Glomerulonephritis_2007_revised

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Glomerular Disease
Farid M. Nakhoul M.D.
Department Of Nephrology
Rambam-Health Care Campus
Email:
f_nakhoul@rambam.health.gov.il
Classification

Based on Clinical Presentation
– History
– Physical Exam (Edema? Hypertension?)
– Urinalysis (Nephritic? Nephrotic?)
– Presence of Renal Failure
– Time Course

Presentation varies from patient to
patient, e.g., IgA Nephropathy
Clinical Features of
Glomerular Diseases
Proteinuria
Hematuria
Edema
Hypertension
Renal Dysfunction
Glomerulonephritis


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Kidney diseases that primarily affect
the glomerulus.
Leading Cause of End Stage Renal
Disease worldwide
Third leading cause of End Stage
Renal Disease in the United States
Introduction-I
• Glomerular disease has clinical
presentations that vary from the
asymptomatic individual who is found
to have hematuria, proteinuria, to a
patient with a fulminant illness with
acute renal failure possibly associated
with life-threatening extrarenal disease.
Introduction -II
• Numerous Inflammatory and Noninflammatory diseases affect the
glomerulus and lead to alterations in
glomerular permeability, structure, and
function.
• GN may be primary , restricted in
clinical manifestations to the kidney, or
it may be part of multisystem Dis. ,
most frequently SLE or vasculitis.
Introduction-III
• The presence of some form glomerular
disease is usually suspected from the
history and from one or more of the
following urinary findings: hematuria
particulary dismorphic red blood cells,
red cell casts, proteinuria, associated
with renal insufficiency (Pcr is high),
oliguria and arterial hypertension>>>>
(Nephritic Syndrome).
GN-Clinical Evaluation
• History>>Family, Hearing loss
• Physical Examination>> Edema,
Purpura
• Laboratory studies>> Urine sediment
• Imaging/US>>To ensure the presence
of two kidneys, to rule out obstruction.
• Renal Biopsy>> require to establish
the type of glomerular disease and to
guide treatment decision.
Nephritic Syndrome
•
•
•
•
•
Decreased urinary output
Dark or smoky urine (hematuria)
Volume-dependent HTN
Edema,CHF, seizures
Urinalysis: dysmorphic RBCs, RBC, WBC,
proteinuria (non-nephrotic)
• C3,C4 are low.
• KNB
• ARF requiring dialysis
Laboratory
1.
2.
3.
4.
5.
6.
7.
Urine Sediment/volume
C3, C4
Anti-DNA/ ANA
CBC/ Kidney Function Tests
ANCA (P,C), Cryoglobulins, Anti-GBM.
HbsAg, Anti-HCV abs,
Liver Function Tests
Classificatio of urinary Casts
• Hyaline: non indicative of renal disease
• Red cell cast: GN, Vasculitis
•
•
•
•
Granular: degenerating cellular cast
Waxy: Advanced Renal Failure
Fatty: Nephrotic syndrome
Epithelial Cell: ATN
RBC Cast
Imaging
• Kidney Ultrasound
• Kidney Biopsy: Closed/ Laparoscopic
Pathogenesis
1.In-situ Immune reaction:
- Anti-GBM nephritis
2. Circulating Immune-Complexes
- Endogenous (DNA) or
- Exogenous(Streptococci, Hepatitis B, C).
Classification
• GN is classified by the different patterns of
histologic injury seen on a renal biopsy
examined by light microscopy,
immunofluorescence, and electron
microscopy.
• It is more helpful to regard the renal biopsy
appearance as a ‘Pattern’ rather than a
disease.
Acute Glomerulonephritis
(KNB)
• Focal Glomerulonephritis
• Diffuse Glomerulonephritis
Focal Glomerulonephritis
• Focal glomerulonephritis is associated with
inflammatory lesions in less than one-half
glomeruli on light microscopy
• The urinalysis reveals red cells ( dysmorphic)
occasionally red cell casts and mild
proteinuria(<1.5gr).
• Renal insufficiency and hypertension are
usually absent.
• These patients often present with asymptomatic
hematuria and proteinuria.
1. Focal Glomerulonephritis
• Mild post-infectious GN
• IgA Nephropathy
• Henoch-Schonlein purpura
IgA Nephropathy and HSP
• IgA nephropathy is a mesangial proliferative
glomerulonephritis, characterized by diffuse
deposition of IgA .
• Clinical presentation is visible Hematuria
provoked by mucosal infection.
• Henoch-Schonlein purpura is a small –vessels
vasculitis affecting the the kidney, skin and gut.
Is characterized by mesangial IgA deposition.
IgA Nephropathy
• In 50% of cases the clinical presentation is
episodic macroscopic hematuria, most
frequently in the second and third decades
of life.
• Hematuria usually follows intercurrent
mucosal infection, usually upper
respiratory tract infection.
• Usually is visible within 24 hours of the
onset of the symptoms of infection.
IgA Nephropathy
Clinical manifestation
•
•
•
•
Macroscopic hematuria
Asymptomatic hematuria and proteinuria
Proteinuria and nephrotic syndrome
Acute renal failure: Crescentic IgA
glomerulonephritis>> STEROIDS!!!
• Chronic renal failure
• The Most Common Cause of GN in the
world.
Diffuse Glomerulonephritis
• Affects most or all of the glomeruli
• Heavy proteinuria, red cell casts,
edema, hypertension, and Renal
Insufficiency.
• Aggressive treatment
Diffuse GN
• Less than 15 yrs: postinfectious GN, MPGN
• 15-40 yrs: Postinfectious, Lupus Nephritis
• Greater than 40 yrs: Vasculitis( including
cryoglobulinemia), Postinfectious GN.
Diffuse GN associated with
Hypocomplementemia
•
•
•
•
Postinfectious GN
Lupus-nephritis
Membranoproliferative GN( MPGN)
Mixed cryoglobulinemia
• Hypocomplementemia in GN is most
often due to complement activation by
immune-deposits.
Postinfectious GN
• Post-streptococcal pharyngitis
• Endocarditis
• Infected Ventricular shunt
• Pyoderma
Postinfectious GN(PSGN)
• Ac. GN can develop 2-3 weeks after
pharyngitis or skin infection with certain
group A, B-hemolytic Streptococci.
• Immune complex deposition of streptococcal
antigens as well as auto-immune reactivity.
• Diffuse proliferative and exudative nephritis
containing many neutrophils and monocytes
• Deposition of C3, IgG, IgM (Subepithelial)
• Rapidly progressive renal failure with cellular
crescents.
Poststreptococcal
Glomerulonephritis
Poststreptococcal GN (Introduction)



