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 M E R U L A R I N J U R Y

CLINICOPATHOLOGIC PRIMARY MECHANISMS CORRELATION BETWEEN SITE AND PRESENTATION CLASIFICATION

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 Schnlein 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 M E R U L A R I N J U R Y

CLINICOPATHOLOGIC PRIMARY MECHANISMS CORRELATION BETWEEN SITE AND PRESENTATION CLASIFICATION

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 antigen

2.

3.

3. Antibody against intrinsic glomerular antigen endothel GBM

epithel

Mechanism of Immune Renal Injury

Etiologic Agent
IR Genes Infections Loss of tolerance

Immune Response
Antibody IgG, IgA T Cells

Deposit Formation
In situ, complex trapping

Mediation
Complement, Chemokines Cytokines, Vasoactive

Effector Cells
PMNs, macrophages Proliferation, PDGF Glomerular cells Scelosis, TGF -

Response

PP

CLINICAL FEATURES
RED BLOOD CELL CASTS PROTEINURIA HEMATURIA

Glomerular injury
Inflammatory glomerular capillary

Perfusion glomerular capillary

FG reabsorption
Na and H2O Tubular volume
Extracelular Volume

AZOEMIA

OLIGURIA HYPERTENSION 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 In spun urine (red blood cells Usually dysmorphic

Nephritic syndrome (Inflamasi glomerulus) Oliguria Hematuria : red cells casts Proteinuria; usually < 3g/day Oedema Hypertension Abrupt onset

Nephrotic syndrome Proteinuria; adult > 3,5 g/day Child > 40 mg/h per m2 Edema Hypercholesterolemia Lipidemia Rapidly progressive glomerulonephritis Renal failure over days/weeks Proteinuria usually < 3 g/day Hematuria; red cell casts Blood pressure often normal May have other features of vasculitis

Cronic glomerulonephritis Hypertension Renal insufficiensy Proteinuria > 3 g/day Shrunkensmooth kidneys

 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)

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 Bergers 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
Anti-GBM and other RPGN

Immunosuppression
Steroids, other agent + plasma exchange Steroids + other agent Steroids + other agent Not indicated Not indicated

Membranous (progressive CRF / bad NS) Steroids + other agent Minimal Change FSGS (immune) FSGS (non-immune) Mesangial IgA disease

Thin membrane disease

Diabetic glomerulosclerosis Endocapillary GN (post-infectious)

Not indicated
Not indicated 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 Primary renal : Post Infectious IgA nephropathy RPGN Nephrotic Syndrome Minimal change Focal Sclerosis Membranous nephropathy Membranoproliferactive GN

Systemic Disease

Vasculitis Wegeners

Diabetes Mellitus Amyloid

Mechanism of Glomerular Immune Deposit Formation

Mechanism Tissue Injury Disesase

Passive complex trapping

In sity immune comp. Form - Fixed glomeruler antigens

1+

? Post-Strep, IgA SLE, MPGN

Goodpastures

2-3+

* GBM
* Cells - Non-glomerular antigens

3+
3+ 3+

? Membranous
? Vasculitis, SLE ? Post-strep, IgA HCV, HBV, SLE

Mediators of Glomerular Injury

Serum Proteins Antibody, complement Circulating Cells Neutrophils Macrophages Lymphocytes Platelets Glomerular Cells Mesangial Epithelial Endothelial Cell - Derived Substances Proteases Oxidants Prostaglandins Leukrotienes Growth factor Polycations Tissue factor Platelet activating factor Tumor necrosis factor Interferons

Tx IgAN

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

Acute Renal Failure : 5% Chronic Renal Failure : 2.5%

Post-Streptococcal GN Course
Etiology Immune response - Group A Strep infection - 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 Effector cells Response Consequences - Strep antigens active C3 directly - Neutrophils, glomerular cells - Diffuse proliferative and exudative GN - Resolution following antigen clearance

IgA Nephropathy
Etiology Immune response Deposite formation Mediation Effector cells Response Consequences - ? Viral infections on mucosal surfaces - IgA with defective glycosylation, impaired IgG - Passive trapping of IgA1 - containing

macromolecular aggregates
- Activation of mesangial cells by IgA aggregates, C5B-9, PDGF, TGF- - Mesangial cells - PDGF driven mesangial proliferation - TGF- driven production of matrix - 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 Focal Sclerosis Membranous Membranoproliferative

70 10 15 10

15 35 (black = 60) 33 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
Brown/red paintess hematuria (no clots); typically coincides with intercurrent infection Asymptomatic hematuria proteinuria between attacks

Nephrotic syndrome
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 Abrupt onset, usually self-limiting

Rapidly progressive glomerulonephritis

Renal failure over days/weeks 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