SM 212 Pathophysiology and Clinical Aspects of Nephrotic Syndrome Flashcards
What are the two components of filtration?
Permissive and Restrictive functions are parts of filtration
What is the permissive aspect of filtration?
Filtration is permissive in the sense that it allows filtration of small molecules
What is the restrictive aspect of filtration?
Filtration is restrictive in the sense that it prevents passage of larger molecules such as Ig’s and plasma proteins into the urine
What must be normal to prevent Ig’s and plasma proteins from entering the urine?
Large molecules are restricted from filtration only if the glomerular basement membrane is normal
What constitutes “normal” proteinuria?
Some minor proteinuria is normal, and includes plasma proteins as well as proteins from tissue
What is intermittent proteinuria?
Proteinuria that comes and goes
What is postural proteinuria?
Proteinuria that only occurs while standing
What is persistent proteinuria?
Proteinuria that is due to kidney damage and occurs constantly
What type of proteinuria is pathological?
Persistent proteinuria
What is permselectivity?
The clearance of a molecule to the ratio of the clearance of creatinine
Explain the shape of the permselectivity curve?
The curve is sharp early indicating high permselectivity for small sized molecules and rapidly flattens out indicating low permselectivity for large sized molecules
What are the key components of the glomerular tuft?
Epithelial podocytes + glomerular basement membrane + endothelial cells
Which cell forms the basement membrane, the podocytes or the endothelial cells?
Both podocytes and endothelial cells form the basement membrane
What is the first part of the filtration barrier for particles attempting to enter the urine from blood?
The fenestrated endothelium, coated by a glycocalyx
What is the purpose of the glycocalyx?
It covers the fenestrated endothelium and acts as a sludge to further slow the entrance of large molecules through the slit processes
What is the second part of the filtration barrier for particles attempting to enter the urine from blood?
After crossing the fenestrated endothelium, the glomerular basement membrane acts as the second barrier
How does the glomerular basement membrane act as a filter?
It has functional pores that slow down movement of large particles
What is the third part of the filtration barrier for particles attempting to enter the urine from blood?
The podocyte is the final part of the filtration barrier, after the fenestrated endothelium and the porous glomerular membrane
Does each podocyte support a single capillary?
Nope; each podocyte forms foot processes on several capillaries
What roles do podocytes play?
Regulate permselectivity
Structural support
GBM secretion/remodelling
How do podocytes foot processes form a slit process network?
The foot processes wrap around capillaries and form interdigitated slits
Why is the permselectivity curve sigmoidal?
While large molecules are strongly impermeable and small molecules are strongly permeable, intermediate sized molecules may or may not pass through the glomerular barriers depending on how they enter/their shape/etc., so the curve is sigmoidal
What factors effect glomerular handling of macromolecules?
Size and charge
Why are negatively charged ions like chloride able to pass through the anionic charge barrier?
These ions are too small to interact with the barrier
Rank the clearance of positive, neutral, and negatively charged molecules through the glomerular membrane?
Positive > Neutral > Negative clearance in terms of clearance through the glomerular membrane
What is the idea of the glomerular polyanion?
Lots of anions in the glomerular membrane that make the membrane less permeable to negatively charged molecules
Describe the charge barrier across the glomerular basement membrane and why it arises?
The glomerular polyanion allows for cations to pass through while restricting cations, resulting in a predominantly negative urinary space and a neutral vascular space (after and prior to filtering)
What is the difference between diffusion and convection?
Diffusion refers to the equilibration of concentration gradients
Convection is “solvent drag” that pulls solute, regardless of size/charge, through a membrane partition
What determines the relative contribution of Diffusion and Convection to glomerular filtration?
The relative contribution of Diffusion and Convection is determined by whether or not filtration equilibrium is reached
Does high flow promote or inhibit filtration equilibration?
High flow inhibits filtration equilibration between hydrostatic and oncotic pressure across the glomeruli, leading to net filtration and Convection
Does low flow promote or inhibit filtration equilibration?
Low flow promotes filtration equilibration and allows time for equilibration to occur between hydrostatic and oncotic pressure across the glomeruli, favoring Diffusion over Convection
What is the autoregulation of blood flow in the kidney?
Constant perfusion at a wide range of blood pressures due to glomerulotubular feedback
What factors mediate autoregulation?
RAAS, neural control, metabolic buildup of vasoactive metabolites
What factors can modulate the passage of macromolecules through the glomerular membrane?
Hypertension = excessive filtration pressure
Fluid overload = filtration disequilibrium = favors convection
Dehydration = hemoconcentration, increased diffusion of protein
Sepsis = podocyte dysfunction alters slit diaphragm
Does HTN promote or inhibit macromolecule transport through the glomerular membrane?
