Gu: Glomerular Diseases

Front 1

Most common cause of nephrotic syndrome in children

Back 1

MCD minimal change disease

Front 2

Minimal change disease causes a ___ proteinuria

Back 2

selective (primarily albumin)

Front 3

MCD: light microscopy, IF, and EM

Back 3

LM: glomeruli, tubules and itnerstitium appear normal

IF: usually neg

EM: diffuse effacement of podocyte (epithelial cell) foot processes

Front 4

Focal segmental glomerulosclerosis can be ___or ___ and causes a ___ syndrome

Back 4

- primary (idiopathic) or secondary (many eitologies)
-nephrotic syn

Front 5

A major cause of nephrotic syndrome in adults is ___

Back 5

Membranous glomerulonephritis (MGN)(Membranous nephropathy)

Front 6

Membranous glomerulonephritis can be secondary to a number of disorders or exposure to antigenic substances

Back 6

- SLE (common)
- malignancy
- gold or mercury
- penicillamine, captopril, NSAIDs
- Hep B

Thought to be a chronic Ag-Ab mediated disease
- Ag deposited in subepithelial space of the glomerular capillary loops

Front 7

MGN: LM, IF, EM

Back 7

LM: early may appear normal (mimic minimal change disease)
- silver stain: thickened capillary walls with subepithelial spikes

IF: + granular IgG and C3

EM: subepithelial electron dense deposits with intervening basement membrane spikes

Front 8

Systemic diseases with glomerular involvement include:

Back 8

Systemic Diseases with Glomerular Involvement:

- Systemic lupus erythematosus
- Diabetes mellitus
- Amyloidosis
- Goodpasture syndrome
- Microscopic polyarteritis/polyangiitis
- Wegener granulomatosis
- Henoch-Schönlein purpura
- Bacterial endocarditis

Front 9

Hereditary disorders with glomerular involvement include:

Back 9

Hereditary Disorders:
- Alport syndrome
- Thin basement membrane disease
- Fabry disease

Front 10

Primary glomerulopathies inlcude:

Back 10

Primary Glomerulopathies:
- Acute diffuse proliferative glomerulonephritis
--Poststreptococcal
--Non-poststreptococcal
- Rapidly progressive (crescentic) glomerulonephritis
- Membranous glomerulopathy
- Minimal change disease
- Focal segmental glomerulosclerosis
- Membranoproliferative glomerulonephritis
- IgA nephropathy
- Chronic glomerulonephritis

Front 11

Because glomerular diseases are often associated with systemic disorders, mainly diabetes mellitus, SLE, vasculitis, and amyloidosis, in any patient with manifestations of glomerular disease, it is essential to ___

Back 11

it is essential to consider these systemic syndromes.

Front 12

The clinical manifestations of glomerular disease are clustered into the five major glomerular syndromes

Back 12

Acute nephritic syndrome:
- Hematuria, azotemia, variable proteinuria, oliguria, edema, and hypertension

Rapidly progressive glomerulonephritis:
- Acute nephritis, proteinuria, and acute renal failure

Nephrotic syndrome:
- >3.5 gm proteinuria, hypoalbuminemia, hyperlipidemia, lipiduria

Chronic renal failure:
- Azotemia: uremia progressing for years

Asymptomatic hematuria or proteinuria:
- Glomerular hematuria; subnephrotic proteinuria

Front 13

Glomerular hypercellularity can be due to:

Back 13

- mesangial or endothelial cell proliferation
- leukocyte inflitration
- crescent formation

Front 14

Glomerular crescents are formed by __

Back 14

- accumulation of parietal epithelial cells and leukocytes
- Fibrin, released into the urinary space by basement membrane injury, is believed to be a major stimulus for crescent formation

Front 15

Glomerular basement membrane thickening is best seen with a ___stain; EM allows __

Back 15

PAS

EM: can determine if thickening is due to deposits on the epithelial side of the BM or within the BM itself or thickening of the BM proper, as in diabetic glomerulosclerosis

Front 16

Anti-GBM antibody-induced nephritis

Back 16

- Ab to BM antigen (NC1 domain of collagen type IV antigen)
IF: linear +, characteristic of anti-GBM Ab deposition (contrast with granular pattern seen with immune complex deposition, circulating or in situ)
(Ab to planted Ag also give a granular pattern)

Front 17

Circulating immune complex nephritis can be due to endogenous and exogenous antigens

Back 17

endogenous:
- SLE

exogenous:
- bacterial (strep, Treponema pallidum)
- viral: HBsAg, HCV Ag,
- parasites: Plasmodium falciparum

Front 18

Circulating immune complex glomerular injury

Back 18

- glomerular lesions usually consist of leukocytic infiltration in glomeruli and proliferation of mesangial and endothelial cells.
- EM: reveals the immune complexes as electron-dense deposits that lie in the mesangium, subendothelial deposits, or subepithelial deposits
- Deposits may be located at more than one site in a given case.
- IF: immune complexes are seen as granular deposits along the basement membrane, in the mesangium, or in both

- immune complexes may eventually be degraded and the inflammatory reaction may then subside (such a course occurs when the exposure to the inciting antigen is short-lived and limited, as in most cases of poststreptococcal glomerulonephritis)
- if a continuous shower of antigens is provided (SLE or viral hepatitis) repeated cycles of immune complex formation, deposition, and injury may occur, leading to a more chronic membranous or membranoproliferative type of glomerulonephritis.

