags protein across filtration barrier

Question 18

Dehydration leads to _____ and _____ of protein

Answer 18

Dehydration leads to hemoconcentration and increased diffusion of protein

Question 19

Sepsis leads to _____, which _____

Answer 19

Sepsis leads to podocyte dysfunction, which alters slit diaphragm structure and function

(increased metabolic activity also modulates glomerular macromolecule handling - fever, obesity)

Question 20

Describe factors involved in glomerular protein filtration

Answer 20

Factors involved in glomerular protein filtration

• Size selectivity from 18 to 56 Angstroms
• Charge selectivity impeding passage of anionic macromolecules
• Effective glomerular capillary pressure and filtrate flow rates
• Macromolecular shape and deformability

Question 21

_____ to reabsorb protein is a potenial cause of proteinuria

Answer 21

Tubular failure to reabsorb protein is a potenial cause of proteinuria

• Proximal tubules absorb albumin and degrade some and absorb some intact (rescue pathway)
• Absorbed through saturable binding to megalin, cubilin, and amnionless in clathrin coated pits
• Accounts for reabsorption of 4-6 g/day from filtrate (glomerular filtrate typically contains 3-4 g/day)

Question 22

Describe tubular diseases

Answer 22

Tubular diseases

• Dent disease: defect in Cl^- transporter
• Fanconi syndrome (amino aciduria, glycosuria, phosphaturia, proximal RTA)
• Tubulointerstitial nephritis
• Nephrotoxins

Question 23

Beta-microglobulin is ____ by the glomerulus and ____ and ____ in the proximal tubule, so levels in the plasma and urine are normally ____

Answer 23

Beta-microglobulin is filtered freely by the glomerulus and reabsorbed and degraded in the proximal tubule, so levels in the plasma and urine are normally low

• Glomerular dysfunction: high serum levels, low urine levels
• Tubular dysfunction: low serum levels, high urine levels

Question 24

Pathologic proteinuria occurs when ______

Answer 24

Pathologic proteinuria occurs when absolute amount of proteinuria is fixed

• Urine [protein] may vary with urine flow rate
• Indication of likely underlying abnormality: increased glomerular permeability to plasma proteins, decreased tubular reabsorption of protein, overflow proteinuria, secretory proteinuria, histuria
• May or may not decrease serum protein levels

Question 25

Fixed proteinuria indicates clinically significant kidney disease to dysfunction of the _____ or _____

Answer 25

Fixed proteinuria indicates clinically significant kidney disease to dysfunction of the glomerulus or tubules

(sufficient loss of protein may have direct effects on homeostasis - specific proteins affect specific systems, generalized effects causing nephrotic syndrome)

Question 26

Nephrosis is _____, leading to _____, _____, and _____

Answer 26

Nephrosis is significant loss of plasma proteins in the urine, leading to decreased levels of plasma proteins, peripheral edema, and multiple metabolic abnormalities

• May represent an appropriate physiological response by kidney to initial change in plasma proteins

Question 27

_____, _____, _____, and _____ occur in nephrotic syndrome

Answer 27

Proteinuria, hypoalbuminemia, edema, and hypercholesterolemia occur in nephrotic syndrome

• Proteinuria: adults 3 g/day, children 50 mg/kg/day, urine protein:creatinine > 2
• (Unofficially: coagulopathy, endocrine dysfunction, and immune dysfunction also)

Question 28

Describe the differences between nephrosis and nephritis

Answer 28

Differences between nephrosis and nephritis

Question 29

The two types of nephrotic patients are _____ and _____

Answer 29

The two types of nephrotic patients are those with mainly albuminuria and those with so much generalized proteinuria that they become hypoalbuminemic

• Mainly albuminuria: decreased fractional excretion of many macromolecules
• Generalzed proteinuria causing hypoalbuminemia: increased macromolecular clearance

Question 30

____ is when podocyte foot processes become disorganized and flattened

Answer 30

Podocyte effacement is when podocyte foot processes become disorganized and flattened

Question 31

Podocyte effacement _____ available filtration surface area, _____ filtration of larger macromolecules

Answer 31

Podocyte effacement decreases available filtration surface area, decreasing filtration of larger macromolecules

Question 32

As albumin clearance increases, filtered load of albumin _____, which _____ tubular reabsorptive capacity

Answer 32

As albumin clearance increases, filtered load of albumin increases, which exceeds tubular reabsorptive capacity

Question 33

Mechanism of nephrotic proteinuria in minimal change disease is _____, causing _____

Answer 33

Mechanism of nephrotic proteinuria in minimal change disease is podocyte effacement, causing loss of streaming potential and charge selectivity

Question 34

Mechanism of nephrotic proteinuria in focal segmental glomerulosclerosis is _____, leading to _____ and _____

Answer 34

Mechanism of nephrotic proteinuria in focal segmental glomerulosclerosis is podocyte dysfunction, leading to effacement and altered glomerular sieving characteristics

Question 35

Mechanism of nephrotic proteinuria in hyperfiltration glomerulosclerosis (diabetes, obesity) is _____, _____, and _____