Usually occurs 10 days
after pharyngitis and 14
days after skin infection
(not synpharyngitic)
Fallen incidence in US, but
common in some rural
areas, poor hygiene
places, and tropical
countries
Occurs more often in
males and children
Poststreptoccal GN (nephritic strains)


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Known nephritic strains
include M types 1, 2, 4,
12, 18, 25, 49, 55, 57, 60
Many proposed
mechanisms: Molecular
mimickry vs. autoimmune
vs. polyclonal activation of
B lymphocytes
Repeat infections are not
common as immunity is
type specific and not
usually transient
Clinical Presentation



Most patients have milder disease
Classically, presents with overt nephritic
syndrome and oliguric ARF
Symptoms can include gross hematuria
(100% microscopic), HA, htn (60-80%),
hypervolemia, and edema (80-90%)
Clinical Presentation


Nephritic urinary
sediment –
dysmorphic RBCs, red
cell casts, leukocytes,
subnephrotic
proteinuria
Nephrotic-range
proteinuria not
common
Post-streptococcal GN
• Sometimes esp. in adults, patients may
develop HTN, proteinuria and renal
insufficiency>>> ESRD>>>Dialysis.
Labs
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Serum Cr can be commonly elevated at presentation, though
mild
C3 and CH50 decreased w/in 2 weeks
C4 usually normal (complement level usually normal within 68 weeks)
Most patients have directed Ab, such as ASO, anti-DNAse B,
etc
Serum IgG and IgM increased in 80% and returns to normal
in 1-2 months
Polyclonal cryoglobulinemia in 75%
Light Microscopy
On light microscopy,
usually see diffuse
proliferative GN
Immunofluorescence Microscopy

Deposition of IgG and
C3
3 patterns
mesangial
Starry sky (mesangial
and capillary wall)
Garland (capillary loops)
Electron Microscopy