Front 19

A membranous pattern of glomerulonephritis suggests ____ deposition

A membranoproliferative pattern is more indicative of ______

Back 19

- in situ deposition
- circulating complexes

Front 20

Once any renal disease, glomerular or otherwise, destroys functioning nephrons and reduces the GFR to about _____ of normal, progression to end-stage renal failure proceeds at a relatively constant rate, independent of the original stimulus or activity of the underlying disease.

Back 20

30-50%

Front 21

Two major histologic features of progressive renal damage are __ and __

Back 21

- focal segmental glomerulosclerosis (FSGS)
- tubulointersitial fibrosis

Front 22

FSGS is a secondary change that results from adaptive changes in unaffected glomeruli of diseased kidneys

Back 22

- compensatory glomerular hypertrophy is associated with hemodynamic changes, including increases in glomerular blood flow, filtration, and transcapillary pressure (capillary hypertension), and often with systemic hypertension

- leads to endothelial and epithelial cell injury, increased glomerular permeability to proteins, and accumulation of proteins in the mesangial matrix
- followed by proliferation of mesangial cells, infiltration by macrophages, increased accumulation of extracellular matrix, and segmental and eventually global sclerosis of glomeruli

- the further loss of glomeruli leads to a viscous cycle of further glomerular injury and loss

Front 23

tubulointerstitial fibrosis is believed to be a result of __

Back 23

- proteinuria-induced activation of and direct injury to tubular cells
- tubular cells relased pro-inflammatory mediators that stimulate interstitial fibrosis and activation of mononuclear cells

Front 24

Poststreptococcal glomerulonephritis

Back 24

- Acute nephritis
- Antibody mediated (circulating or planted antigen)
- LM: diffuse proliferation; leukocytic infiltration
- IF: granular IgG and C3 in GBM and mesangium
- EM: Subepithelial humps

Front 25

Goodpasture syndrome

Back 25

- rapidly progressive (crescentic) glomerulonephritis
- Anti-GBM COL4-A3 antigen
- LM: proliferation; crescents
- IF: linear IgG and C3; fibrin in crescents
- EM: NO deposits; GBM disruptions; fibrin

Front 26

Membranous glomerulopathy

Back 26

- Nephrotic syndrome
- In situ antibody-mediated; antigen unknown
- LM: diffuse capillary wall thickening (silver stain)
- IF: Granular IgG and C3; diffuse
- EM: subepithelial deposits

Front 27

Minimal change disease

Back 27

- Nephrotic syndrome
- Pathogenesis Unknown, loss of glomerular polyanion; podocyte injury
- LM: Normal; lipid in tubules
- IF: Negative
- EM: Loss of foot processes; no deposits

Front 28

Focal segmental glomerulosclerosis

Back 28

- Nephrotic syndrome; non-nephrotic proteinuria
- pathogenesis unknown,
- LM: focal and segmental sclerosis and hyalinosis
- IF: focal IgM and C3
- EM: loss of foot processes; epithelial denudation

Front 29

Membranoproliferative glomerulonephritis, type I

Back 29

- Nephrotic syndrome
- pathogenesis: immune complex
- LM: Mesangial proliferation; basement membrane thickening; splitting
- IF: IgG + C3; C1q + C4
- EM: subendothelial deposits

Front 30

MPGN type II (dense deposit disease)

Back 30

- Hematuria; chronic renal failure
- pathogenesis: autoantibody
- LM:
- IF: alternative complement pathway C3 ± IgG; no C1q or C4
- EM: dense deposits

Front 31

IgA nephropathy

Back 31

- Recurrent hematuria or proteinuria
- pathogenesis unknown
- LM: mesangial widening
- IF: IgA +/- IgG, IgM, and C3 in mesangium
- EM: mesangial and paramesangial dense deposits

Front 32

Patient with acute nephritis presents with ___

Back 32

- hematuria
- red cell casts in the urine
- azotemia
- oliguria
- mild to moderate hypertension

- The patient also commonly has proteinuria and edema, but these are not as severe as those encountered in the nephrotic syndrome

Front 33

Poststreptococcal Glomerulonephritis

Back 33

- 1-4 weeks after streptococcal pharyngitis or skin infection (impetigo)
- mostly in children (6-10 yo), but adults too

