Pathophys and Clinical Nephrotic Syndrome

Question 1

What is the upper limit of normal protein excretion per day?

Answer 1

100 mg per day, with an average concentration of 7 mg/dl

Question 2

What is the breakdown of normal protein in urine?

Answer 2

plasma protein (50%) and tissue origin protein (50%)

plasma protein is mostly albumin

Question 3

Define postural proteinuria

Answer 3

Postural proteinuria is observed only when the subject assumes an upright or lordotic position. It may be associated with mild glomerular histological abnormalities, but there is no evidence linking this finding with significant renal disease.

Question 4

Define persistent proteinuria?

Answer 4

Persistent proteinuria is present when several urine collections obtained with the subject supine at rest contain detectable protein.

Question 5

What shape is the permselectivity curve that defines fractional clearance of a solute?

Answer 5

sigmoidal - upper limit is 56 angstroms in size

Question 6

What is steric hindrance?

Answer 6

size selective permeability

Question 7

How does convection lead to macromolecule movement across a barrier?

Answer 7

dragged across by increased filtration

Question 8

How does diffusion lead to macromolecule movement across a barrier?

Answer 8

down a concentration gradient

Question 9

A patient who has strong perfusion of fluid through the glomerular filter may pass more protein by: convection or diffusion?

Answer 9

convection

Question 10

a patient who is dehydrated may filter more protein by: diffusion or convection?

Answer 10

diffusion because dehydration concentrates the plasma proteins.

Question 11

Where is urumucoid protein (tamm horsfall protein) added to the urine?

Answer 11

the distal tubule

Question 12

Define primary nephrotic syndrome

Answer 12

persistent proteinuria caused by selective mechanisms that affect handling of protein

Question 13

What are examples of nephrotic diseases caused by decreased tubular REABSORPTION of protein?

Answer 13

Fanconi syndrome
Dent disease 
tubulointerstitial nephritis 
drugs 
toxins

Question 14

What processes would cause overflow proteinuria in the setting of normal renal function?

Answer 14

repeated albumin infusions or blood transfusions; myeloma,leukemia

Question 15

What are the four findings that define nephrotic syndrome?

Answer 15

1. proteinuria
2. hypoproteinemia/hypoalbuminemia
3. edema
4. hypercholesterolemia

Question 16

What is the cut off for hypoalbuminemia?

Answer 16

serum albumin of less than 2 gm/dl

Question 17

What is nephritis?

Answer 17

Nephritis may show

varied symptoms, but basically is a pathologic diagnosis denoting renal inflammation.

Question 18

What is nephrosis?

Answer 18

Nephrosis characterizes the symptom complex described above and does not invoke any particular disease process.

Question 19

Low serum albumin 
peripheral edema 
decreased intravascular volume 
significant edema 
sometimes HTN 
normal heart and pleural fluid on CXR

These are traits of: nephrotic syndrome or nephritis?

Answer 19

nephrotic syndrome

Question 20

renal inflammation 
decreased GFR
increased intravascular volume 
mild edema 
HTN 
cardiomegaly/pulmonary edema 

These are traits of: nephrotic syndrome or nephritis?

Answer 20

nephritis (symptomatic)

Question 21

Can albuminuria in nephrosis occur without filter damage?

Answer 21

yes. Since it may occur in the absence of disruption of the glomerular filter (e.g., in minimal change disease), such
loss may not be caused by obvious physical damage to
that filter.

Question 22

Does overall macromolecular clearance increase in nephrosis?

Answer 22

Not necessarily.

Importantly, even if overall macromolecular clearance is decreased, if the relative clearance of albumin increases, the consequences could be clinically significant

Question 23

Do patients with severe fanconi or dent disease develop nephrotic syndrome?

Answer 23

no

Question 24

What is the mechanism for nephrotic proteinuria?

Answer 24

The latticework of the epithelial slit diaphragm is comprised of a number of molecules that bridge between the podocyte foot- processes of adjacent cells. Principal among these is nephrin, which has homotypic protein-protein interactions that create the interdigitating “fingers” of the slit diaphragm (see Figure 4), along with other molecules. Importantly, these molecules are further anchored in the cell by intracellular molecules such as actin. Interaction with the actin cytoskeleton maintains the slit diaphragm and slit pore structural integrity.

In nephrotic syndrome, when the actin cytoskeleton is disrupted, this disrupts the anchorage of the slit- diaphragm molecules, changing their interaction and the structure of the slit pore. That event causes a sufficient increase in the slit pore size to increase the amount of albumin that transits the glomerular filter. As a secondary event, the loss of cytoskeletal integrity also leads to podocyte effacement, disrupting streaming potential. The resulting loss of charge selectivity serves as an amplifying or maintenance factor in albuminuria.

Question 25

Why would nephrotic patients with less albumin develop edema?

Answer 25

According to the balance of Starling forces at the capillary wall, the difference between hydrostatic and oncotic pressure at the beginning of the capillary permits perfusion of all cells, whereas a shift in that balance permits reabsorption of extravasated fluid at the end of the capillary. In this model, nephrotic patients have less albumin and therefore less impetus for the return of fluid to the vascular space. This sets up a vicious cycle in which fluid is lost, decreasing venous return to the heart. As a result, perfusion pressure drops and the kidney, responding appropriately to an abnormal stimulus, produces renin. ** this model has issues though - congenital hypoalbuminemia does not develop nephrotic syndrome

Question 26

WHy is hepatic synthesis of lipoprotein increased in nephrotic syndrome?

