Glomerulonephritis

Lestariningsih

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

Glomerulonephritis

LestariningsihSubBag Nefrologi-Hipertensi

Bagian Ilmu Penyakit Dalam

FK UNDIP / RSUP Dr. Kariadi Semarang

GENERALITIES

CLINICOPATHOLOGIC

PRIMARY MECHANISMS

CORRELATION BETWEEN SITE AND PRESENTATION

CLASIFICATION

GLOMERULAR

INJURY

Normal Glomerulus

1. Bowman space2. 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 artery9. Efferen artery10.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

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

Glomerular injury

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

CLINICOPATHOLOGIC

PRIMARY MECHANISMS

CORRELATION BETWEEN SITE AND PRESENTATION

CLASIFICATION

GLOMERULAR

INJURY

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 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,

1.

2.

3.

GBM

epithel endothel

1. Deposition of circulating immune complex

2. Circulating antibody against “planted” antigen

3. Antibody against intrinsic glomerular antigen

PATHOGENESIS GLOMERULONEPHRITIS

Mechanism of Immune Renal Injury

Etiologic Agent

Immune Response

Deposit Formation

Mediation

Effector Cells

Response

InfectionsLoss of tolerance

IR Genes

AntibodyIgG, IgA T Cells

In situ, complex trapping

Complement, Chemokines Cytokines, Vasoactive

PMNs, macrophages Glomerular cells

Proliferation, PDGF Scelosis, TGF -

PP

Glomerular injury

Inflammatory glomerular capillary

Perfusion glomerular capillary

FG reabsorption

Na and H2O

Acute renal failure

Tubular volume

Extracelular Volume

CLINICAL FEATURES

RED BLOOD CELL CASTS

PROTEINURIA

HEMATURIA

AZOEMIA

OLIGURIA HYPERTENSION

EDEMA

CLINICOPATHOLOGIC

Renal failure

• 1/Cr plot• Linear deterioration

• eGFR and CKD

AsymptomaticProteinuria 150mg to 3g/dayHematuria > 2 red blood cells

Perhigh-power field (> 10x106 cells/LIn spun urine (red blood cells

Usually dysmorphic

Cronic glomerulonephritisHypertension

Renal insufficiensyProteinuria > 3 g/day

Shrunkensmooth kidneys

Nephritic syndrome(Inflamasi glomerulus)

Oliguria Hematuria : red cells casts

Proteinuria; usually < 3g/dayOedema

HypertensionAbrupt onset

Nephrotic syndromeProteinuria; adult > 3,5 g/day

Child > 40 mg/h per m2 Edema

Hypercholesterolemia Lipidemia

Rapidly progressive glomerulonephritisRenal failure over days/weeksProteinuria usually < 3 g/day

Hematuria; red cell castsBlood pressure often normal

May have other features of vasculitis

Clinical Presentations of glomerular disease

• 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 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.PlasmapheresisACEI

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 ImmunosuppressionAnti-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, IgASLE, 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 15Focal Sclerosis 10 35 (black = 60)Membranous 15 33Membranoproliferative 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

AsymptomaticProteinuria 150mg to 3g per day

Hematuria >2 red blood cellsper high-power field (>10 x 106 cells/L)

in spun urine (red blood cells usually dysmorphic)

Macroscopic hematuriaBrown/red paintess hematuria

(no clots); typically coincides withintercurrent infection

Asymptomatic hematuria ± proteinuriabetween attacks

Nephrotic syndromeProteinuria : adult >3.5 g/day;

child >40mg/h per m2

Hypoalbuminemia <3.5g/dlEdema

HypercholesterolemiaLipiduria

Clinical Clasification

Nephritic syndromeOliguria

Hematuria : red cell castsProteinuria : ussually <3g/day

EdemaHypertension

Abrupt onset, usuallyself-limiting

Rapidly progressive glomerulonephritisRenal failure over days/weeksProteinuria : usually <3g/day

Hematuria : red cell castsBlood pressure often normal

May have other features of vasculitis

Chronic glomerulonephritisHypertension

Renal insufficiencyProteinuria >3g/day

Shrunken smooth kidneys