Glomerulonephritis

Lestariningsih
Glomerulonephritis

The acute nephritic syndrome is characterized by

hematuria and RBC cast in the urine sediment along
whith other signs of acute inflammatory renal
injury, including proteinuria, peripheral edema,
hypertension, or renal insufficiency with or without
oliguria
 Lestariningsih
SubBag Nefrologi-Hipertensi
Bagian Ilmu Penyakit Dalam
FK UNDIP / RSUP Dr. Kariadi Semarang
 GENERALITIES
G
L
O CLINICOPATHOLOGIC
M
E
R
U PRIMARY MECHANISMS
L
A
R
CORRELATION BETWEEN
I SITE AND PRESENTATION
N
J
U
R CLASIFICATION
Y
Normal Glomerulus

1. Bowman space
2. Bowman capsule with epithelial
cells (parietal epithelial cells)
3. Podocytes, foot processes
(visceral epithelial cells)
4. Endothelial cells (yellow)
5. Mesangial matrix (blue)
6. Mesangial cells (red)
7. Macula densa
8. Afferen artery
9. Efferen artery
10.Distal convuluted tubule
Glomerulus
Matriks ekstraseluler
 NOMENCLATURE

• Glomerulonephritis: (GN) injury with

evidence of inflammation such as
leukocyte infiltration, antibody deposition,
and complement activation.

• GN primary: pathology is confined to the kidney.

• GN secondary: when part of a multisystem disorder.
 NOMENCLATURE

• Acute: glomerular injury occurring over

days or weeks.
• Subacute or rapidly progressive: over weeks
or a few months.
• Chronic: over many months or years.
 NOMENCLATURE

• Diffuse: affect > 50% of glomeruli.

• Focal: affect < 50% of glomeruli.

• Global: affect > 50% of glomerular tuft.

• Segmental: < 50% of glomerular tuft

 NOMENCLATURE

• Proliferative: glomerular cell number (intracapillary

and extracapillary)
• A crescent: is a half-moon shaped. Cells in Bowman`s
space.
• Membranous : expansion of the GBM by immune
deposits.
• Sclerosis: nonfibrilar extracellular material
• Fibrosis: Collagens type I and III
 Glomerular injury

1. Overview of slides : assesses injury and localizes to

the specific anatomic compartment (glomerular/
vascular/ tubulointerstitial).

2. Assessment of type of injury, extent of injury in each

glomerulus.
Terminology : diffuse, focal, global and segmental
CLINICOPATHOLOGIC
 Diffuse proliferative GN
• Clinical Presentation
• Acute nephritic syndrome, acute renal failure over
days to weeks, hipertension, edema,oliguria, active
urine sediment, subnephrotic proteinuria.
• Pathology Findings
• Diffuse increase in cellularity of tufts. Infiltration by
neutrophis ans monocytes, and proliferation of
glomerular endothelial and mesangial cells.
• Etiologies
• Immune complex GN, idiopathic, postinfectious,
SLE, cryoglobulinemia, Henoch Schönlein purpura.
 Crescentic GN
• Clinical Presentation
• Rapidly progresive GN, subacute renal failure,
active urine sediment, subnephrotic proteinuria.
• Pathology Findings
• Fibrinoid necrosis and crescents in Bowman`s space
(parietal epithelial cells), infiltrating macrophages,
and fibrin)
• Etiologies
• Inmune Complex GN, pauci-immune GN,
Wagener`s granulomatosis, microscopic
polyarteritis nodosa.
 Focal proliferative GN
• Clinical Presentation
• Mild to moderate glomerular inflammation. Active
urine sediment, and mild to moderate decline in GF.
• Pathology Findings
• Segmental areas of proliferation and necrosis in less
than 50% of glomeruli, occasionally with crescent
formation
• Etiologies
• Early and milder forms of most diseas causing
diffuse proliferative and crescentic GN.
 Mesangial proliferative GN

• Clinical Presentation
• Chronic glomerular inflammation: proteinuria,
hematuria, hypertension, variable effect on GF.
• Pathology Findings
• Proliferation of mesangial cells and matrix
• Etiologies
• Early and milder forms of most diseas causing
diffuse proliferative and crescentic GN. IgA
nephropathy.
 Membanoproliferative GN