Front 34

only certain __ of group A beta-hemolytic streptococci cause poststreptococcal glomerulonephritis

Back 34

- nephritogenic strains
- 90% due to types 12, 4, and 1
- typing by M protein in cell wall

Front 35

poststreptococcal GN is due to ___

Back 35

- immune complex deposition (exogenous antigen)
- the latent period between infection and onset of nephritis is compatible with the time required for the production of antibodies and the formation of immune complexes
- IF: granular immune deposits

Front 36

Histologic features seen in poststreptococcal GN

Back 36

Classic diagnostic picture:
- enlarged, hypercellular glomeruli; diffuse and global

Hypercellularity is caused by:
(1) infiltration by leukocytes, both neutrophils and monocytes
(2) proliferation of endothelial and mesangial cells
(3) in severe cases by crescent formation

- combination of proliferation, endothelial cell swelling, and leukocyte infiltration obliterates the capillary lumens
- may be interstitial edema and inflammation
- tubules often contain red cell casts

Front 37

characteristic EM features seen in poststreptococcal GN

Back 37

- discrete, amorphous, electrondense deposits on the epithelial side of the membrane (often having the appearance of "humps")
-- presumably representing the antigen-antibody complexes at the epithelial cell surface.

Front 38

Clinical course of poststreptococcal GN; adults and children

Back 38

In the classic case:
- a young child abruptly develops malaise, fever, nausea, oliguria, and hematuria (smoky or cocoa-colored urine) 1 to 2 weeks after recovery from a sore throat
-- red cell casts in the urine
-- mild proteinuria (usually less than 1 mg/day)
-- periorbital edema
-- mild to moderate HTN

In adults, the onset is more likely to be atypical:
- sudden appearance of HTN or edema, frequently with elevation of BUN

During epidemics caused by nephritogenic streptococcal infections, glomerulonephritis may be asymptomatic, discovered only on screening for microscopic hematuria.

Important laboratory findings include:
- elevations ASO titers
- decline in the serum C3 and other complenent components
- presence of cryoglobulins in the serum

More than 95% of affected children eventually recover totally with conservative therapy aimed at maintaining sodium and water balance.
-- A small minority of children (perhaps less than 1%) do not improve, become severely oliguric, and develop a rapidly progressive form of glomerulonephritis (described later). Some of the remaining patients may undergo slow progression to chronic glomerulonephritis with or without recurrence of an active nephritic picture.
-- Prolonged and persistent heavy proteinuria and abnormal GFR mark patients with an unfavorable prognosis.

In adults, the disease is less benign.
- Although the overall prognosis in epidemics is good, in only about 60% of sporadic cases do the patients recover promptly. In the remainder, the glomerular lesions fail to resolve quickly, as manifested by persistent proteinuria, hematuria, and hypertension. In some of these patients, the lesions eventually clear totally, but others develop chronic glomerulonephritis. Some patients will develop a syndrome of rapidly progressive glomerulonephritis.

Front 39

Nonstreptococcal Acute Glomerulonephritis (Postinfectious Glomerulonephritis)

Back 39

- other bacterial infections (e.g., staphylococcal endocarditis, pneumococcal pneumonia, and meningococcemia)
- viral disease (e.g., hepatitis B, hepatitis C, mumps, human immunodeficiency virus [HIV] infection, varicella, and infectious mononucleosis)
- parasitic infections (malaria, toxoplasmosis)

In this setting, granular immunofluorescent deposits and subepithelial humps characteristic of immune complex nephritis are present.

Front 40

RAPIDLY PROGRESSIVE (CRESCENTIC) GLOMERULONEPHRITIS

Back 40

- RPGN is a syndrome associated with severe glomerular injury and DOES NOT denote a specific etiologic form of glomerulonephritis.

- characterized clinically by rapid and progressive loss of renal function associated with severe oliguria and (if untreated) death from renal failure within weeks to months

Front 41

Regardless of the cause, the classic histologic picture of RPGN is characterized by

Back 41

- the presence of crescents in most of the glomeruli (crescentic glomerulonephritis).

Front 42

RPGN is categorized based on the immune mechanism into:

Back 42

- Type I RPGN (Anti-GBM Antibody)
- Type II RPGN (Immune Complex)
- Type III RPGN (Pauci-Immune)

In each group the disease may be a/w a known disorder or be idiopathic

Front 43

Type I RPGN (Anti-GBM Antibody) includes:

Back 43

Idiopathic
Goodpasture syndrome

Front 44

Type II RPGN (Immune Complex)includes:

Back 44

- Idiopathic
- Postinfectious
- SLE
- Henoch-Schönlein purpura (IgA)
- Others

Front 45

Type III RPGN (Pauci-Immune) includes:

Back 45

- ANCA associated
- Idiopathic
- Wegener granulomatosis
- Microscopic polyarteritis nodosa/microscopic polyangiitis

Front 46

Goodpasture syndrome is due to __

Back 46

- anti-GBM antibodies cross-react with pulmonary alveolar basement membranes
- produce the clinical picture of pulmonary hemorrhage associated with renal failure

Front 47

Part of the treatment for Type I RPGN (Anti-GBM Antibody) includes ___ to remove __

Back 47

- plasmapheresis
- remove the pathogenic circulating antibodies
- also includes therapy to suppress the underlying immune response

Front 48

Type II RPGN (Immune Complex) can be a complication of any type of immune complex-mediated nephritis

Can plasmapheresis help these patients?

