SM_212a: Pathophysiology and Clinical Aspects of Nephrotic Syndrome Flashcards
_____ filtration facilitates filtration of small molecules
Permissive filtration facilitates filtration of small molecules
_____ filtration resists or prevents the passage of larger molecules and solid elements of the blood
Restrictive filtration resists or prevents the passage of larger molecules and solid elements of the blood
Describe normal proteinuria
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
Small macromolecules have ____ % clearance, while larger macromolecules have ____ % clearance
Small macromolecules have high % clearance, while larger macromolecules have low % clearance
The glomerular filtration barrier is composed of _____, _____, _____, and _____
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
Slit diaphragm is composed of _____
Slit diaphragm is composed of protein (nephrin) that has multiple immunoglobulin-like repeats that interdigitate
Permselectivity curve is _____ in shape due to _____
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
Albumin does not pass through the filtration barrier because it is ______
Albumin does not pass through the filtration barrier because it is negatively charged
_____ charged molecules are preferentially filtered, while _____ charged molecules are repelled by the filtration barrier
Positively charged molecules are preferentially filtered, while negatively charged molecules are repelled by the filtration barrier
Glomerular polyanion is ______
Glomerular polyanion is a negatively charged glycoprotein that coats foot processes of podocytes and basement membrane
(allows for charge selectively of filtration barrier)
In streaming potential for glomerular filtration, _____
In streaming potential for glomerular filtration, more negative charges get through filtration barrier into urinary space
Diffusion is _____
Diffusion is equilibration of concentration gradients
Convection is _____
Convection is “solvent drag” that takes solute particles across the partitioning membrane
If there is a differnece between hydrostatic pressure and oncotic pressure, there is _____ flow, _____, and _____
If there is a differnece between hydrostatic pressure and oncotic pressure, there is high flow, filtration, and disequilibrium
Autoregulation is ______
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)
Hypertension leads to _____ filtration pressure, unless _____
Hypertension leads to excessive filtration pressure, unless protected by autoregulation
Fluid overload prevents _____, so convection _____
Fluid overload prevents filtration equilibrium from being reached, so convection drags protein across filtration barrier
Dehydration leads to _____ and _____ of protein
Dehydration leads to hemoconcentration and increased diffusion of protein
Sepsis leads to _____, which _____
Sepsis leads to podocyte dysfunction, which alters slit diaphragm structure and function
(increased metabolic activity also modulates glomerular macromolecule handling - fever, obesity)
Describe factors involved in glomerular protein filtration
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
_____ to reabsorb protein is a potenial cause of proteinuria
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)
Describe tubular diseases
Tubular diseases
- Dent disease: defect in Cl- transporter
- Fanconi syndrome (amino aciduria, glycosuria, phosphaturia, proximal RTA)
- Tubulointerstitial nephritis
- Nephrotoxins
Beta-microglobulin is ____ by the glomerulus and ____ and ____ in the proximal tubule, so levels in the plasma and urine are normally ____
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
Pathologic proteinuria occurs when ______
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
Fixed proteinuria indicates clinically significant kidney disease to dysfunction of the _____ or _____
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)
Nephrosis is _____, leading to _____, _____, and _____
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
_____, _____, _____, and _____ occur in nephrotic syndrome
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)
Describe the differences between nephrosis and nephritis
Differences between nephrosis and nephritis
The two types of nephrotic patients are _____ and _____
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
____ is when podocyte foot processes become disorganized and flattened
Podocyte effacement is when podocyte foot processes become disorganized and flattened
Podocyte effacement _____ available filtration surface area, _____ filtration of larger macromolecules
Podocyte effacement decreases available filtration surface area, decreasing filtration of larger macromolecules
As albumin clearance increases, filtered load of albumin _____, which _____ tubular reabsorptive capacity
As albumin clearance increases, filtered load of albumin increases, which exceeds tubular reabsorptive capacity
Mechanism of nephrotic proteinuria in minimal change disease is _____, causing _____
Mechanism of nephrotic proteinuria in minimal change disease is podocyte effacement, causing loss of streaming potential and charge selectivity
Mechanism of nephrotic proteinuria in focal segmental glomerulosclerosis is _____, leading to _____ and _____
Mechanism of nephrotic proteinuria in focal segmental glomerulosclerosis is podocyte dysfunction, leading to effacement and altered glomerular sieving characteristics
Mechanism of nephrotic proteinuria in hyperfiltration glomerulosclerosis (diabetes, obesity) is _____, _____, and _____
Mechanism of nephrotic proteinuria in hyperfiltration glomerulosclerosis (diabetes, obesity) is podocyte stress, hypertrophy, and failure
Mechanism of nephrotic proteinuria in inflammation is _____, leading to _____ and _____
Mechanism of nephrotic proteinuria in inflammation is disruption of filtration barrier, leading to massive proteinuria and loss of charge gradient
Describe minimal change nephrotic syndrome
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
The underfilling model of edema formation in nephrotic syndrome indicates that _____ and _____ cause edema
The underfilling model of edema formation in nephrotic syndrome indicates that renin secretion (via thirst) and increased sodium reabsorption cause edema
_____ and _____ are associated with but may not cause nephrotic edema
Proteinuria and hypoalbuminemia are associated with but may not cause nephrotic edema
In the overflow model, _____ via _____ is the primary cause of nephrotic edema
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)
Greater plasminogen is associated with _____ proteinuria
Greater plasminogen is associated with greater proteinuria
(serine proteases are time activator of ENaC - inhibiting urinary serine protease activity blocks nephrotic sodium retention)
Inhibiting _____ blocks ENaC channels, preventing nephrotic sodium retention
Inhibiting urine serine protease activity blocks ENaC channels, preventing nephrotic sodium retention
_____ 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
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
Decreased albumin contributes to ______
Decreased albumin contributes to hypercholesterolemia
- Normally removes products of LCAT reaction from equilibrium so hypoalbuminemia indirectly inhibits progression of the LCAT reaction
Hypercoagulability results from nephrosis and is best correlated with _____
Hypercoagulability results from nephrosis and is best correlated with decreased free protein S
____ metabolism is inhibited in nephrotic syndrome due to loss of Vitamin D-binding protein and Vitamin D metabolites in the urine
Bone metabolism is inhibited in nephrotic syndrome due to loss of Vitamin D-binding protein and Vitamin D metabolites in the urine
Describe other consequences of nephrotic proteinuria
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
Describe other clinical concerns in nephrotic syndrome
Other clinical concerns in nephrotic syndrome
Specific causes of nephrotic syndrome include _____, _____, and _____
Specific causes of nephrotic syndrome include primary podocytopathy (MCD, FSGS), primary glomerular diseases (MN, MPGN), and systemic disorders (diabetes, lupus, vasculitides, amyloidosis)
Describe minimal change disease
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
Describe focal segmental glomerulosclerosis
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
____ defects can disrupt podocyte function
Single gene defects can disrupt podocyte function
Describe treatment of nephrotic syndrome
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