Excessive filtration pressure favors macromolecule transport
Does fluid overload promote or inhibit macromolecule transport through the glomerular membrane?
Fluid overload prevents filtration equilibrium from being reached and favors Convection to drag protein across the filtration barrier
Does dehydration promote or inhibit macromolecule transport through the glomerular membrane?
Dehydration causes hemoconcentration of macromolecules that promotes diffusion of macromolecules across the filtration barrier
Does sepsis promote or inhibit macromolecule transport through the glomerular membrane?
Sepsis causes podocyte dysfunction alters the slit diaphragm function
Broadly speaking, what factors effect glomerular protein filtration?
Size (small)
Charge (anionic repulsion)
Glomerular capillary pressure
Macromolecular shape and deformability
How do the tubules normally handle protein?
The PCT normally reabsorbs protein via absorptive endocytosis via non-specific binding to Cubulin and Megalin
How does the PCT relate to proteinuria?
PCT failure to reabsorb protein is a potential cause of proteinuria, and may occur when excess protein crosses the GBM
What is Fanconi Syndrome?
Amino aciduria
Glycosuria
Phosphaturia
Proximal RTA
What is Beta2 Microglobulin?
A protein that is part of MHCI which is freely filtered by the glomerulus and degraded by the PCT
How does Glomerular dysfunction effect protein levels in the serum and urine?
Glomerular dysfunction prevents passage of proteins through the GBM leading to high serum and low urine
How does Tubular dysfunction effect protein levels in the serum and urine?
Tubular dysfunction prevents passage of proteins through the GBM leading to low serum and high urine
Is the amount of protein in pathologic proteinuria fixed?
The absolute amount of protein in proteinuria is fixed and varies little with time, since it depends solely on the permeability of the GBM
Is the concentration of protein in pathologic proteinuria fixed?
The concentration of protein in proteinuria is varied, since it depends on the amount of volume being excreted
What underlying abnormality of proteinuria suggest?
Increased glomerular permeability to proteins
Decreased tubular reabsorption of proteins
What are the two broad causes of fixed proteinuria?
Glomerular and Tubular
Does protein loss in proteinuria effect specific systems or the entire body?
Specific protein loss = specific systems
Generalized protein loss = nephrotic syndrome
What does significant loss of plasma protein in nephrotic syndrome lead to?
Decreased levels of plasma proteins, peripheral edema, and metabolic abnormalities
How is proteinuria defined by grams of protein?
3gm/day of protein = Nephrotic Syndrome
How is proteinuria defined by ratio?
Urine Protein:Creatinine > 2 = Nephrotic Syndrome
What are the additional components of true Nephrotic Syndrome, beyond high protein?
Hypoalbuminemia
Edema
Hypercholesterolemia
How do Nephrosis and Nephritis compare in terms of the inciting derangement?
Nephrosis is caused by low serum Albumin
Nephritis is caused by renal inflammation
How do Nephrosis and Nephritis compare in terms of resulting physiology?
Nephrosis leads to peripheral edema
Nephritis leads to decreased GFR
How do Nephrosis and Nephritis compare in terms of vascular effects?
Nephrosis leads to decreased intravascular volume
Nephritis leads to increased intravascular volume
How do Nephrosis and Nephritis compare in terms of vascular effects?
Nephrosis leads to decreased intravascular volume
Nephritis leads to increased intravascular volume
How do Nephrosis and Nephritis compare in terms of edema?
Nephrosis leads to significant edema
Nephritis leads to mild edema
How do Nephrosis and Nephritis compare in terms of causing hypertension?
Nephrosis occasionally causes HTN
Nephritis usually causes HTN
Which is more likely to cause edema, Nephrosis or Nephritis?
Nephrosis is more likely to cause edema than Nephritis
Which is more likely to cause HTN, Nephrosis or Nephritis?
Nephritis is more likely to cause HTN than Nephrosis
How does Nephrosis alter clearance of large molecules?
Nephrosis leads to increased clearance of large molecules
How do albuminuria and proteinuria relate in nephrotic patients?
Two types: primarily albuminuria and generalized proteinuria that leads to hypoalbuminemia
Why is the clearance of some macromolecules decreased in nephrotic syndrome?
Podocyte effacement involves flattening of the foot processes and decreases the surface area on the capillary available for clearing macromolecules
How does podocyte effacement effect the podocytes in nephrotic syndrome?
Podocyte effacement = flattening = less surface area because the slits are closer together = decreased clearance
Why is albumin excretion increased in Nephrotic syndrome?
