Nephrotic and Nephritic syndrome Flashcards Preview

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Flashcards in Nephrotic and Nephritic syndrome Deck (49):
1

What are the renal limited diseases that result in glomerulonephritis?

• IgA nephropathy
• Anti-GBM disease (the kidney version of Goodpasteur's)
• MPGN, membranoproliferative glomerulonephritis
• Renal limited vasculits (ANCA associated)
• Hemolytic-uremic syndrome
• C3 glomerulopathy/Dense deposit disease

2

What are the systemic diseases that can result in glomerulonephritis?

• Henoch-Schonlein purpura
• Goodpasture's syndrome
• Lupus nephritis
• ANCA associated vasculitis
• Infection assoiated
• Post-infectious
• Endocarditis/shunt nephritis
• Cryoglobulinemia
• Immunoglobulin deposition diseases

3

How should the approach to a patient with possible glomerular disease begin?





• Assessment of the protein excretion in the urine
• Microscopic analysis of the urine for dysmorphic RBCs and/or RBC casts
• Biopsy can confirm suspicions

4

What are the primary characteristics of nephritic syndrome?

• Reduction in GFR (elevated serum creatinine)
• Active urine sediment (RBCs, WBCs and RBC casts)
• Proteinuria (usually sub-nephrotic)
• Edema
• hypertension

5

What is the clinical presentation of nephritic syndrome?

• Mild proteinuria, mild hematuria are possible
• More common = hematuria, dysmorphic RBC or RBC casts, proteinuria (though not the nephrotic range???)
• Proteinuria can range 200mg to 10gm a day
• Accompanied by HYPERTENSION AND EDEMA

6

What are the three primary systemic diseases that cause secondary nephrotic syndrome?

• Diabetes
○ Most common cause of nephrotic syndrome in adults
○ Usually present with nephrotic proteinuria, commonly microhematuria
○ Biopsy shows nodular glomerulosclerosis with mesangial expansion and thickening of GBM
○ Treatment is better glucose control, BP control and ACEI
• SLE
○ More often presents with nephritic presentation, but can cause nephrotic syndrome through a membranous histologic pattern. Treated with prednisone and mycophenolate
• Amyloidosis
○ Need free plasma light chains, serum and urine protein electrophoresis and renal biopsy

7

What is MPGN?



• MPGN = membranoproliferative glomerulonephritis
• Histologic pattern where there is both proliferation (mesangial proliferation in a lobar pattern) AND thickening of GBM
• Separated into type I and II
• Type I = immune complex deposits
• Type 2 = complement activation in capillary wall but no immune deposits
• Most often associated with Hepatitic C infection or some other chronic systemic infection

8

What is the clinical presentation and treatment of MPGN?

• A decent proportion of MPGN present with acute nephritis
• Hypertension is common early on in this disease
• HCV infection is common
• Associated with cryoglobulins, rheumatoid factor and low C3 and C4 compliment levels
• Can be associated with C3Nef or nephritic factor, which activates compliment in circulation
• Treatment = anti-HCV therapies, immunosuppression in acute nephritis presentation, treat underlying chronic infection, ecluzimab (targets compliment)

9

What makes a pathologist think MPGN?

• MPGN = membranoproliferative glomerulonephritis
• Light microscope = type I shows thickening of GBM, mesangial cell proliferation and a lobulated appearance of the glomerulus. C3 deposits prominent on capillary walls and in the mesangium. IgG deposits also seen
• EM = type I shows subendothelial and mesangial deposits (immune complexes)
• Type II looks similar but differs by IF because only C3 but no IgG and differs by EM by showing dense deposits of unknown etiology

10

What is membranous nephropathy?


• Immune mediated glomerular disease associated with immune complex deposits in the subepithelial space (between podocyte and GBM)
• Called membranous because of thick GBM on light microscopy
• Most common cause for idiopathic nephrotic syndrome in older (like above 40s) adults

11

What is the clinical presentation and treatment of membranous nephropathy?

