Renal Nephrotic Diseases 1

Front 1

Describe nephrotic syndrome

Back 1

-Glomerular disease associated with heavy albuminuria (>3-3.5 g/day)
-You have:
-Hypoalbuminemia
-Edema
-Hyperlipidemia
-Thrombotic tendency

Front 2

Describe the genesis of hypoalbuminemia

Back 2

-Glomeular disease leads to proteinuria
-Much of the albumin that gets filtered gets past the glomerular capillary wall and can be reabsorbed by the proximal tubule
-The proximal tubule can reabsorb some of it and catabolize it
-The rest comes out in urine
-The catabolism and the proteinuria lead to hypoalbuminemia

Front 3

Describe the edema of the nephrotic patient

Back 3

-Periorbital edema in the morning
-Leg and pedal edema at the end of the day

Front 4

Describe the first theory of pathogenesis of nephrotic edema

Back 4

-Hypoalbuminemia
-Low plasma oncotic pressure
-Increased capillary filtration
-Decreased plasma volume
-Secondary renal Na rention
-Na and water retention
-High hydrostatic pressure

Front 5

Describe the second theory of pathogenesis of nephrotic edema

Back 5

-Glomerular disease
-Proteinuria
-Causes hypoalbuminemia and primary renal sodium retention
-Increases plasma volume
-Increases capillary filtration
-Leads to edema

Front 6

Describe the therapy of edema in nephrotic syndrome

Back 6

-Put the patient on a low Na+ diet
-Use oral loop diuretics
-Start with low dose - double doses
-Add zaroxolyn
-+/- high BID doses
-IV diuretics and colloid rarely needed
-Goal is 1-2 lbs edema loss/day
-Fluid comes from intravascular space
-If you remove too fast the patient goes into shock

Front 7

Describe lipiduria

Back 7

-Manifestation of nephrotic syndrome
-Cholesterol and cholesterol esters and other lipoportiens enter urine
-Oval fat bodies/Maltese crosses in urine

Front 8

Describe cholesterol levels in patients with nephrotic syndrome

Back 8

High
-87% have >200 mg/dl
-53% have >300 mg/dl
-25% have >400 mg/dl
-LDL is high as well

Front 9

What are the most common causes of nephrotic syndrome?

Back 9

-Idiopathic
-Membranous nephropathy (most common in white americans)
-Focal sclerosis (most common in black americans)

Front 10

Describe treatment of hyperlipidemia of the nephrotic syndrome

Back 10

-Select high risk patient (high LDL, low HDL, unlikely to rapidly remit)
-Attempt to induce a remission of the proteinuria (ACEi/ARBs, specific immunosuppressives, etc)
-Dietary therapy
-Medical therapy (statins +)

Front 11

Describe treatment principles of nephrotic syndrome

Back 11

-Treatment of primary disease - often immune modulating medications
-Syptomatic treatment - diuretics, statins, diet, in some anticoagulation
-Reduction of proteinuria/slowing progression
-Makes it easier to treat the edema, hyperlipidemia, etc

Front 12

What are the goals of treating nephrotic patient?

Back 12

1) Decrease the proteinuria, correct the edmea, hyperlipidemia
2) Try to prevent eventual scarring of the glomerular filters

Front 13

Describe how to reduce proteinuria and slow progression

Back 13

-Blood pressure reduction
-Inhibition of the renin-angiotensin-aldosterone axis

Front 14

What is the relationship between blood pressure and the decline in GFR?

Back 14

The lower the BP the slower the loss of kidney function

Front 15

Which BP medications are better for the kidney?

Back 15

-Diuretics, ACEi, AII receptor blockers are the treatment of choice in anyone with proteinuria
-These lower proteinuria
-The ACE inhibitor lowers proteinuria because you opened up the efferent arteriole coming out of the glomerulus, resulting in less pressure in the glomerular capillaries, less proteinuria and less glomerular scarring over time.

Front 16

What is the most common cause of nephrotic syndrome in young children?

Back 16

Minimal change disease

Front 17

Describe Minimal Change Disease

Back 17

-Also called Lipoid nephrosis
-Proximal tubules become stuffed with reabsorbed lipid
-Patients lose protein and become hypoalbuminemic
-Liver starts synthesis of proteins and cholesterol
-Kidney filters lipid and the tubules reabsorb it and get stuffed

Front 18

What are the synonyms of Minimal change disease?

Back 18

-Nil disease
-Lipoid nephrosis
-Childhood nephrosis

Front 19

Back 19

-Nephrotic disease
-Left: Periorbital edema
-Right: Leg and pedal edema

Front 20

Back 20

-Child with periorbital, leg, and pedal edema indicating nephrotic disease
-Likely minimal change disease

Front 21

Back 21

-Minimal change disease
-Kidney looks as if it is filled iwth lipid
-Yellow instead of brown

Front 22

Back 22

-Minimal change disease
-Proximal tubules are stuffed with reabsorbed lipid
-Liver has ramped up production of cholesterol and the kidney is filling up trying to reabsorb it

Front 23

Back 23

-Urine sediment for a patient with minimal change disease
-Oval fat bodies present

Front 24

Back 24

-Glomeruli in minimal change disease
-No obvious abnormalities

Front 25

Back 25

-Immunofluorescence in minimal change disease
-No immune deposits

Front 26

Back 26

-EM of minimal change disease
-Podocyte foot processes have been effaced

Front 27

Back 27

-EM of minimal change disease
-Podocyte foot processes have been effaced
-Podocyte has filled with transport vesicles

Front 28

Describe the evidence for immunologic derangements in Nil Disease

Back 28

-Viral infections may precede onset or recrudescences
-May follow recent immunizations
-Altered in vitro response to mitogens
-Circulating lymphocytotoxins
-Association of Hodgkin's Disease and other lymphoproliferative disease
-There may be a circulating factor produced by the lymphocyte that is acting at a distance to cause some injury to the podocyte.