Back 48

- usually NOT
- have to treat the underlying disease process if possible

Front 49

Type III RPGN (Pauci-Immune)is defined by lack of __ and__

Back 49

- lack of anti-GBM Ab and immune complexes

Front 50

Most patients with type III RPGN (Pauci-Immune) have ___ in the serum

Back 50

- antineutrophil cytoplasmic antibodies (ANCA)
-- cytoplasmic (C)pattern
-- perinuclear (P)pattern

Type III RPGN (Pauci-Immune)can be part of a systemic vasculitis (WG, microscopic polyarteritis)

In many cases Type III RPGN (Pauci-Immune)is isolated and thus idiopathic
-- more than 90% of these idiopathic cases also have either cANCA or pANCA in the serum

believe that all Type III RPGN (Pauci-Immune) cases, including idiopathic, are part of a spectrum of vasculitis

Front 51

Are ANCA's the causative agent in Type III RPGN (Pauci-Immune?

Back 51

- not known

Front 52

The common denominator in all types of RPGN is ___

Back 52

severe glomerular injury.

Front 53

In RPGN, IF shows:

Back 53

- postinfectious cases exhibit granular immune deposits
- Goodpasture syndrome cases show linear fluorescence for immunoglobulin and complement
- pauci-immune cases have little or no deposition of immune reactants

Front 54

Renal manifestations of all forms of RPGN include:

Back 54

- hematuria with red cell casts in the urine
- moderate proteinuria (occasionally reaching the nephrotic range)
- variable HTN and edema

Goodpasture syndrome:
- the course may be dominated by recurrent hemoptysis or even life-threatening pulmonary hemorrhage.

Front 55

Serum analyses for __,___, and ___ are helpful in the diagnosis of specific subtypes of RPGN

Back 55

- anti-GBM antibodies
- antinuclear antibodies
- ANCA

Front 56

Outcome of RPGN

Back 56

- milder forms of glomerular injury may subside
- renal involvement is usually progressive over a matter of weeks and culminates in severe oliguria

Goodpasture syn:
- recovery of renal function may follow early intensive plasmapheresis (plasma exchange) combined with steroids and cytotoxic agents
- this therapy appears to reverse both pulmonary hemorrhage and renal failure

Other forms of RPGN also respond well to steroids and cytotoxic agents.

Despite therapy, patients may eventually require chronic dialysis or transplantation.

Front 57

The manifestations of the nephrotic syndrome include:

Back 57

1. Massive proteinuria, with the daily loss of 3.5 gm or more of protein (less in children)

2. Hypoalbuminemia, with plasma albumin levels less than 3 gm/dL

3. Generalized edema

4. Hyperlipidemia and lipiduria

Front 58

selectivity of proteinuria

Back 58

- highly selective proteinuria consists mostly of low-molecular-weight proteins (albumin: 70 kDa; transferrin: 76 kDa molecular weight)
- poorly selective proteinuria consists of higher-molecular-weight globulins in addition to albumin.

Front 59

In nephrotic syndrome, the lipid appears in the urine either as ___ or as ___

Back 59

- free fat
- oval fat bodies
-- representing lipoprotein resorbed by tubular epithelial cells and then shed along with the degenerated cells

Front 60

Patients with nephrotic syndrome are at risk for complicating events such as __

Back 60

- infection (esp staphylococci and pneumococci)
-- could be related to loss of immunoglobulins or low-molecular-weight complement components in the urine

- thrombotic/thromboembolic events
-- owing in part to loss of anticoagulant factors (e.g., antithrombin III) and antiplasmin activity
-- renal vein thrombosis

Front 61

__ is the most common cause of nephrotic syn in adults

Back 61

membranous glomerulopathy (membranous nephropathy)

Front 62

Membranous nephropathy is characterized by ___

Back 62

- thickening of the glomerular capillary wall
- accumulation of electron-dense, immunoglobulin-containing deposits along the subepithelial side of the basement membrane

Front 63

Secondary membranous nephropathy can be a/w:

Back 63

Immune complex mediated disease


- Drugs (penicillamine, captopril, gold, NSAIDs)
- Underlying malignant tumors (particularly carcinoma of the lung and colon and melanoma)
- Infections (chronic hepatitis B, hepatitis C, syphilis, schistosomiasis, malaria)
- Other autoimmune disorders, such as thyroiditis