large electron – dense
immune deposits in
subendothelial,
subepithelial, and
mesangial areas
Course
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Irreversible Renal Failure rare – less than 1 % in
children, slightly higher in adults
Resolution usually quick, plasma Cr usually
returns to previous levels by 3-4 weeks
Hematuria resolves usually within 3-6 months,
proteinuria falls at a slower rate
Some patients experience htn, recurrent
proteinuria, and renal insufficiency 10-40 yrs after
> 20% of adults may have some degree of
persistent proteinuria and or compromise of GFR
1 year out
Treatment
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Eliminate strep infxn with abx
Supportive therapy
Diuretics and antihypertensives to control
bp and extracellular fluid volume
Rapidly Progressive GN
(Crescentic)
• RPGN describes the clinical situation in
which glomerular injury is so acute and
severe that renal function deteriorates over
days or weeks. The patient may present as a
uremic emergency, with nephritic syndrome
that is not self-limiting but moves on rapidly
to renal failure.
• The histologic counterpart of RPGN is
crescentic GN.
Crescentic GN
• Crescents are inflammatory collections of
cells in Bowman’s space. They appear when
severe glomerular injury results in local
rupture of the capillary wall allowing plasma
proteins and inflammatory material to escape
from the capillary into Bowman’s space.
Crescents consist of both proliferating
parietal cells and invading inflammatory
cells, both lymphocytes and
monocytes/macrophages.
• They are destructive, rapidly increasing in
size and squeezing the glomeruli tuft until it
is occluded.
Rapidly progressive
(Crescentic)
Glomerulonephritis(RPGN)
•
Anti-glomerular basement membrane
antibody disease( with pulmonary
disease, Goodpasteure’s Syndrome).
•
Immune Complex-mediated GN.
•
Pauci-immune GN, usually ANCApositive.
Therapy
A. -Pulse Therapy: IV Methylprednisolone
followed by PO Prednisone 1mg/Kg.
-IV Cyclophosphamide or Cell-Cept Or Imuran.
B. Plasmapheresis
C. Hemodialysis( Hyperkalemia, Hypervolemia).
Acute GN and Pulmonary Hemorrhage
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ANCA associated systemic vasculitis and antiGBM - common causes
Also reported to occur in SLE, HSP, mixed
Cryoglobulinemia
Study of 88 patients with Pulmonary Hemorrhage
and Nephritis: 48 ANCA, 6 Anti GBM, 7 both, 27
neither ANCA nor anti-GBM (latter group – not
many causes could explain both findings)
Anti-glomerular basement
membrane disease and
Goodpasture’s Syndrome
• Anti-GBM anti-body disease is a rare
autoimmune disorder associated with antibodies
specific for any components of the GBM.
• Characterized by rapidly progressive GN with
crescentic changes that affect most glomeruli
on renal biopsy.
• When pulmonary hemorrhage present>>>>>
Goodpsteur Syndrome !!!!
Anti-GBM Disease
•
•
•
•
•
•
•
Breathlessness and cough>> Hemoptysis
X-Ray >>Alveolar shadowing
Carbon-Monoxide transfer factor(KCO)
Low incidence 1/1000,000
20% of all RPGN
Spring , early summer
ANCA-Systemic vasculitis (30%)
Anti-GBM Disease
• Bimodal age distribution with peak incidence in
the third and sixth decades.
• Males>females
• Influenza Vaccination: Viral Infection ??
• Most patients present with the combination of
RPGN and lung hemorrhage, although 30-40%
present with isolated renal involvement.
• Acute nephritis
• Arterial hypertension is late feature.
Goodpasteur’s Disease
• Disease associated with autoantibodies
specific for Noncollagenous domain
(NC1) of the alpha-3 chain of type (IV)
collagene>>>ELISA highly sensitive
and specific.
• May include RPGN , lung hemorrhage,
or both.
Type IV collagen exists as a complex supramolecular network. Three
individual 3(IV) chains are interwoven to form a triple helix, known as the
protomer. The NC1 domains are arranged in a head-to-head fashion to
form hexamers, and binding through the 7S domains completes the
network structure. Hexamers can be dissociated to form dimers and
monomers of NC1 domains, allowing identification of 3(IV)NC1 as the
autoantigen (redrawn with permission from [72]).
Membranoproliferative GN
• Primary ( Idiopathic)
• Secondary) Cryoglobulinemia)
MPGN
• MPGN also called mesangiocapillary
glomerulonephritis.
• MPGN is a renal disease characterized
by diffuse mesangial proliferation and
thickening of the capillary wall.
MPGN
• MPGN type I: Subendothelial /Mesangial
Deposits ( HCV: 70-90%).
• MPGN type II: Mesangial ( Dense deposit
disease).
• MPGN type III: Subendothelial, GBM,
Subepithelial Deposits.
MPGN/Etiology
•
•
•
•
•
•
Cryoglobulinemia (type-I)
Infections
Complement Abnormalities or deficiencies
Malignancies
Chronic liver disease
Collagen vascular disease
MPGN /Clinically
• MPGN is one of the major causes of nephrotic
syndrome which include MCD, FSGS, MGN
• 5-20% of all primary glomerulonephritis
• May present as microscopic hematuria, nonnephrotic proteinuria (35%), nephrotic syndrome
with renal insufficiency, chronically progressive
glomerulonephritis (20%), or as rapidly
progressive renal failure.
• Systemic hypertension 50-80%
• Can present with systemic cryoglobulinemia
(HCV+): purpura, weakness, arthralgia.
MPGN
•
•
•
•
•
C3 and C4 are low (type1 with cryo +)
Circulating immune-complexes
RF+
HCV-RNA + (PCR)
KNB !!
MPGN recurs in renal transplant
recipients with a frequency of 20-30%
in type-I, 80-90% in type-II.
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