• Clinical Presentation
• Combination of nephritic and nephrotic features,
acute or subacute decline in GF.
• Pathology Findings
• Diffuse proliferation of mesangial cells and
infiltration of glomeruli by macrophages
• Etiologies
• Immune complex GN, In association with
thrombotic microangiophaties, in association with
deposition diseases.
 Membanoproliferative GN
• Clinical Presentation
• Combination of nephritic and nephrotic features,
acute or subacute decline in GF.
• Pathology Findings
• Diffuse proliferation of mesangial cells and
infiltration of glomeruli by macrophages
• Etiologies
• Immune complex GN, In association with
thrombotic microangiophaties, in association with
deposition diseases.
 Deposition diseases
• Clinical Presentation
• Combination of nephritic and nephrotic features.
Renal failure over months to years.proteinuria,
hematuria and hypertension.
• Pathology Findings
• Mesangial expansion and thinckening of glomerular
capillari wall
• Etiologies
• Amyloid, Cryoglobulinemia, Light chain deposition
disease.
 GENRALITIES
G
L
O CLINICOPATHOLOGIC
M
E
R
U PRIMARY MECHANISMS
L
A
R
CORRELATION BETWEEN
I SITE AND PRESENTATION
N
J
U
R CLASIFICATION
Y
Primary Mechanisms of Glomerular Injury
 Immunologic
• Defects
• Inmmunoglobulin
• Cell-mediated injury
• Cytokine (or other soluble factor)
• Persistent complement activation
• Glomerular Disease
• Immune complex-mediated GN
• Pauci-immune GN
• Primary focal segmental glomerulosclerosis
• Membranoproliferative GN type II
 Inherited

• Defects
• Defect in gene for a 5 chain of type IV collagen
• Abnormally thin basement membrane
• Glomerular Disease
• Alport`s syndrome
• Thin basement membrane disease
 CLINICAL PRESENTATIONS

• 1)Acute nephritic syndrome

• 2) Asymptomatic abnormalities of the
urinary sediment
• 3) Chronic glomerulonephritis
• 4) nephrotic syndrome
 ACUTE NEPHRITIC SYNDROME

• ANS is the clinical correlate of acute

glomerular immflamation. Characterized by
sudden onset (over days to weeks)of acute
renal failure and oliguria (<400ml/day)
• Renal blood flow and glomerular filtration
rate fall as a result of obstruction of the
glomerular capillary lumen by infiltrating
inflammatory cells and proliferating resident
glomerular cells.
• Extracellular fluid volume expansion,
edema and hypertension develope because
of impaired GFR and enhanced tubular
reabsorption of salt and water.
• As a result of injury to the glomerular
capillary wall,
 PATHOGENESIS GLOMERULONEPHRITIS

1. 1. Deposition of circulating immune

complex

2. Circulating antibody against “planted”

2. antigen

3. 3. Antibody against intrinsic glomerular

antigen
epithel endothel
GBM
 Mechanism of Immune Renal Injury
Etiologic Agent Infections
Loss of tolerance
IR Genes

Immune Response
Antibody
IgG, IgA T Cells

Deposit Formation
In situ, complex trapping

Mediation
Complement, Chemokines Cytokines, Vasoactive

Effector Cells
PMNs, macrophages Glomerular cells

Proliferation, PDGF Response Scelosis, TGF - 

 PP
CLINICAL FEATURES
Glomerular injury
Inflammatory glomerular RED BLOOD
capillary CELL CASTS
PROTEINURIA
Perfusion glomerular
capillary HEMATURIA

FG AZOEMIA
reabsorption
Na and H2O
Tubular
volume OLIGURIA
Extracelular HYPERTENSION
Volume EDEMA
Acute renal failure
CLINICOPATHOLOGIC
Renal failure

• 1/Cr plot
• Linear deterioration

• eGFR and CKD

 Clinical Presentations of glomerular disease

Asymptomatic
Proteinuria 150mg to 3g/day
Hematuria > 2 red blood cells
Perhigh-power field (> 10x106 cells/L
Nephritic syndrome In spun urine (red blood cells
(Inflamasi glomerulus) Usually dysmorphic
Oliguria
Hematuria : red cells casts
Proteinuria; usually < 3g/day Nephrotic syndrome
Oedema Proteinuria; adult > 3,5 g/day
Hypertension Child > 40 mg/h per m2
Abrupt onset Edema
Hypercholesterolemia
Lipidemia

Cronic glomerulonephritis Rapidly progressive glomerulonephritis

Hypertension Renal failure over days/weeks
Renal insufficiensy Proteinuria usually < 3 g/day
Proteinuria > 3 g/day Hematuria; red cell casts
Shrunkensmooth kidneys Blood pressure often normal
May have other features of vasculitis
• Urianalisis typically reveal red blood cell
casts, dydmorphic red blood cells,
leukocytes, and subnephrotic proteinuria of
< 3.5 g per 24 h (nephritic urinary
sediment) Hematuria is often macroscopic.
Non-dysmorphic vs dysmorphic

dysmorphic
 3 Broad diagnostic categories
• 1) Granular deposits of inmunoglobulin
(immune complex GN)