Front 64

__% of membranous nephropathy cases are idiopathic

Back 64

85%! (majority)

Front 65

The antigen responsible for idiopathic membranous nephropathy is ___, but is believe to be __

Back 65

- unknown!!
- an autoantigen (autoimmune disease)

Front 66

Membranous nephropathy is generally a __ disease

There is a ___ proteinuria that ___ responds well to corticosteroid therapy

Back 66

- indolent

- non-selective proteinuria (contrast with selective proteinuria of minimal change disease)

- usually does NOT respond well to corticosteroid therapy

- 60% have persistent proteinuria, but only 10% die or progress to renal failure within 10 years
- overall only 40% eventually develop renal insufficiency

- spontaneous remission and a benign course is more common in women and pts with non-nephrotic range proteinuria

Front 67

membranous nephropathy
LM, IF, EM

Back 67

LM:
- uniform, diffuse thickening of the glomerular capillary wall (PAS stain)
- Basement membrane material is laid down between deposits, appearing as irregular spikes protruding from the GBM (best seen by silver stains)

EM:
- thickening is seen to be caused by irregular dense deposits between the basement membrane and the overlying epithelial cells, the latter having effaced foot processes

IF:
- deposits contain both immunoglobulins and various amounts of complement

Front 68

Clinical course of membranous nephropathy

Back 68

- in a previously healthy individual, this disorder usually begins with the insidious onset of the nephrotic syndrome
- 15% of patients, with non-nephrotic proteinuria
- Hematuria and mild HTN present in 15% to 35%

***It is necessary in any patient to first rule out the secondary causes described earlier, since treatment of the underlying condition (malignant neoplasm, infection, or SLE) or discontinuance of the offending drug can reverse progression.

Front 69

minimal change disease (aka____) is a relatively benign disorder and the most common cause of ___

Back 69

- lipoid nephrosis
- nephrotic syn in children

Front 70

MCD peak incidence is between ages __

Back 70

2-6 yo

Front 71

MCD is characterized by___

Back 71

characterized by diffuse effacement of foot processes of epithelial cells in glomeruli that appear virtually normal by light microscopy

Front 72

the most characteristic clinical feature of minimal change disease (MCD) is its___

Back 72

characteristic feature is its usually dramatic response to corticosteroid therapy

Front 73

Evidence that supports an immune-related mechanism(s) behind MCD

Back 73

(1) the clinical association with respiratory infections and prophylactic immunization;
(2) the response to corticosteroids and/or other immunosuppressive therapy (3) the association with other atopic disorders (e.g., eczema, rhinitis)
(4) the increased prevalence of certain HLA haplotypes in patients with minimal change disease associated with atopy (suggesting a genetic predisposition)
(5) the increased incidence of minimal change disease in patients with Hodgkin disease, in whom defects in T cell-mediated immunity are well recognized
(6) reports of proteinuria-inducing factors in the plasma or lymphocyte supernatants of patients with minimal change disease and focal glomerulosclerosis.

Front 74

Foot process effacement, is it specific for MCD?

Back 74

NO!!

Foot process effacement is also present in other proteinuric states (e.g., membranous glomerulopathy, diabetes); it is only when effacement is associated with normal glomeruli by light microscopy that the diagnosis of minimal change disease can be made.

Front 75

Lipoid nephrosis

Back 75

MCD

The cells of the proximal tubules are often laden with lipid and protein, reflecting tubular reabsorption of lipoproteins passing through diseased glomeruli (thus, the historical term lipoid nephrosis

Front 76

In MCD, IF shows___

Back 76

no immunoglobulin or complement deposits

Front 77

The proteinuria seen in MCD is ___

Back 77

- highly selective (mostly albumin)
- despite massive proteinuria, renal function remains good
- usually no HTN or hematuria
- 90% of children respond to corticosteroid therapy

Front 78

Adults with minimal change disease __ respond to steroids

Back 78

- also respond to steroid therapy, but they may me slower to responde
- long-term px is still excellent

Front 79

FSGS is often accompanied by ___ or __

Back 79

nephrotic syn or heavy proteinuria

Front 80

Focal segmental glomerulosclerosis (FSGS) occurs in the following settings

Back 80

• In association with other known conditions, such as HIV infection (HIV nephropathy), heroin addiction (heroin nephropathy), sickle cell disease, and massive obesity

• As a secondary event, reflecting glomerular scarring, in cases of focal glomerulonephritis (e.g., IgA nephropathy)

• As a component of the adaptive response to loss of renal tissue (renal ablation) in advanced stages of other renal disorders, such as reflux nephropathy, hypertensive nephropathy, or with unilateral renal agenesis

• In certain inherited forms of nephrotic syndrome where the disease, in some pedigrees, has been linked to mutations in genes encoding nephrin, podocin, or α-actinin 4