Answer 26

•Increased hepatic lipoprotein synthesis (probably related to viscosity) •Urinary loss of HDL and lecithin-cholesterol acyl transferase •Decreased lipoprotein lipase activity

Question 27

Do the lipid abnormalities in nephrotic syndrome respond to diet?

Answer 27

no - but yes to drugs

Question 28

What are some additional manifestations of nephrotic syndrome beyond the classic triad?

Answer 28

``` disordered hemostasis susceptibility to infection bone disease thyroid issues iron binding protein loss albumin changes in metabolism and buffering ```

Question 29

Why are nephrotic patients prone to developing clots?

Answer 29

* Hemoconcentration from fluid extravasation. •Increased production of certain clotting factors. * Urinary loss of anticoagulant proteins. Antithrombin III is often referred to in the literature, but the most likely implicated factor is loss of free protein S. * Because of fluid excretion, hemoconcentration and loss of natural anticoagulants in the urine, the radicles of the renal vein are a likely site for coagulation to cause renal veinthrombosis. •When the ambient albumin concentration is decreased, platelets become hyperaggregable.

Question 30

Why are nephrotic syndrome patients more susceptible to infection?

Answer 30

loss of other proteins involved in: •Immunoglobulin: in some cases this is sufficiently severe to make patients become extremely susceptible to common organisms. •Alternative complement pathway factors B and D are important opsonizing factors. Patients are particularly sensitive to infection with encapsulated organisms such as Pneumococcus. •Abdominal ascites is an excellent growth medium for bacteria. •Patients with minimal change disease may be poorly responsive to immunizations. This may be a primary manifestation of the disease causing nephrosis rather than a direct manifestation of proteinuria.

Question 31

What kind of infections are nephrotic syndrome patients more susceptible to?

Answer 31

encapsulated organisms.

Question 32

how does ascites cause infection?

Answer 32

it's a good medium for growing bacteria

Question 33

Why does osteopenia happen in nephrotic syndrome?

Answer 33

Patients with nephrotic syndrome lose Vitamin D-binding protein in their urine. In extreme (unremitting) cases they may have little 1,25-(OH)2 vitamin D3 and virtually no 25-OH-D3. Corticosteroids used to treat the disease may exacerbate osteopenia. Vitamin D supplementation is often indicated in chronically nephrotic patients.

Question 34

When is the loss of thyroid binding globulin significant in nephrotic syndrome?

Answer 34

in Finnish type congenital nephrotic syndrome

Question 35

What part of the filter is most commonly affected in nephrotic syndrome?

Answer 35

the podocytes

Question 36

Minimal change disease, FSGS, diffuse mesangial sclerosis, collapsing glomerulopathy, and congenital nephrotic syndrome (finnish type) are all pathologies of what part of the kidney?

Answer 36

the podocytes

Question 37

In uncomplicated nephrotic syndrome, is renal function impaired?

Answer 37

no! this is an "appropriate" response to abnormal physiological circumstances that cause urinary protein loss

Question 38

An extremely edematous child is seen in the emergency ward for relapse of known minimal change nephrotic syndrome. What are the benefits and problems in treating the edema with furosemide?

Answer 38

Benefits: -decreased fluid retention -may interrupt the “vicious cycle” of nephrotic sodium retention Problems: -may be poorly effective if renal perfusion is poor -dries out the vascular space, which may be “underfilled” -may exacerbate hemoconcentration, predisposing to thrombosis -wastes total body potassium stores

Question 39

The most critical determinant of whether or not a molecule of effective Stokes radius = 40 Å is filtered by the glomerulus is: a. Blood pressure b. Hydration status c. The endothelial glycocalyx d. The lamina densa of the glomerular basement membrane e. The epithelial slit pore

Answer 39

e - epithelial split pore

Question 40

A patient is admitted with facial and abdominal swelling. She has gained 5 kg in the past week and her urine shows 300 mg/dl albumin. Her serum albumin is 1.9 gm/dl. What steps should you take to evaluate her condition?

Answer 40

- Check blood pressure - Full clinical history and physical exam for evidence of systemic illnesses - Evaluate urine for presence of blood, a possible indicator of underlying nephritis -Measure serum creatinine to evaluate kidney function. - Measure serum complements and anti-nuclear antibody to rule out inflammatory causes -Obtain daily weight and follow intake and output to monitor fluid balance - Consider vascular volume depletion in evaluating potential pharmacological diuresis

Question 41

A patient is admitted with facial and abdominal swelling. She has gained 5 kg in the past week and her urine shows 300 mg/dl albumin. Her serum albumin is 1.9 gm/dl. What potential complications might you anticipate as you treat the patient ?

Answer 41

- Renal vein thrombosis -Excessive dehydration and shock -Infectious complications - Bone tissue loss

Question 42

Name four drugs or minerals that are bound to albumin and therefore are affected in nephrosis.

Answer 42

``` Drugs: -digoxin -barbiturates -some diuretics Minerals: -iron -calcium -zinc ```