Glo Me Rulo Nephritis

Kida

GlomerulonephritisGlomerulonephritis

Masatoshi Kida, MDDept. of Pathology

University of Vermont College of Medicine

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glomerulonephritisglomerulonephritis- etiology -- etiology -

“primary” (idiopathic)- pathology is confined to the kidney- any systemic features as direct consequence of glomerular dysfunction

“secondary”- kidney abnormality as a part of

multisystem disorder

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glomerulonephritisglomerulonephritis- chronology -- chronology -

“acute”: days to weeks

“subacute/rapidly progressive”:

over weeks to few months

“chronic”: many months to years

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glomerulonephritisglomerulonephritis- location -- location -

“focal”:<50% of all glomeruli

“diffuse”: ≥50% of all glomeurli

“segmental”: part of individual glomerulus

“global”: entire glomerulus

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glomerulonephritisglomerulonephritis- pathology -- pathology -

“proliferative”: increased glomerular cell #

“intracapillary/endocapillary”endothelial or mesangial cells

“extracapillary”cells in Bowman’s space

“crescent”: half-moon-shaped collection of cells in Bowman’s space

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“proliferative”: increased glomerular cell #

“intracapillary/endocapillary”endothelial or mesangial cells

“extracapillary”cells in Bowman’s space

“crescent”: half-moon-shaped collection of cells in Bowman’s space

often associated with rapidly progressive renal failure

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“membranous”:- expansion of glomerular basement membrane as a dominant feature

“sclerosis”:- increased amount of homogenous non-fibrillar

extracellular material (similar to GBM and mesangeal matrix)

“fibrosis”- deposition of type I and III collagen- commonly as a consequence of healing of crescents or tubulointerstitial inflammation

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glomerulopathyglomerulopathy

most glomerulopathies are classified and named according to their morphologic features

I presenting with nephritic-type “active” urine sediment

II presenting with nephrotic-rage proteinuria

III presenting with hybrid of nephritic and nephrotic features

IV glomerular deposition diseases

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I. Presenting with nephritic-type “active” urine sediment

1) diffuse proliferative glomerulonephritis

2) crescentic glomerulonephritis

3) focal proliferative glomerulonephritis

II. presenting with nephrotic-range proteinuria

4) membranous glomerulopathy

5) minimal change disease

6) focal and segmental glomerulosclerosis

III. presenting with hybrid of nephritic and nephrotic features

7) membranoproliferative glomerulonephritis

IV. glomerular deposition diseases

glomerulopathyglomerulopathy

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major determinants of glomerular injurymajor determinants of glomerular injury

1. nature of primary insult and secondary mediator systems

2. site of injury within glomerulus

3. nature of injury- speed of onset- extent- intensity

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1. primary insult1. primary insult

major insult to glomerulus

a. immune attack

b. metabolic stress

c. mechanical stress

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2. site of injury2. site of injury

a. injury to endothelium and subendothelial aspect of GBM(1) recruitment of leukocytes

inflammatory glomerulonephritis(2) perturbed hemostasis

thrombotic microangiopathy(1) or (2) + intrarenal vasoconstriction

mesangial cell contractionrenal failure

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b. injury localized to mesangial area

asymptomatic abnormalities of urinary sediment

mild renal insufficiency

c. injury to subendothelial aspect of GBM and visceral endothelial cells

proteinuria

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d. injury to mesangium

mildly compromised GFR

e. injury to parietal epithelial cells

crescent formation

(acute or subacute renal failure)

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3. nature of injury3. nature of injury

a. rapid, extensive, immune complex deposition (poststreptococcal glomerulonephritis)

diffuse acute inflammation

“acute diffuse proliferative glomerulonephritis”

acute renal failure

- complement activation- leukocyte recruitment- lysosomal enzyme release- free radical generation- purturbation of vascular tone & permeability