• As a primary disease (idiopathic focal segmental glomerulosclerosis)

Front 81

FSGS (both primary and secondary forms) has increased in incidence and is now the most common cause of nephrotic syndrome in _____in the United States

Back 81

adults (35%)
- particularly common cause of nephrotic syndrome in Hispanic and African Americans

(less common cause in children)

Front 82

FSGS responds ___ to steroid therapy

Back 82

responds poorly

Front 83

FSGS progresses to ___

Back 83

chronic glomerulosclerosis, with at least 50% developing ESRD within 10 years

Front 84

FSGS: IF may show some __

Back 84

non-specific IgM and C3 trapping in the sclerotic foci

Front 85

By LM, FSGS shows

Back 85

- focal and segmental lesions
- lesions initially tend to involve the juxtamedullary glomeruli, although they subsequently become more generalized
- sclerotic segments, there is collapse of basement membranes, increase in matrix, and segmental insudation of plasma proteins along the capillary wall (hyalinosis), which may extend to aggregates within glomerular capillaries that occlude the lumina
- Lipid droplets and foam cells are often present

Front 86

FSGS could be missed by a renal bx that has an ___

Back 86

- insufficient number of glomeruli for evaluation
(focal and segmental lesions!!)

Front 87

FSGS, EM:

Back 87

EM:
- both sclerotic and nonsclerotic areas show the diffuse effacement of foot processes characteristic of minimal change disease, but in addition, there may be focal detachment of the epithelial cells with denudation of the underlying GBM

Front 88

with progression of FSGS there is __

Back 88

- increased numbers of glomeruli involved
- sclerosis spreads within each glomerulus
- there is an increase in mesangial matrix

In time, this leads to total sclerosis of glomeruli, with pronounced tubular atrophy and interstitial fibrosis.

Front 89

A morphologic variant of focal segmental glomerulosclerosis, called collapsing glomerulopathy is characterized by ___ and often a/w ___

Back 89

- collapse and sclerosis of the entire glomerular tuft in addition to the usual focal segmental glomerulosclerosis lesions

- HIV (HIV nephropathy)

Front 90

idiopathic FSGS may be a distinct disease or possible a phase in the evolution of a subset of pts with minimal change disease

Back 90

- both are characterized (by EM) by epithelial cell effacement

Front 91

A genetic basis has been discovered for few cases of "idiopathic" FSGS

Back 91

Mutations in genes for:
- nephrin (NPHS1 gene, chr 19)
- podocyin (NPHS2 gene, chr 1)
- alpha-actinin 4

They are all components of the slit diphragm between podocyte foot processes, and required for normal function

Front 92

Clinical course for idiopathic FSGS

Back 92

- few spontaneous remission
- response to steroids is variable
- progression to renal failure occurs at variable rates
- children have a better px

- some (20%) have a rapidly progressive course with ESRD within 2 years!!

- 25-50% recurrence rate in those receiving allograft transplants!!

Front 93

membranoproliferative GN is characterized histologically by___,___ and ___

Back 93

(MPGN)

- alterations in the basement membrane
- proliferation of glomerular cells
- leukocyte infiltration

Front 94

In MPGN, the proliferation is often localized to the ___

Back 94

- mesangium

Because the proliferation is predominantly in the mesangium, a frequently used synonym is mesangiocapillary glomerulonephritis

Front 95

MPGN accounts for 10-20% of nephrotic syn in __

Back 95

- children and adults
Some present with:
- mixed nephritic-nephrotic pattern
- only non-nephrotic proteinuria or hematuria

Front 96

MPGN can be seondary and primary, primary is divided into __ and __

Back 96

- type I MPGN
- type II MPGN

Front 97

Type I and II MPGN look ___ by LM

Back 97

similar

- glomeruli are large and hypercellular
- hypercellularity is due to both proliferation of cells in the mesangium and so-called endocapillary cell proliferation involving capillary endothelium and infiltrating leukocytes
- parietal epithelial crescents are present in many cases
- glomeruli have a "lobular" appearance accentuated by the proliferating mesangial cells and increased mesangial matrix
- GBM is clearly thickened, often focally (most evident in the peripheral capillary loops)
- glomerular capillary wall often shows a "double-contour" or "tram-track" appearance (silver or PAS stains)
-- caused by "duplication" of the basement membrane, usually as the result of new basement membrane synthesis.
-- within the besement membrane there is inclusion or interposition of cellular elements, which can be of mesangial, endothelial, or leukocytic origin. Such interposition gives rise to the appearance of "split" basement membranes

