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129 Cards in this Set

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Most common cause of nephrotic syndrome in children
MCD minimal change disease
Minimal change disease causes a ___ proteinuria
selective (primarily albumin)
MCD: light microscopy, IF, and EM
LM: glomeruli, tubules and itnerstitium appear normal

IF: usually neg

EM: diffuse effacement of podocyte (epithelial cell) foot processes
Focal segmental glomerulosclerosis can be ___or ___ and causes a ___ syndrome
- primary (idiopathic) or secondary (many eitologies)
-nephrotic syn
A major cause of nephrotic syndrome in adults is ___
Membranous glomerulonephritis (MGN)(Membranous nephropathy)
Membranous glomerulonephritis can be secondary to a number of disorders or exposure to antigenic substances
- 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
MGN: LM, IF, EM
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
Systemic diseases with glomerular involvement include:
Systemic Diseases with Glomerular Involvement:

- Systemic lupus erythematosus
- Diabetes mellitus
- Amyloidosis
- Goodpasture syndrome
- Microscopic polyarteritis/polyangiitis
- Wegener granulomatosis
- Henoch-Schönlein purpura
- Bacterial endocarditis
Hereditary disorders with glomerular involvement include:
Hereditary Disorders:
- Alport syndrome
- Thin basement membrane disease
- Fabry disease
Primary glomerulopathies inlcude:
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
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 ___
it is essential to consider these systemic syndromes.
The clinical manifestations of glomerular disease are clustered into the five major glomerular syndromes
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
Glomerular hypercellularity can be due to:
- mesangial or endothelial cell proliferation
- leukocyte inflitration
- crescent formation
Glomerular crescents are formed by __
- 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
Glomerular basement membrane thickening is best seen with a ___stain; EM allows __
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
Anti-GBM antibody-induced nephritis
- 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)
Circulating immune complex nephritis can be due to endogenous and exogenous antigens
endogenous:
- SLE

exogenous:
- bacterial (strep, Treponema pallidum)
- viral: HBsAg, HCV Ag,
- parasites: Plasmodium falciparum
Circulating immune complex glomerular injury
- 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.
A membranous pattern of glomerulonephritis suggests ____ deposition

A membranoproliferative pattern is more indicative of ______
- in situ deposition
- circulating complexes
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.
30-50%
Two major histologic features of progressive renal damage are __ and __
- focal segmental glomerulosclerosis (FSGS)
- tubulointersitial fibrosis
FSGS is a secondary change that results from adaptive changes in unaffected glomeruli of diseased kidneys
- 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
tubulointerstitial fibrosis is believed to be a result of __
- 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
Poststreptococcal glomerulonephritis
- 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
Goodpasture syndrome
- 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
Membranous glomerulopathy
- Nephrotic syndrome
- In situ antibody-mediated; antigen unknown
- LM: diffuse capillary wall thickening (silver stain)
- IF: Granular IgG and C3; diffuse
- EM: subepithelial deposits
Minimal change disease
- Nephrotic syndrome
- Pathogenesis Unknown, loss of glomerular polyanion; podocyte injury
- LM: Normal; lipid in tubules
- IF: Negative
- EM: Loss of foot processes; no deposits
Focal segmental glomerulosclerosis
- 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
Membranoproliferative glomerulonephritis, type I
- Nephrotic syndrome
- pathogenesis: immune complex
- LM: Mesangial proliferation; basement membrane thickening; splitting
- IF: IgG + C3; C1q + C4
- EM: subendothelial deposits
MPGN type II (dense deposit disease)
- Hematuria; chronic renal failure
- pathogenesis: autoantibody
- LM:
- IF: alternative complement pathway C3 ± IgG; no C1q or C4
- EM: dense deposits
IgA nephropathy
- Recurrent hematuria or proteinuria
- pathogenesis unknown
- LM: mesangial widening
- IF: IgA +/- IgG, IgM, and C3 in mesangium
- EM: mesangial and paramesangial dense deposits
Patient with acute nephritis presents with ___
- 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
Poststreptococcal Glomerulonephritis
- 1-4 weeks after streptococcal pharyngitis or skin infection (impetigo)
- mostly in children (6-10 yo), but adults too
only certain __ of group A beta-hemolytic streptococci cause poststreptococcal glomerulonephritis
- nephritogenic strains
- 90% due to types 12, 4, and 1
- typing by M protein in cell wall
poststreptococcal GN is due to ___
- 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
Histologic features seen in poststreptococcal GN
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
characteristic EM features seen in poststreptococcal GN
- 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.
Clinical course of poststreptococcal GN; adults and children
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.
Nonstreptococcal Acute Glomerulonephritis (Postinfectious Glomerulonephritis)
- 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.
RAPIDLY PROGRESSIVE (CRESCENTIC) GLOMERULONEPHRITIS
- 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
Regardless of the cause, the classic histologic picture of RPGN is characterized by
- the presence of crescents in most of the glomeruli (crescentic glomerulonephritis).
RPGN is categorized based on the immune mechanism into:
- 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
Type I RPGN (Anti-GBM Antibody) includes:
Idiopathic
Goodpasture syndrome
Type II RPGN (Immune Complex)includes:
- Idiopathic
- Postinfectious
- SLE
- Henoch-Schönlein purpura (IgA)
- Others
Type III RPGN (Pauci-Immune) includes:
- ANCA associated
- Idiopathic
- Wegener granulomatosis
- Microscopic polyarteritis nodosa/microscopic polyangiitis
Goodpasture syndrome is due to __
- anti-GBM antibodies cross-react with pulmonary alveolar basement membranes
- produce the clinical picture of pulmonary hemorrhage associated with renal failure
Part of the treatment for Type I RPGN (Anti-GBM Antibody) includes ___ to remove __
- plasmapheresis
- remove the pathogenic circulating antibodies
- also includes therapy to suppress the underlying immune response
Type II RPGN (Immune Complex) can be a complication of any type of immune complex-mediated nephritis