• Nephrotic syndrome and edema
• Hypertension and renal failure are uncommon at presentation, but they do develop
• Compliment levels normal
• Need to look for underlying cancer of breast, lung, GI tract
• Treatment = steroids and cytotoxic drugs (cyclophosphamide), ACEI to lower proteinuria

12

What causes membranous nephropathy?

• Autoimmune and mediated by an antibody directed against an antigen on the podocyte
• Often M-type phospholipase A2 or PLA2 receptor
• Antibody binding initates compliment fixation and direct podocyte damage
• Complexes are then capped and shed to subepithelial space
* In about 85% of cases, membranous nephropathy is caused by autoantibodies that cross-react with antigens expressed by podocytes.
*In the remainder 15%(secondary membranous nephropathy), it occurs secondary to other disorders, including infections, tumors, SLE, inorganic salts, NSAIDs

13

What does a pathologist look for in dx of membranous nephropathy?

• Varies according to GBM thickening seen by light microscopy
• Cellularity is normal
• Silver dyes reveal spikes along basement membrane (new material between immune complexes)
• Must see on the subepithelial side of the basement membrane
• IF = granular depostis of immunoglobulin and C3 along GBM, typical of immune complex disease
• EM = electron dense subepithelial deposits

14

What is the genetic factor that is important to associate with FSGS?



• APOL-1
• Apolipoprotein
• Especially with HIV infection
* maybe hypoxic too (like in sickle cell)

15

How do FSGS patients present and how are they treated?

• Present with idopathic nephrotic syndrome
• May be hypertensive or have microhematuria (not like minimal change)
• Treatment = ACEI treatment to reduce protein loss and have some other effects on glomerular wall
• Prolonged corticosteroid therapy (6 months) can result in remission
• If untreated, can progress to renal failure and need transplantation

16

In whom would you more likely consider FSGS?

• Young, 20-40 year old African Americans
• Can be HIV associated and can be heroin associated
• Most cases are idiopathic though

17

What is seen by a pathologist that makes him say "that's FSGS"?

• Light microscopy = segmental scarring (sclerosis) in some glomeruli but not all
• IF = normal with some non-specific staining of IgM and C3 in sclerotic areas
• EM = diffuse podocyte fusion consistent with capillary wall defect

18

What is FSGS?

• FSGS = focal segmental glomerulosclerosis
• Type of nephrotic syndrome especially common in young adults and in african americans
• Light microscopy = normal glomeruli with mixed scarred/fibrotic glomeruli
• Non-scarred glomeruli are the ones that show increased permeability to proteins

19

What is minimal change disease?


• Most Common cause of idiopathic nephrotic syndrome IN CHILDREN, and is named because glomeruli appear normal by light microscopy
• Common cause in adults
• IF = No immunoglobulin or complement
• EM = only foot process fusion of podocytes, reflects podocyte injury only

20

What is the clinical presentation of Minimal Change Disease?

• Edema and weight gain most commenly
• Renal function is normal and hypertension absent
• Massive proteinuria possible 3-20 gm/day
• Often co-presents with upper viral RTI
• Normal compliment levels, but hypoabluminemia
• Can be associated with Hodgkin's disease
• Treated with steroid therapy (prednisone, cyclophosphamide)

21

What are the three most common protein mutations that can cuase hereditary glomerular disease?

• Nephrin (NPHS1)
• Podocin (NPHS2)
• WT-1, or wilms tumor antigen
• Represents a steroid-resistant nephrotic syndrome, and can be quite early in life
• Treated with reducing proteinuria by way of ACE inhibitors, eventually kidney transplant

22

What are the renal only diseases that can cause nephritis?



• Post infectious (post-strep and thus type III immunopathology)
• IgA nephropathy
• Rapidly Progressive Glomerular nephropathy (RPGN)
○ Anti-GBM nephritis, idiopathic RPGN

23

What are the four histologic patterns of idiopathic nephrotic syndrome?