• 2) Linear deposition of immunoglobulin

along the GBM (anti-GBM disease)

• 3) paucity or absence of immunoglobulin

(pauci-immune GN)
 Clinical Clasification

Asymptomatic
Proteinuria 150mg to 3g per day
Hematuria >2 red blood cells
per high-power field (>10 x 106 cells/L)
in spun urine (red blood cells usually dysmorphic)

Macroscopic hematuria Nephrotic syndrome

Brown/red paintess hematuria
(no clots); typically coincides with
intercurrent infection
Asymptomatic hematuria ± proteinuria
between attacks
Proteinuria : adult >3.5 g/day;
child >40mg/h per m2
Hypoalbuminemia <3.5g/dl
Edema
Hypercholesterolemia
Lipiduria
 Clinical Clasification

Nephritic syndrome
Oliguria
Hematuria : red cell casts
Proteinuria : ussually <3g/day
Edema
Hypertension Rapidly progressive glomerulonephritis
Abrupt onset, usually Renal failure over days/weeks
self-limiting Proteinuria : usually <3g/day
Hematuria : red cell casts
Blood pressure often normal
May have other features of vasculitis

Chronic glomerulonephritis
Hypertension
Renal insufficiency
Proteinuria >3g/day
Shrunken smooth kidneys
Glomerular changes in disease
• Proliferation
• Sclerosis
• Necrosis
• Increase in mesangial
matrix
• Changes to basement
membrane
• Immune deposits
• Diffuse vs focal
• Global vs segmental
Thin membrane disease

• Most common GN
• Microscopic haematuria
• Familial
• Benign
• No treatment needed
• Most young people with
isolated microscopic
haematuria have thin
membrane disease
Mesangial IgA disease

• Classical Berger’s Disease

• Microscopic haematuria
• Proteinuria (rarely nephrotic)
• Hypertension
• Chronic renal failure
• ? Failure of hepatic
clearance of IgA
• Association with GI disease
• No specific treatment
Minimal Change Disease

• Usually children
• Nephrotic syndrome with
highly selective
proteinuria and
generalised oedema
• Rarely hypertension or
ARF
• T cell mediated – VPF
• Steroid sensitive usually
• Spectrum of disease to
FSGS
 Minimal chance

• Komplemen (C3, C4)↓  proses sistemik

• Tx : sesuaikan derajat proteinuri dan fungsi
ginjalnya (diagram).
• Pulse dose methylprednisolone 1 g dalam 3 hari
 dilanjutkan
• Oral methylprednisolone 0,4 mg/ kgBB/ hari
selama 27 hari ( bulan ke 1, 3, 5).
• CYC 2,5 mg/ kgBB/ hari atau chlorambusil
• 0,2 mg/ kgBB/ hari (bulan ke 2, 4, 6)
FSGS
Membranous Glomerulopathy
• Proteinuria (often
nephrotic)
• CRF
• Hypertension
• Third improve; third
stable; third progress
• In situ immune complex
formation
• May be secondary to
tumours etc
• Immunosuppression if
bad NS / progressive
Diffuse Endocapillary Proliferative GN
(Post Streptococcal GN)

• Diffuse endocapillary
proliferative GN
• Post infectious; usually
Gp A Strep
• Acute nephritic syndrome
• Uraemia rare
• Self-limited; rarely death
from BP
• Abnormal RUA for up to
2 yrs
• Circulating immune
complex mediated
 FSGS
 Primer / sekunder (hepatitis A, HIVAN).
 Tx CST 1 – 2 mg/ kgBB/ hari (3-4 bulan) 
tappering  terapi > 6 bulan
 Kombinasi dengan CyA  menurunkan
relaps.
 CyA : 4 – 20 mg/ kgBB /hari  hambat
kerusakan glomerulus.
 Plasmapheresis
 ACEI
 AntiGBM disease

• RPGN + Lung
haemorrhage
• Destructive process –
medical emergency!
• Antibody-mediated
• One hit
• High dose
immunosuppression
• Plasma exchange
Tx MN
Tx MCNS
 Immunosuppression in GN: Summary

Histological Type Immunosuppression

Anti-GBM and other RPGN Steroids, other agent + plasma
exchange
Membranous (progressive CRF / bad NS) Steroids + other agent
Minimal Change Steroids + other agent
FSGS (immune) Steroids + other agent
FSGS (non-immune) Not indicated
Mesangial IgA disease Not indicated
Thin membrane disease Not indicated
Diabetic glomerulosclerosis Not indicated
Endocapillary GN (post-infectious) Not indicated
 Treatment Glomerulonephritis

• Oral Prednison
• Cyclophosphamide and Oral Prednison
• Chlorambucil and Methylprednisolon
• Cyclosporin
 Response to Steroid