Can plasmapheresis help these patients?
- usually NOT
- have to treat the underlying disease process if possible
Type III RPGN (Pauci-Immune)is defined by lack of __ and__
- lack of anti-GBM Ab and immune complexes
Most patients with type III RPGN (Pauci-Immune) have ___ in the serum
- 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
Are ANCA's the causative agent in Type III RPGN (Pauci-Immune?
- not known
The common denominator in all types of RPGN is ___
severe glomerular injury.
In RPGN, IF shows:
- 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
Renal manifestations of all forms of RPGN include:
- 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.
Serum analyses for __,___, and ___ are helpful in the diagnosis of specific subtypes of RPGN
- anti-GBM antibodies
- antinuclear antibodies
- ANCA
Outcome of RPGN
- 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.
The manifestations of the nephrotic syndrome include:
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
selectivity of proteinuria
- 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.
In nephrotic syndrome, the lipid appears in the urine either as ___ or as ___
- free fat
- oval fat bodies
-- representing lipoprotein resorbed by tubular epithelial cells and then shed along with the degenerated cells
Patients with nephrotic syndrome are at risk for complicating events such as __
- 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
__ is the most common cause of nephrotic syn in adults
membranous glomerulopathy (membranous nephropathy)
Membranous nephropathy is characterized by ___
- thickening of the glomerular capillary wall
- accumulation of electron-dense, immunoglobulin-containing deposits along the subepithelial side of the basement membrane
Secondary membranous nephropathy can be a/w:
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
__% of membranous nephropathy cases are idiopathic
85%! (majority)
The antigen responsible for idiopathic membranous nephropathy is ___, but is believe to be __
- unknown!!
- an autoantigen (autoimmune disease)
Membranous nephropathy is generally a __ disease

There is a ___ proteinuria that ___ responds well to corticosteroid therapy
- 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
membranous nephropathy
LM, IF, EM
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
Clinical course of membranous nephropathy
- 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.
minimal change disease (aka____) is a relatively benign disorder and the most common cause of ___
- lipoid nephrosis
- nephrotic syn in children
MCD peak incidence is between ages __
2-6 yo
MCD is characterized by___
characterized by diffuse effacement of foot processes of epithelial cells in glomeruli that appear virtually normal by light microscopy
the most characteristic clinical feature of minimal change disease (MCD) is its___
characteristic feature is its usually dramatic response to corticosteroid therapy
Evidence that supports an immune-related mechanism(s) behind MCD
(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.
Foot process effacement, is it specific for MCD?
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.
Lipoid nephrosis
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
In MCD, IF shows___
no immunoglobulin or complement deposits
The proteinuria seen in MCD is ___
- highly selective (mostly albumin)
- despite massive proteinuria, renal function remains good
- usually no HTN or hematuria
- 90% of children respond to corticosteroid therapy
Adults with minimal change disease __ respond to steroids
- also respond to steroid therapy, but they may me slower to responde
- long-term px is still excellent
FSGS is often accompanied by ___ or __
nephrotic syn or heavy proteinuria
Focal segmental glomerulosclerosis (FSGS) occurs in the following settings
• 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)
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
adults (35%)
- particularly common cause of nephrotic syndrome in Hispanic and African Americans