Front 98

Which is more common type I or II MPGN

Back 98

Type I

Type II is rare

Front 99

Type I MPGN is characterized by __

Back 99

- EM: subendothelial electron-dense deposits

-IF: some IgG and C3 suggesting a immune complex mechanism

Front 100

Type II MPGN is characterized by __

Back 100

- EM: the lamina densa of the GBM is transformed into an irregular, ribbon-like, extremely electron-dense structure because of the deposition of dense material of unknown composition in the GBM proper
- IF: dense deposits are NOT complement or Ig; unknown content

Front 101

Pathogenesis of type I MPGN

Back 101

- idiopathic case, the Ag is unknown

- in secondary cases, the Ag is presumed to be that of the underlying disease
-- Ag from HBV or HCV
- Ab either bind Ag that has been planted in the GBM or preformed Ag-Ab complexes deposit in the GBM

Front 102

Pathogenesis of type II MPGN is

Back 102

unknown

Front 103

MPGN ususally presents as a __ in ___ and __

Back 103

- nephrotic syndrome; usually with a nephritic component (hematuria)
- slow progressive course (few spontaneous remissions)
- some develop RPGN
- 50% develop chronic renal failure within 10 yrs
- steroids, other immunosuppressive tx, and antiplatelet drugs offer no significant benefit

- high rate of recurrence after transplant!!

Front 104

Secondary MPGN is invariably type __, and is more common in __

Back 104

- type I
- adults

• Chronic immune complex disorders, such as SLE; hepatitis B infection; hepatitis C infection, usually with cryoglobulinemia; endocarditis; infected ventriculoatrial shunts; chronic visceral abscesses; HIV infection; and schistosomiasis

• α1-Antitrypsin deficiency

• Malignant diseases (chronic lymphocytic leukemia and lymphoma)

• Hereditary deficiencies of complement regulatory proteins

Front 105

IgA nephropathy is aka __

Back 105

Berger disease

Front 106

IgA nephropathy is characterized histologically by

Back 106

presence of prominent IgA deposits in the mesangial regions, detected by immunofluorescence microscopy

- can only be suspected by LM, but requires IF

Front 107

IgA is a frequent cause of ____ and is probably the most ___

Back 107

- recurrent gross and microscopic hematuria
- most common type of GN worldwide

Front 108

Normally, in the serum, IgA is present ....

In patients with IgA nephropathy ...

Back 108

- low levels
- monomeric form (polymeric form is degraded by the liver)

IgA nephropathy:
- IgA (specifically IgA1) is increased with increased polymeric forms
- some IgA containing immune complexes detected

- increased IgA alone is not sufficient to induce IgA nephropathy

Front 109

IgA nephropathy can be a/w with other disorders

Back 109

- Celiac disease
- Liver disease (impaired ability to clear IgA-containing immune complexes)

Front 110

Pathogenesis of IgA nephropathy is

Back 110

unknown
- involves immune-mediated mechanisms
- possibly related to some infectious or food antigen or possibly a defect in IgA1

Front 111

IgA nephropathy, LM, IF, EM:

Back 111

LM:
- glomeruli may be normal
- may show mesangial widening and proliferation (mesangioproliferative glomerulonephritis)
- segmental proliferation confined to some glomeruli (focal proliferative glomerulonephritis)
- rarely, overt crescentic glomerulonephritis
- presence of leukocytes within glomerular capillaries is a variable feature

IF: mesangial deposition of IgA

EM: electron-dense deposits in the mesangium.

Front 112

IgA nephropathy affects mostly __

Back 112

- older children, young adults
- any age can be affected

Front 113

clinical course of IgA nephropathy

Back 113

- many patients present with gross hematuria after an infection of the respiratory or, less commonly, gastrointestinal or urinary tract
- 30% to 40% have only microscopic hematuria, with or without proteinuria
- 5% to 10% develop a typical acute nephritic syndrome

- hematuria typically lasts for several days and then subsides, only to return every few months
- subsequent course is highly variable

- many patients maintain normal renal function for decades
- slow progression to chronic renal failure occurs in 15% to 40% of cases over a period of 20 years

- onset in old age, heavy proteinuria, hypertension, and the extent of glomerulosclerosis on biopsy are clues to an increased risk of progression

- recurrence of IgA deposits in transplanted kidneys is frequent
-- approximately 15% of those with recurrent IgA deposits, there is resulting clinical disease, which most frequently runs the same indolent, slowly progressive course as that of the primary IgA nephropathy

Front 114

Two examples of hereditary nephritis are __ and __

Back 114

- Alport syndrome
- Thin basement membrane disease

Front 115

Alport syndrome

Back 115

- fully developed, is manifest by nephritis progressing to chronic renal failure, accompanied by nerve deafness and various eye disorders, including lens dislocation, posterior cataracts, and corneal dystrophy.