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3. nature of injury3. nature of injury

b. slow, but sustained IgA-immune complex formation (IgA nephropathy)

less active inflammation

relatively well maintained GFR

or

slowly progressive renal insufficiency over decades

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major mechanisms of injurymajor mechanisms of injury

a. immune attack (immunologic glomerular injury)

background abnormalitiesi. dysregulation of humoral immunity autoantibody

ii. cellular immune mechanism

modulating antibody production

antibody-dependent cell cytotoxicity

“pauci-immune” glomerulonephritis

robust glomerular inflammation without immunoglobulin deposition

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a. immune attacha. immune attach

i. humoral Ab-mediated injury1) circulating autoantibodies

reacting with normal glomerular component example: anti-GBM disease

(Goodpastures syndrome)2) in situ formation of immune complexes 2° to entrapped

extrinsic Ags and circulating Abs example: post-infectious glomerulonephritis

3) entrapment of circulating Ag-Ab complexes example: cryoglobulinemia-associated

glomerulonephritis4) circulating autoantibodies as a part of systemic disease

- antineutrophilic cytoplasmic antibodies (ANCA) - antiendothelial cell antibodies (AECA)

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a. immune attacka. immune attack

ii. antibody-dependent cell cytotoxicity

iii. cellular antibody-indipendent injury

T-cells mediated “pauci immune” injury

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b. metabolic stress (metabolic injury)b. metabolic stress (metabolic injury)

hyperglycemia

(1) advanced glycosylation end-products (AGEs)(2) reactive oxygen species

cell sorbitol accumulationmitogen-activated protein

kinase activation (3) high glucose-triggered glomerular hypertension

(i) mesangial cell hypertrophy

(ii) increased mesangial cell matrix production

(iii) reduced matrix catabolism

(iv) glomerulosclerosis

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c. mechanical stressc. mechanical stress(hemodynamic glomerular injury)(hemodynamic glomerular injury)

i. systemic hypertension

malignant hypertensionmassive fibrinoid necrosis of afferent arteriole and glomeruli

thrombotic microangiopathy

nephritic urinary sediment

acute renal failure

chronic sustained hypertensionarteriolar vasoconstriction and sclerosis

secondary glomerular and tubulointerstitial atrophy and sclerosis

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c. mechanical stressc. mechanical stress(hemodynamic glomerular injury)(hemodynamic glomerular injury)

ii. glomerular hypertensionglomerular hypertension as an adaptive response to increased workload 2° to loss of other nephrons

sustained glomerular hypertension

increased mesangial matrix production

glomerulosclerosis

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final common pathways of final common pathways of glomerular injuryglomerular injury

1. secondary focal segmental glomerulosclerosis

2. tubulointerstitial inflammation and fibrosis (tubulointerstitial fibrosis)

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final common pathways of glomerular injuryfinal common pathways of glomerular injurysecondary focal segmental glomerulosclerosissecondary focal segmental glomerulosclerosis

a. nephron loss

compensatory changes in surviving nephrons

1. vasodilation of afferent arterioles

2. glomerular hypertension

3. glomerular hyperfiltration

sustained glomerular hypertension and hyperfiltrationTGF-β, angiotensin II, PDGF, CTGF, endothelins

accumulation of extracellular matrix

focal and segmental glomerulosclerosis

global sclerosis proteinuria, hypertension, progressive renal

insufficiency

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final common pathways of glomerular injuryfinal common pathways of glomerular injurysecondary focal segmental glomerulosclerosissecondary focal segmental glomerulosclerosis

b. glomerular hypertrophy

intracapillary microthrombi

recruited macrophages

hyperlipidemia

glomerulosclerosis

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final common pathways of glomerular injuryfinal common pathways of glomerular injurytubulointerstitial inflammation and fibrosistubulointerstitial inflammation and fibrosis

potential mechanisms

1) autoimmune disease

involves both glomeruli and tubointerstitium

2) mediators generated by diseased glomeruli

3) excessive filtered protein

tubal epithelial damage

(“protein overload” hypothesis)

4) ischemia in downstream areas

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acute nephritic syndrome and RPGN as acute nephritic syndrome and RPGN as parts of a spectrum of immunologically parts of a spectrum of immunologically

mediated proliferative glomerulonephritismediated proliferative glomerulonephritis