(less common cause in children)
FSGS responds ___ to steroid therapy
responds poorly
FSGS progresses to ___
chronic glomerulosclerosis, with at least 50% developing ESRD within 10 years
FSGS: IF may show some __
non-specific IgM and C3 trapping in the sclerotic foci
By LM, FSGS shows
- 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
FSGS could be missed by a renal bx that has an ___
- insufficient number of glomeruli for evaluation
(focal and segmental lesions!!)
FSGS, EM:
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
with progression of FSGS there is __
- 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.
A morphologic variant of focal segmental glomerulosclerosis, called collapsing glomerulopathy is characterized by ___ and often a/w ___
- collapse and sclerosis of the entire glomerular tuft in addition to the usual focal segmental glomerulosclerosis lesions

- HIV (HIV nephropathy)
idiopathic FSGS may be a distinct disease or possible a phase in the evolution of a subset of pts with minimal change disease
- both are characterized (by EM) by epithelial cell effacement
A genetic basis has been discovered for few cases of "idiopathic" FSGS
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
Clinical course for idiopathic FSGS
- 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!!
membranoproliferative GN is characterized histologically by___,___ and ___
(MPGN)

- alterations in the basement membrane
- proliferation of glomerular cells
- leukocyte infiltration
In MPGN, the proliferation is often localized to the ___
- mesangium

Because the proliferation is predominantly in the mesangium, a frequently used synonym is mesangiocapillary glomerulonephritis
MPGN accounts for 10-20% of nephrotic syn in __
- children and adults
Some present with:
- mixed nephritic-nephrotic pattern
- only non-nephrotic proteinuria or hematuria
MPGN can be seondary and primary, primary is divided into __ and __
- type I MPGN
- type II MPGN
Type I and II MPGN look ___ by LM
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
Which is more common type I or II MPGN
Type I

Type II is rare
Type I MPGN is characterized by __
- EM: subendothelial electron-dense deposits

-IF: some IgG and C3 suggesting a immune complex mechanism
Type II MPGN is characterized by __
- 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
Pathogenesis of type I MPGN
- 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
Pathogenesis of type II MPGN is
unknown
MPGN ususally presents as a __ in ___ and __
- 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!!
Secondary MPGN is invariably type __, and is more common in __
- 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
IgA nephropathy is aka __
Berger disease
IgA nephropathy is characterized histologically by
presence of prominent IgA deposits in the mesangial regions, detected by immunofluorescence microscopy

- can only be suspected by LM, but requires IF
IgA is a frequent cause of ____ and is probably the most ___
- recurrent gross and microscopic hematuria
- most common type of GN worldwide
Normally, in the serum, IgA is present ....

In patients with IgA nephropathy ...
- 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
IgA nephropathy can be a/w with other disorders
- Celiac disease
- Liver disease (impaired ability to clear IgA-containing immune complexes)
Pathogenesis of IgA nephropathy is
unknown
- involves immune-mediated mechanisms
- possibly related to some infectious or food antigen or possibly a defect in IgA1
IgA nephropathy, LM, IF, EM:
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.
IgA nephropathy affects mostly __
- older children, young adults
- any age can be affected
clinical course of IgA nephropathy
- 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
Two examples of hereditary nephritis are __ and __
- Alport syndrome
- Thin basement membrane disease
Alport syndrome
- 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
Characteristic EM findings in fully developed hereditary nephritis (Alport syndrome)
- 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
The underlying defect in hereditary nephritis (Alport syndrome)
- 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)
Clinical presentation of Alport syndrome (hereditary nephritis) X-linked type
- 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.
Thin Basement Membrane Disease (Benign Familial Hematuria)
- 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
Patient with X-linked Alport syndrome, a skin biopsy sent for IHC staining for __ would be negative
α5-chain of collagen type IV (COL4A5)
X-linked Alport syndrome, benign familial hematuria, and IgA nephropathy all can cause ___
hematuria
- must be distinguished from one another
Chronic glomerulonephritis is best considered a pool of end-stage glomerular disease fed by a number of streams of specific types of glomerulonephritis
- 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
Gross and histologic findings in chronic GN
- 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
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.
- 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)
In nephrotic patients, as glomeruli become obliterated, the protein loss in the urine ____
decreases

(not a good sign)
Diabetic Glomerulosclerosis (Diabetic nephropathy)is one of the leading causes of __ in the US
chronic renal failure
In the kidney, diabetes effects __
- 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
Proteinuria in diabetes
- 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
Diabetes: morphologic changes in the glomeruli include
1) capillary basement membrane thickening
(2) diffuse mesangial sclerosis
(3) nodular glomerulosclerosis