- In the most common X-linked form, males express the full syndrome, and females are carriers in whom manifestations of disease are typically limited to hematuria

Front 116

Characteristic EM findings in fully developed hereditary nephritis (Alport syndrome)

Back 116

- GBM shows irregular foci of thickening alternating with attenuation (thinning), with pronounced splitting and lamination of the lamina densa, often with a distinctive basket-weave appearance
- similar alterations can be found in the tubular basement membranes

Front 117

The underlying defect in hereditary nephritis (Alport syndrome)

Back 117

- defective GBM synthesis because of the production of abnormal collagen type IV underlies the renal lesions
- in patients with X-linked disease, the defect is caused by mutations in the gene encoding the α5-chain of collagen type IV (COL4A5)

Front 118

Clinical presentation of Alport syndrome (hereditary nephritis) X-linked type

Back 118

- most common presenting sign is gross or microscopic hematuria, frequently accompanied by erythrocyte casts
- proteinuria may occur, and rarely, the nephrotic syndrome develops

- Symptoms appear at ages 5 to 20 years, and the onset of overt renal failure is between ages 20 and 50 years in men.

- The auditory defects may be subtle, requiring sensitive testing.

Front 119

Thin Basement Membrane Disease (Benign Familial Hematuria)

Back 119

- fairly common
- manifested clinically by familial asymptomatic hematuria—usually uncovered on routine urinalysis

- morphologically there is diffuse thinning of the GBM to between 150 and 250 nm (compared with 300 to 400 nm in normal adult individuals)

- although mild or moderate proteinuria may also be present, renal function is normal

- prognosis is excellent

- recessive defect in genes encoding α3- or α4-chains type IV collagen

Front 120

Patient with X-linked Alport syndrome, a skin biopsy sent for IHC staining for __ would be negative

Back 120

α5-chain of collagen type IV (COL4A5)

Front 121

X-linked Alport syndrome, benign familial hematuria, and IgA nephropathy all can cause ___

Back 121

hematuria
- must be distinguished from one another

Front 122

Chronic glomerulonephritis is best considered a pool of end-stage glomerular disease fed by a number of streams of specific types of glomerulonephritis

Back 122

- poststreptococcal glomerulonephritis is a rare antecedent of chronic glomerulonephritis, except in adults

- patients with RPGN, if they survive the acute episode, usually progress to chronic glomerulonephritis

- Membranous GN
- MPGN
- IgA nephropathy
- FSGS

- some idiopathic cases

Front 123

Gross and histologic findings in chronic GN

Back 123

- kidneys are symmetrically contracted, with diffusely granular, cortical surfaces
- on section, the cortex is thinned, and there is an increase in peripelvic fat

- glomerular histology depends on the stage of the disease; early cases, the glomeruli may still show evidence of the primary disease (e.g., membranous glomerulopathy or MPGN)

- eventually hyaline obliteration of glomeruli occurs, transforming them into acellular eosinophilic masses; hyaline represents a combination of trapped plasma proteins, increased mesangial matrix, basement membrane-like material, and collagen

- because hypertension is an accompaniment of chronic glomerulonephritis, arterial and arteriolar sclerosis may be conspicuous
- marked atrophy of associated tubules, irregular interstitial fibrosis, and mononuclear leukocytic infiltration of the interstitium also occur

Front 124

Patients dying with chronic glomerulonephritis also exhibit pathologic changes outside the kidney that are related to the uremic state and are also present in other forms of chronic renal failure.

Back 124

- uremic pericarditis
- uremic gastroenteritis
- secondary hyperparathyroidism with nephrocalcinosis and renal osteodystrophy
- left ventricular hypertrophy due to hypertension
- pulmonary changes of diffuse alveolar damage often ascribed to uremia (uremic pneumonitis)

Front 125

In nephrotic patients, as glomeruli become obliterated, the protein loss in the urine ____

Back 125

decreases

(not a good sign)

Front 126

Diabetic Glomerulosclerosis (Diabetic nephropathy)is one of the leading causes of __ in the US

Back 126

chronic renal failure

Front 127

In the kidney, diabetes effects __

Back 127

- most common lesions involve the glomeruli
Are associated clinically with three glomerular syndromes:
- non-nephrotic proteinuria
- nephrotic syndrome
- chronic renal failure

- affects arterioles, causing hyalinizing arteriolar sclerosis

- increases susceptibility to the development of pyelonephritis and particularly papillary necrosis

- variety of tubular lesions

Front 128

Proteinuria in diabetes

Back 128

- sometimes in the nephrotic range, occurs in about 50% of both type 1 and type 2 diabetics
- usually discovered 12 to 22 years after the clinical appearance of diabetes
- often heralds the progressive development of chronic renal failure ending in death or end-stage disease within a period of 4 to 5 years

- overt proteinuria is preceded by the development of lesser degrees of protein leakage into the urine, termed "microalbuminuria," which may occur within a few years of the onset of diabetes

Front 129

Diabetes: morphologic changes in the glomeruli include

Back 129

1) capillary basement membrane thickening
(2) diffuse mesangial sclerosis
(3) nodular glomerulosclerosis