• Minimal change disease
• Idiopathic focal and segmental glomerulosclerosis (FSGS)
• Membranous nephropathy (MN)
• Membranoproliferative glomerulonephritis (MPGN)

24

What are the systemic diseases that can cause nephritis?

• ANCA-associated vasculitis
• Microscopic polyangiitis (MPA) and granulomatous polyangiitis (GPA)
• Henoch-Schonlein Purpura
• HCV-associated cryoglobulinemia
• Systemic Lupus erythematosus

25

What is the difference in the presentation of nephrotic vs. nephritic syndromes?




• Nephrotic = 5 signs of proteinuria (over 3gm/day), hypoalbuminemia, hyperlipidemia, pitting edema and lipiduria
• Nephritic = less protein in urine, can even be normal levels, microhematuria, leukocyturia, red cell casts sometimes, decreased GFR, hypertension and edema

26

What are the systemic diseases that can cause nephrotic syndrome?

• Diabetes
• Amyloid
• Light chain deposition disease
• SLE membranous type

27

What are the renal only diseases that can cause nephrotic syndrome?

• Hereditary Nephrotic syndromes
• Minimal change disease
• Focal glomerular Sclerosis
• Membranous Nephropathy
• Membranoproliferative Glomerular nephropathy (MPGN)

28

In nephrotic syndrome, what almost always causes the proteinuria manifestation of the disease?




• Problems in the slit diaphragm between podocytes. That's either by direct mutation in proteins or through damage from inflammation,toxins or antibodies

29

What are common complications of nephrotic syndrome?

• Increased risk for infections (loss of IgG and compliment factor B, especially risky for pneumococcus infectious pneumonia)
• Increased risk for thrombosis (liver is overproducing clotting factors, kidney's lose antithrombin III)
• Poor growth in children and osteomalacia (loss of vitamin D)
• Protein malnutrition

30

If you see a "maltese cross" under polarized light in microscopic urinalysis, what must you think?

• Lipiduria, both as a result of slit diaphragm damage and glomerular over-permeability but also because of the hyperlipidemia due to liver production

31

What's up with the hyperlipidemia in nephrotic syndrome?

• Increased lipoprotein synthesis (VLDL, LDL) in the liver and decreased peripheral removal of VLDL
• Decrease in plasma protein seems to be the stimulus for increasing liver production of protein
• Can severely increase risk for CAD if hypertension and low HDL is present

32

Why does nephrotic syndrome result in edema?

• Classic mechanism = loss of oncotic pressure in capillaries thus fluid does not come back into the blood from the interstitium
○ Results in depletion of intravascular volume and RAAS activation, salt and water retention (children primarily)
• Adults don't show volume depletion, but through eNAC, a sodium channel in the collecting duct, actually increase their hydrostatic pressures

33

Is there such a thing as "normal" protein filtration?





• Yes, proteins do make it into bowman's space in a "regular" manner
• 500mg of albumin, most of it reabsorbed by the proximal tubule where it is degraded
• Normal EXCRETION of albumin is 20mg/day
• Secreted proteins = tamm-horsfall protein and IgA

34

What are the objective qualifications of nephrotic syndrome?

• Proteinuria (more than 3 grams per day or more than 40mg/hr/M2 in children)
• Hypoalbuminemia (less than 3gm/dL)
• Edema
• Hyperlipidemia
• lipiduria

35

What is nephritic syndrome?

• Active inflammation within the glomerulus leads to damage to the glomerulus with subsequent loss of filtration and a reduction in GFR

36

What is nephrotic syndrome?

• Protein loss from glomerular permeability problems to the point that serum albumin goes down
• Principally shows up as edema and hypalbuminemia
• The major glomerular abnormality is an excessive leak of protein through the glomerular capillary wall into the urinary space

37

When can proteinuria be detected by dip stick?

• Over 300mg/day albumin excretion results in a positive dipstick (range = 0-4+)
• 300mg-2g per day can be either glomerular or tubular disease
• Albuminuria over 3 grams a day is only in glomerular permeability defects
• At this point the loss can cause nephrotic syndrome

38

What is considered abnormal protein excretion?