Agimmune assault

acute nephritic synd

diffuse prolif GN

RPGN slowly progress renal insuff

asymptomatic hematuria with focal prolif

mesangioprolif GN

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acute glom inflammation

obstruction of glom capillary lumen

renal blood flow

GFR

intrarenal vasoconstriction

mesangial cell constriction

acute nephritic syndromeinflammatory infiltrateglom cellular proliferation

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extracellular fluid volume expansion

edema

hypertension

impaired GFR

enhanced tubular salt reabsorption

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injury to glomerular capillary wall

urinalysis red blood cell castsdysmorphic red blood cellsleukocytessubnephrotic proteinuria(<3.0 g/24 hr)

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depending on the extent of glomerular injury, several morphologic variations can be seen

acute infl of most of glomeruli acute diffuse prilif GN<50% of glomeruli involved focal proliferative GNcellular prolif confined to mesang mesangioproliferative GN

Rapidly Progressive Glomerulonephritis (RPGN)• more subacute process• renal failure over weeks to months• crescent formation

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acute nephritic syndrome and RPGNacute nephritic syndrome and RPGN- - etiology -etiology -

1. immune-complex glomerulonephritis

in situ formation

glomerular trapping of circulating complex

i. idiopathic

ii. with known antigenic stimulus

(“infection-associated GN”)

iii. part of multisystem disorder

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2. anti-GBM diseases

autoantibody directed at 28 kDa Ag on α3 chain of type VI collagen

3. pauci-immune glomerulonephritis

(ANCA-associated small vessel vasculitis)i. idiopathic renal-limited crescentic glomerulonephritis

ii. microscopic polyangiitis nodosa

iii. Wegener’s granulomatosis

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immune complex GN

pauci-immune GN

anti-GBM disease

serum complement anti-GBM ANCA

normal

normal

neg

neg

neg**

neg**

pos

pos

low*

*: exception IgA nephropathy (normal)

**: ~20% have low level ANCA

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acute nephritic syndrome and RPGNacute nephritic syndrome and RPGNimmune-complex glomerulonephritisimmune-complex glomerulonephritis

ii. infection-associated GNpoststreptococcal glomerulonephritis

• a leading cause of acute nephritic syndrome• group A-hemolytic strepotococcal infection• 10 days after pharyngitis/2 weeks after skin inf.

clinical Sx:• acute renal insufficiency failure• hematuria (gross hematuria) (red or “smoky”)• headache• generalized symptoms (anorexia, nausea, vomiting,

malaise)• flank or back pain renal capsular swelling

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poststreptococcal glomerulonephritisphysical exam:

• hypovolemia• edema• hypertension

urinalysis:“nephritic” urine sediment• dysmorphic red blood cells• red cell casts• leukocytes• subnephrotic proteinuria• occasional leukocyte casts

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poststreptococcal glomerulonephritisserum:

• creatinine: mildly elevated• C3 levels: depressed• C4 levels: normal

complement levels usually return to normal within 6 to 8 wk• transient hypergammaglobulinemia• transient cryoglobulinemia• circulating Abs against streptococcal enzymes (>90%)

• antistreptolysin O (ASO)• anti-deoxyribonuclease B (anti-DNAse B)• antistreptokinase (ASKase)• anti-nicotynyl adenine dinucleotidase (anti-NADase)• antihyaluronidase (AHase)

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poststreptococcal glomerulonephritispathology:

LM: diffuse proliferativce glomerulonephritis

IF: diffuse glomerular deposition of IgG & C3

(“starry sky” appearance)

EM: large electron-dense immune deposits in subendothelial, subepithelial and mesangial areas

Dx: based on clinical and serological grounds with a typical antecedent history

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poststreptococcal glomerulonephritisTx: (1) antibiotics to eliminate streptococcal infection

(2) supportive therapy until spontaneous resolution (3) diuretics

(4) antihypertensive agent(s)(5) dialysis rarely

needed (to control hypervolemia or uremic syndrome)

prognosis:excellent• spontaneous resolution in children• some degree of persistent proteinuria in 20% of adults

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iii. as a part of multisystem disorder