• Remission Complete
• Remission Partial
• Steroid Resistant
 Glomeruler Disease

Nephritis Nephrotic Syndrome

Primary renal : Post Infectious Minimal change

IgA nephropathy Focal Sclerosis
RPGN Membranous nephropathy
Membranoproliferactive GN

Systemic Disease Vasculitis Diabetes Mellitus

Wegener’s Amyloid
 Mechanism of Glomerular Immune Deposit
Formation

Mechanism Tissue Injury Disesase

• Passive complex trapping 1+ ? Post-Strep, IgA
SLE, MPGN
• In sity immune comp. Form
- Fixed glomeruler antigens 2-3+ Goodpasture’s
* GBM 3+ ? Membranous
* Cells 3+ ? Vasculitis, SLE

- Non-glomerular antigens 3+ ? Post-strep, IgA

HCV, HBV, SLE
 Mediators of Glomerular Injury

 Serum Proteins Cell - Derived Substances

Antibody, complement Proteases
 Circulating Cells Oxidants
Neutrophils Prostaglandins
Macrophages Leukrotienes
Lymphocytes Growth factor
Platelets Polycations
 Glomerular Cells Tissue factor
Mesangial Platelet activating factor
Epithelial Tumor necrosis factor
Endothelial Interferons
Tx IgAN
 Post-Streptococcal GN Course

Sign Resolution
• Diuresis 1 week
• Hypertension 2 weeks
• Cr to normal (longest on HD-38 days) 3-4 weeks
• EM Humps 6-7 weeks
• Hematuria 3-6 weeks
• Proteinuria 3 years : 15%; 10 years : 2%

Acute Renal Failure : 5%

Chronic Renal Failure : 2.5%
 Post-Streptococcal GN Course

Etiology - Group A Strep infection

Immune response - IgG anti-strep antibody, 10-21 days
( like serum sickness )
Deposite formation - Humps; in situ, cationic strep antigens
- mesangial, subendothelial : trapped or local
formation of strep antigen immune complexes
Mediation - Strep antigens active C3 directly
Effector cells - Neutrophils, glomerular cells
Response - Diffuse proliferative and exudative GN
Consequences - Resolution following antigen clearance
 IgA Nephropathy

Etiology - ? Viral infections on mucosal surfaces

Immune response - IgA with defective glycosylation, impaired IgG
Deposite formation - Passive trapping of IgA1 - containing
macromolecular aggregates
Mediation - Activation of mesangial cells by IgA aggregates,
C5B-9, PDGF, TGF-
Effector cells - Mesangial cells
Response - PDGF driven mesangial proliferation
- TGF-  driven production of matrix
Consequences - Focal proliferative GN with mesangial
 Types of FGS
• Primarily idiopathic*
- Acute, nephrotic syndrome, diffuse FP fusion
• Acute, severe nephrotic syndrome, black > white
- HIV-associated
- non-HIV
• Secondary FGS
Insidious onset, non-nephrotic, focal FP fusion
- Nephron loss
• Inflamation, hypertension
• Reflux, PKD, renal agenesis
- Obesity
• Familial FGS
* Recurs in transplants
 Causes of Idiopathic Nephrotic
Syndrome

Disease Children Adult ( 1,2 )

Minimal change 70 15
Focal Sclerosis 10 35 (black = 60)
Membranous 15 33
Membranoproliferative 10 10
 Minimal change / Focal Sclerosis

• Etiology : unknown
• Immune response : T cell
• Deposit formation : none
• Mediation : T cell permeability factor (s)
• Response : Effacement, detachment
• Concequences : proteinuria
 Clinical Clasification

Asymptomatic
Proteinuria 150mg to 3g per day
Hematuria >2 red blood cells
per high-power field (>10 x 106 cells/L)
in spun urine (red blood cells usually dysmorphic)

Macroscopic hematuria Nephrotic syndrome

Brown/red paintess hematuria
(no clots); typically coincides with
intercurrent infection
Asymptomatic hematuria ± proteinuria
between attacks
Proteinuria : adult >3.5 g/day;
child >40mg/h per m2
Hypoalbuminemia <3.5g/dl
Edema
Hypercholesterolemia
Lipiduria
 Clinical Clasification

Nephritic syndrome
Oliguria
Hematuria : red cell casts
Proteinuria : ussually <3g/day
Edema
Hypertension Rapidly progressive glomerulonephritis
Abrupt onset, usually Renal failure over days/weeks
self-limiting Proteinuria : usually <3g/day
Hematuria : red cell casts
Blood pressure often normal
May have other features of vasculitis

Chronic glomerulonephritis
Hypertension
Renal insufficiency
Proteinuria >3g/day
Shrunken smooth kidneys