• Greater then 30mg/day is abnormal albumin excretion
• Range of 30-300mg/day is MICROalbuminuria, not detectable by routine urinalyses
• Persistent microalbuminuria is strongly suggestive of early glomerular damage. You look for this is diabetic patients, predicts diabetic nephropathy

39

What are the two barriers to protein filtration in the Glomerular basement membrane?

• There is both a size cut-off of about 100kDa (or 60?) and a charge barrier (opposes negative charge)
• Heparan sulfates in the basement membrane confer the charge barrier

40

Where is the glomerular mesangial cell and what does it do?


• It is centrally located and it secretes part of the basement membrane matrix for structural support
• Aslo has smooth muscle properties and contracts, affecting capillary surface area and filtration
• Some macrophage-like proterties like secreting cytokines, growth factos, proteases and oxidants

41

What is considered the most important part of the filtration barrier in the glomerulus?

• The slit-diaphragms between podocyte processes

42

What type of collagen makes up the glomerular basement membrane?

• Mainly type IV collagen
• Also contains laminin, entacting, heparan sulfate
○ Structure, negative charge, gel matrix

43

What is the glomerular capillary permeable to?



• Salt, water, metabolic waste products like creatinine and urea

44

What makes up the glomerular filtration barrier?

• Endothelial cell layer, glomerular basement membrane, glomerular epithelial cells (podocytes and slit diaphragms)

45

Type II MPGN is better known as what?

By contrast, in the aptly named dense deposit disease (formerly MPGN II) the lamina densa and the subendothelial space of the GBM are transformed into an irregular, ribbon-like, extremely electron-dense structure, resulting from the deposition of material of unknown composition. C3 is present in irregular chunky and segmental linear foci in the basement membranes and in the mesangium. IgG and the early components of the classical complement pathway (C1q and C4) are usually absent.

46

What's the Robbins definition of nephritic syndrome?

The nephritic syndrome is a clinical complex, usually of acute onset, characterized by (1) hematuria with dysmorphic red cells and red cell casts in the urine; (2) some degree of oliguria and azotemia; and (3) hypertension.
*Although proteinuria and even edema also may be present, these usually are not as severe as in the nephrotic syndrome. The lesions that cause the nephritic syndrome have in common proliferation of the cells within the glomeruli, often accompanied by an inflammatory leukocytic infiltrate. This inflammatory reaction severely injures the capillary walls, permitting blood to pass into the urine and inducing hemodynamic changes that lead to a reduction in the GFR. The reduced GFR is manifested clinically by oliguria, fluid retention, and azotemia. Hypertension probably is a result of both the fluid retention and some augmented renin release from the ischemic kidneys.

47

What's up with IgA nephropathy and is it common?

Yes, it's the most common cause of nephritic syndrome world-wide. Be not confused by the "opathy" part of it. it causes nephritic syndrome
• IgA nephropathy, characterized by mesangial deposits of IgA-containing immune complexes, is the most common cause of the nephritic syndrome worldwide; it is also a common cause of recurrent hematuria; it commonly affects children and young adults and has a variable course.

48

What is the clinical course of RPGN?

*RPGN = rapidly progressive glomerulonephritis

*The onset of RPGN is much like that of the nephritic syndrome, except that the oliguria and azotemia are more pronounced. Proteinuria sometimes approaching nephrotic range may occur. Some affected persons become anuric and require long-term dialysis or transplantation.
*The prognosis can be roughly related to the fraction of involved glomeruli: Patients in whom crescents are present in less than 80% of the glomeruli have a better prognosis than those in whom the percentages of crescents are higher.
*Plasma exchange is of benefit in those with anti-GBM antibody GN and Goodpasture disease, as well as in some patients with ANCA-related pauci-immune crescentic GN.

49

Wagener's granulomatosis may result in what kind of kidney damage?

RPGN. ANCA-related pauci-immune crescentic glomerulonephritis