Front 29

Describe Minimal Change Disease

Back 29

-5-10% of adults with idiopathic nephrotic syndrome, >85% of children
-Usually sudden onset, heavy proteinuria, and edema
-High BP 30%, Microhematuria 30%, +/- low GFR
-Course: Responds to steroids, relapse, no renal failure as long as you get rid of the proteinuria

Front 30

What is the most common cause of nephrotic syndrome?

Back 30

Diabetes

Front 31

Describe the pathology of Minimal change disease

Back 31

-Normal under light microscopy
-Immunofluorescence negative
-EM shows fused podocyte feet

Front 32

Back 32

-Focal segment glomerulosclerosis
-Involves some glomeruli and not others
-Affects glomeruli segmentally

Front 33

Back 33

-Focal segmental glomerulosclerosis
-Increase laying down of ECM segmentally
-Neighboring capillaries look normal, but have effaced foot processes

Front 34

Back 34

-Focal segmental glomerulosclerosis
-Areas of scarring have entrapment of hyaline (red staining)
-There are plasma proteins such in areas of sclerosis

Front 35

Describe the laying down of new basement membrane in focal segmental glomerulosclerosis

Back 35

-This shows the segmental nature of the laying down of this basement membrane material which obliterates the glomerular capillaries.
-Over time more and more of the tuft is replaced by this matrix material until the sclerosis goes from segmental to global.

Front 36

Back 36

-Immunofluorescence panel for focal segmental glomerulosclerosis
-IgM present
-Large MW cause in areas of sclerosis (byproduct of sclerosis)
-IgM not pathogenic, but helps identify disease

Front 37

Back 37

-EM of Focal segmental glomerulosclerosis
-Podocytes have fused foot processes (more severe than minimal change disease)
-Produces non-selective proteinuria
-Podocyte has lifted off the sclerosing glomerular basement membrane

Front 38

Describe the progression of focal segmental glomerulosclerosis

Back 38

-Over time disease progresses to end stage renal failure
-Along the way segmentally sclerotic glomeruli become globally sclerotic
-Entire tuft replaced by matrix material (collagen IV)
-There is dependent atrophy for the more distal portions of the nephron because glomeruli sclerose and cant pass filtrate

Front 39

Back 39

-Focal segmental glomerulosclerosis
-End stage, more global

Front 40

Back 40

-Focal segmental glomerulosclerosis
-From a patient with a single kidney

Front 41

Describe the cause of primary focal segmental glomerulosclerosis

Back 41

Circulating factors

Front 42

Secondary FSGS can be due to adaptive responses of what?

Back 42

-Reflux nephropath: urine reflux to kidney can cause repeated injury
-Renal agenesis (solitary functioning kidney)
-Any chronic renal disease: Once you have lost a certain number of nephrons you get progressive hyperfiltration in the remnant nephrons driving increased segmental and global sclerosis in the remaining filtering nephrons.
-Obesity

Front 43

How does obesity lead to focal segmental glomerulosclerosis?

Back 43

In obesity the glomerulus becomes stressed. The kidney has an increased need in filtration to service this whole body and the strain on the glomerulus leads to adaptive responses that over the long term become maladaptive, leading to sclerosis.

Front 44

Describe the mechanism of how obesity or a solitary kidney leads to focal segmental glomerulosclerosis

Back 44

-Decrease in resistant of both afferent (more) and efferent (less) arteriole leading to increased capillary flow
-Elevated glomerular hydrostatic pressures develop
-Leads to glomerular hypertension
-Tension on capillary wall increases radius
-Large hypertrophies glomeruli leads to microaneurysmal dilations
-Podocytes stretch, become detached, and then are lost
-Over time there is progression to segmental sclerosis

Front 45

Back 45

-HIV associated nephropathy
-Severe form of focal segmental glomerulosclerosis
-Has a collapsing pattern of focal sclerosis where the whole tuft retracts and the podocytes undergo a peculiar hypertrophy and hyperplasia
-Very progressive form
-Renal failure in weeks if no antiretrovirals

Front 46

Back 46

-Focal segmental glomerulosclerosis
-There is dilation of many of the tubules which increases the total kidney volume

Front 47

Back 47

-EM of Focal segmental glomerulosclerosis
-There are tubuloreticular inclusions
-There are inclusions in the endothelial cells of the glomerular capillary
-These are induced by interferon
-Seen in many viral infections

Front 48

Describe the pathogenic factors (known and hypothetical) in FSGS

Back 48

-Hemodynamic: Glomerular Hyperfiltration
-Genetic: Glomerular Hyperfiltration
-Immunological: Permeability factors
-Toxic
-Viral: HIV

Front 49

Describe focal segmental glomerulosclerosis

Back 49

-Increased frequency >20% nephrotic syndrome
-Especially in blacks
-In adults onset 2/3 NS, 1/3 proteinuria
-HBP>30%, Microhematuria>30%, Renal dysfunction 50%
-Predictors of ESRD: heavy proteinuria, blacks, high creatinine
-On biopsy there is intimal fibrosis and collapse
-Steroids >50% respond, cytoxan, cyA, MMF
-Recurs 1/3 post-transplant
-There is some circulating factor which is causing the permeability of those glomerular basement membranes and capillary loops to change so they are leaking albumin into the urine.