Answer 35

Mechanism of nephrotic proteinuria in hyperfiltration glomerulosclerosis (diabetes, obesity) is podocyte stress, hypertrophy, and failure

Question 36

Mechanism of nephrotic proteinuria in inflammation is _____, leading to _____ and _____

Answer 36

Mechanism of nephrotic proteinuria in inflammation is disruption of filtration barrier, leading to massive proteinuria and loss of charge gradient

Question 37

Describe minimal change nephrotic syndrome

Answer 37

Minimal change nephrotic syndrome

• Clinical course: initiated by respiratory infection, albuminuria, anasarca, remitting and relapsing course, pallor, counter-irritant induces relapse, spontaneous remission
• Treatment: 3 pints of water, digitalis, iron perchloride, potassium acetate and iron acetate, sulfate and iron, gallic acid

Question 38

The underfilling model of edema formation in nephrotic syndrome indicates that _____ and _____ cause edema

Answer 38

The underfilling model of edema formation in nephrotic syndrome indicates that renin secretion (via thirst) and increased sodium reabsorption cause edema

Question 39

_____ and _____ are associated with but may not cause nephrotic edema

Answer 39

Proteinuria and hypoalbuminemia are associated with but may not cause nephrotic edema

Question 40

In the overflow model, _____ via _____ is the primary cause of nephrotic edema

Answer 40

In the overflow model, renal tubular sodium retention via ENaC is the primary cause of nephrotic edema

(primary sodium retention -> increased plasma volume and circulatory overload -> renin and aldosterone decreased)

Question 41

Greater plasminogen is associated with _____ proteinuria

Answer 41

Greater plasminogen is associated with greater proteinuria

(serine proteases are time activator of ENaC - inhibiting urinary serine protease activity blocks nephrotic sodium retention)

Question 42

Inhibiting _____ blocks ENaC channels, preventing nephrotic sodium retention

Answer 42

Inhibiting urine serine protease activity blocks ENaC channels, preventing nephrotic sodium retention

Question 43

_____ abnormalities occur due to urinary protein loss and increase slowly with relapse and then decrease slowly with remission but may persist in patients with frequent relapses

Answer 43

Lipid abnormalities occur due to urinary protein loss and increase slowly with relapse and then decrease slowly with remission but may persist in patients with frequent relapses

Question 45

Decreased albumin contributes to ______

Answer 45

Decreased albumin contributes to hypercholesterolemia

• Normally removes products of LCAT reaction from equilibrium so hypoalbuminemia indirectly inhibits progression of the LCAT reaction

Question 46

Hypercoagulability results from nephrosis and is best correlated with _____

Answer 46

Hypercoagulability results from nephrosis and is best correlated with decreased free protein S

Question 47

____ metabolism is inhibited in nephrotic syndrome due to loss of Vitamin D-binding protein and Vitamin D metabolites in the urine

Answer 47

Bone metabolism is inhibited in nephrotic syndrome due to loss of Vitamin D-binding protein and Vitamin D metabolites in the urine

Question 48

Describe other consequences of nephrotic proteinuria

Answer 48

Other consequences of nephrotic proteinuria

• Thyroid binding globulin - not significant in minimal change disease, significant in congenital nephrotic syndrome
• Immune dysfunction
• Anemia due to deficiency of iron binding proteins
• Loss of albumin as carrier protein

Question 49

Describe other clinical concerns in nephrotic syndrome

Answer 49

Other clinical concerns in nephrotic syndrome

Question 50

Specific causes of nephrotic syndrome include _____, _____, and _____

Answer 50

Specific causes of nephrotic syndrome include primary podocytopathy (MCD, FSGS), primary glomerular diseases (MN, MPGN), and systemic disorders (diabetes, lupus, vasculitides, amyloidosis)

Question 51

Describe minimal change disease

Answer 51

Minimal change disease

• Podocyte effacement on EM
• Particularly common in children
• Responsive to corticosteroid treatment
• Often triggered by immune stimulus (URI, allergy, bee sting)
• Experimental studies: alpha-dystroglycan redistributed away from basal surface of podocyte

Question 52

Describe focal segmental glomerulosclerosis

Answer 52

Focal segmental glomerulosclerosis

• Podocyte effacement
• Solidifcation of glomerular tuft
• Types: genetic, acquired (often transplant)
• Acquired: may be associated with circulating factor that causes rapid recurrence of proteinuria in transplanted kidney - known mutation w/o recurrence or no mutation w/ recurrence or no mutation w/o recurrence

Question 53

____ defects can disrupt podocyte function

Answer 53

Single gene defects can disrupt podocyte function

Question 54

Describe treatment of nephrotic syndrome

Answer 54

Treatment of nephrotic syndrome

• Diuretics
• Albumin infusion: may help acutely but may cause HTN, worsened edema, or prolonged glomerular disease
• Given appropriate response of kidney to abnormal stimulus, kidney may oppose many of these treatments
• Specific treatment of bone, lipid, coagulation, etc
• Diet ineffective for protein or lipid abnormalities
• Treating the underlying disease