Lupus nephritis• seen 40-85% of SLE patients• triggered by formation of immune complexes within

glomerular capillary wall

Lab: range of serologic abnormalities

• hypocomplementemia (75 to 90%)• antinuclear Abs (ANA) (95 to 99%)• anti-double-stranded DNA (ds-DNA) Abs

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Lupus nephritislupus-related antiphospholipid antibody syndrome

tissue plasminogen activator

α2-antiplasmin

variable degree of renal impairment• intervascular microthrombi• swelling of endothelial cells

thrombosis

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Lupus nephritisTx:

• treatment is based largely on (1) class of injury and (2) disease activity

• renal biopsy: important guide to therapy

normal bx no therapy

mesangial deposit only

proliferative nephritis glucocorticoidscyclophosphamide

• mycophenolate mofetil

therapeutic option for cyclophosphamide resistant case

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iii. as a part of multisystem disordercryoglobulinemia glomerulopathy

mixed cryoglobulinemias (types II & III)• female• sixth decade• variable combination of

leukocytoclastic vasculitis skin ulcerationarthralgia fatigueRaynaud’s phenomenon

• renal disease as a complication in 50% of cases• developing after 12 to 24 months• acute nephritic syndrome in 20-30% of renal disease• oliguric acute renal failure in 50% of renal disease

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cryoglobulinemia glomerulopathyLab:

• depressed circulating levels of C3, C4 and CH50(80% of cases of renal involvement)

• transient ANA positivity• hepatitis C (HCV) RNA has been isolated

Tx:• glucocorticoids• with or without cyclophosphamide• plasmaphresis• HCV infection interfeon α

prognosis:• 75% alive at 10yr

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acute nephritic syndrome and RPGNacute nephritic syndrome and RPGNanti-GBM diseaseanti-GBM disease

Goodpasture syndrome• usually as RPGN (crescentic glomerulonephritis)• acute nephritic syndrome is rare• pulmonary hemorrhage (50-70%) predates by wks to months• 2 peaks of patient population

(1) young (5 to 40 yr) male (6M:1F)(2) sixth decade both sexes (less pulm

hemorrhage)

clinical Sx/Lab:• hematuria• nephritic urinary sediment• subnephrotic proteinuria• rapidly progressive renal failure over weeks• with or without pulmonary hemorrhage

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Goodpasture syndromeDx:

• circulating anti-GBM antibodies• renal biopsy is the gold standard

pathology:

LM: crescentic glomerulonephritis- diffuse proliferative

glomerulonephritis with focal necrotizing lessions and crescents in >50% of glomeruli

IF: linear ribbon-like deposition of IgG along GBM

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Goodpasture syndromeTx:

• early and aggressive use of plasmapheresis, glucocorticoids, cyclophophamide and azothioprine is key

• speed of initiation therapy is a critical determinant of outcome• emergency plasmapheresis

daily or alternate days until no detectable anti-GBM

(may take 1 to 2 wks)

prognosis:• requiring dialysis at presentation as a poor prognostic sign

(no recovery of renal function)• relapse not uncommon

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acute nephritic syndrome and RPGNacute nephritic syndrome and RPGNpauci-immune glomerulonephritispauci-immune glomerulonephritis

a spectrum of a single disease(ANCA-associated small vessel vasculitis)

• old (~57yr) white• non-specific constitutional signs and symptoms

lethargy fevermalaise arthralgiaanorexia myalgia

wt. loss

• non-specific lab abnormalities• rapid sedimentation rate• elevated C-reactive protein• normochromic, normocytic anemia• normal serum complement levels• leukocytosis• thrombocytosis

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acute nephritic syndrome and RPGNacute nephritic syndrome and RPGNpauci-immune glomerulonephritispauci-immune glomerulonephritis

LM: focal, segmental, necrotizing glomerulonephritis with crescent formation

IF, EM: paucity or absence of immunoglobulin, complement, and immune deposits

Tx:• glucocorticoids and cyclophophamide• azathioprine or mycophenolate• plasmapheresis• dialysis• renal transplant

30% will relapse after treatment-induced remission• trimethoprim-sulfamethoxazole reduces relapse rate

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Glo Me Rulo Nephritis