Albumin excretion increases the charge barrier is lost in the barrier and Albumin itself is relatively small
How does Minimal Change Disease lead to Nephrotic Proteinuria?
Podocyte effacement leads to charge selectivity
How does FSGS lead to Nephrotic Proteinuria?
Podocyte dysfunction leads to altered glomerular sieving
How does Hyperfiltration lead to Nephrotic Proteinuria?
Occurs in diabetes, leads to glomerular hypertrophy and failure
How does Inflammation lead to Nephrotic Proteinuria?
Disruption of the filtration barrier leads to massive proteinuria
Which Nephrotic syndrome is initiated by respiratory infection?
Minimal Change Disease
Which Nephrotic syndrome tends to remit and relapse?
Minimal Change Disease
What does Minimal Change Disease look like on labs and physical exam?
Labs = albuminuria
Physical Exam = Anascara (total body edema)
How is Minimal Change Disease treated?
Corticosteroids
How does edema occur in Nephrotic syndrome?
Nephrotic syndrome = low albumin = loss of oncotic pressure = edema throughout the body (Anascara)
What is the underfilling model of edema in Nephrotic syndrome?
Hypoalbuminemia leads to edema
Edema = lower EABV
Lower EABV = lower glomerular perfusion
Low glomerular perfusion = Renin secretion + RAAS
RAAS = increased sodium reabsorption = Edema
How does Renin cause edema in Nephrotic syndrome?
Edema from hypoalbuminemia and low oncotic pressure causes less fluid delivery to the JGA releasing Renin
Renin causes thirst and sodium retention which worsens edema
Is protein loss the cause of Nephrotic edema?
Potentially, proteinuria is associated with edema
What is the primary sodium retention model of edema in Nephrotic syndrome?
Serine proteases like Plasmin that leak into the Nephron during Nephrotic syndrome activate eNaC
eNaC promotes sodium retention which causes fluid retention and edema
How do the underfilling and primary sodium retention models of edema vary?
The underfilling model involves low EABV and compensatory high RAAS + Aldosterone
The primary sodium retention model involves activation of eNaC by Serine proteases and fluid retention, with low compensatory RAAS + Aldosterone
How do lipid levels rise in Nephrotic syndrome?
Nephrotic syndrome causes lipid levels to rise
Why do lipid levels rise in Nephrotic syndrome?
Since lipids are bound to lipoproteins Albumin, decreased lipoproteins from proteinuria acts as a signal to the Liver to increase lipid production
Why does hypercholesterolemia occur in Nephrotic syndrome?
Albumin, a transport protein for Cholesterol esters, is lost, inhibiting the conversion of Cholesterol to Cholesterol esters by LCAT and causing cholesterol levels to rise
Why does hypercoagulability occur in Nephrotic syndrome?
Proteinuria in Nephrotic syndrome causes a decrease in anti-coagulant proteins like Protein S
Dehydration from edema and water loss increases the effective concentration of pro-coagulants
What platelet abnormalities accompany Nephrotic syndrome?
Altered fibrinolysis
Increased aggregation due to loss of Albumin carrier protein
Glycoprotein charge on platelet and vessel wall
Name an anti-coagulant protein factor lost in Nephrotic syndrome?
Protein S is an anti-coagulant lost in Nephrotic syndrome
How is bone metabolism effected in Nephrotic syndrome?
Vitamin D Binding Protein is lost in Nephrotic syndrome leading to decreased Ca absorption and increased PTH to compensate for less Ca, leading to bone loss
How does Nephrotic syndrome effect the immune system?
Nephrotic syndrome causes immune dysfunction due to urinary loss of opsonizing factors and Immunoglobulins
What disease are Nephrotic patients susceptible to and why?
Nephrotic patients lose opsonizing factors and antibodies which predisposes Strep. Pneumo immunization, due to that bacterium’s antiphagocytic capsule only being vulnerable to antibodies
How does Nephrotic syndrome cause anemia?
Nephrotic syndrome can cause loss of Iron binding proteins
How does Nephrotic syndrome effect drug metabolism?
Nephrotic syndrome leads to the loss of Albumin as a drug carrier protein, altering metabolism
What triggers Minimal Change Disease?
Immune stimuli like upper respiratory infections and allergies
How does Minimal Change Disease present on electron microscopy?
Podocyte effacement
What disease present with podocyte effacement?
Minimal Change Disease and FSGS
Is FSGS acquired or genetic?
Both; genetic causes due to loss of function in Nephrin and other basement membrane proteins
How can diet treat protein or lipid abnormalities in Nephrotic syndrome?
It doesn’t
