GLOMERULONEPHRITIS

Main patterns of renal diseases

Glomerular nephropathies

Tubular nephropathies Vascular nephropathies

1.Glomerular nephropathies 2.Tubulo-interstitial nephropathies 3.Vascular nephropathies

Interstitial nephropathies 2

Glomerulonephritis - definition
Diseases of the renal corpuscle (or glomerulus) Etiology - often unknown Mechanisms:
immune non-immune
biochemical haemodynamic

Characteristics:
Histopatholgy - glomerular damage: native renal cells proliferation, GBM lesions, deposits of various substances, hialino-sclerosis etc Clinical presentation - proteinuria associated with haematuria, oedema, arterial high blood pressure and renal insufficiency

Evolution - variable, but frequently to CRF

GN incidence (ANZ DATA)

Relatively rare diseases
Australia
GN incidence - 126 pmp (0,01%) GN incidence in ESRD - 15 pmp (0,001%) Nephropathy

Renal biopsy per milion pop years (%) 42,87 (34,1%)

21,27 (16,9%) 17,40 (13,9%) 15,60 (12,3%) 13,27 (10,6%) 5,59 (4,0%)

IgAN
FSGS Lupus GN Vasculitis Membranous N MCD

Romania (by extrapolation)

GN incidence ~ 2.250 new cases/year (0,01%) GN incidence in ESRD ~ 900 new cases/year (0,004%)

Thrombotic N
MPGN

3,18 (2,5%)
2,74 (2,2%)

Post-inf. GN
Goodpasture Total

2,41 (1,9%)
0,99 (0,8%) 125,76 (100%)

4 Briganti EM et al, Nephrol Dial Transplant. 2001 Jul;16(7):1364-7

Terminology
Glomerulitis diseases with inflammatory, proliferative lesions, limited to glomerulus Glomerulo-nephritis diseases with inflammatory, proliferative lesions, involving glomeruli and other renal structures Glomerular nephropathies diseases with noninflammatory, non-proliferative lesions, involving glomeruli and other renal structures Glomerular diseases diseases with renal lesions, inflammatory proliferative - or not, predominantly or initially glomerular
5

Terminology - Classification
1. Based on etiology
Idiopathic GN unknown aetiology Secondary GN identified aetiology Primary GN: lesions localized initially in the kidney (systemic lesions are direct consequences of the glomerular ones) Secondary GN: renal lesions are components / consequences of a systemic disorder Acute GN days, weeks, months Subacute GN weeks, months Chronic GN months, years

2. Based on histopathology

3. Based on evolution

Renal corpuscle = Capillary tuft (glomerulus) + Bowmans capsule

Efferent arteriole
Afferent arteriole

Glomerular filtration membrane

Renal tubule

Bowmans capsule

Parietal epithelium

Filtration space
Visceral epithelium

Capillary tuft
7

Renal corpuscle
Cells
a) Resident cells
Endothelial Mesangial Epithelial:
visceral (podocytes) parietal

b) Migrating cells

Sustaining tissue
a) Basement membranes Renal corpuscle (LM) = b) Extracellular matrix glomerulus (capillary tuft)
Bowmans capsule

+
8

Glomerular capillary loop (EM)

Glomerular capillary loop (EM)

10

Basic glomerular lesions

1. Cells proliferation = increased number of resident glomerular cells or inflammatory infiltrate localized:
a) Intracapillary (endocapillary) endothelial or mesangial cells, leucocytes b) Extracapillary parietal epithelial cells of the Bowmans capsule (crescent formation)

2. Lesions of the glomerular basement membrane:

thickening, neoformation thinning longitudinal splitting holes

11

Basic lesions
3. Deposits:
Type:
Organized/Amorphous

Localization

External side
(extra/epi-membranous, subepithelial)

Granular
Mesangium Linear

Internal side
(endomembranous, subendothelial)
12

Basic lesions
4. Sclerosis = formation of an homogenous, nonfibrillary material, chemically and ultrastructurally resembling GBM or mesangial matrix

5. Hyalinosis = accumulation of an eosinophilic,

translucent material

6. Fibrosis = collagen type I, II (not type IV) deposition 7. Necrosis of the flocculus

13

Classification
Based on histopatology:
1) Etio-pathogenesis of GN is often unknown 2) Clinical features are rather unspecific 3) Various etiological factors can produce the same histopathology pattern 4) The same etiological factor can lead to different histopathology patterns of GN 5) Several well characterized histopathology patterns, with unitary enough clinical, therapeutic and prognostic characteristics were defined
14

Classification process extension

a) diffuse/focal GN

b) global/segmental GN

>50% glomeruli

<50% glomeruli

whole capillary tuft

only few (parts of) capillary loops

Classification clinical
1.

with NEPHRITIC syndrome

acute glomerulonephritis subacute glomerulonephritis

2.

with NEPHROTIC syndrome

chronic glomerulonephritis (primary/secondary)
1. 2. 3. 4. minimal change disease (MCD) membranous nephropathy (MN) focal and segmental glomerulosclerosis (FSGS) membrano-proliferative glomerulonephritis (MPGN)

3.

with (MINOR) URINARY ABNORMALITIES

chronic glomerulonephritis (primary/secondary)
1. IgA nephropathy (Berger d. )
17

Etiological factors
Specific mechanisms
a) Immune mechanisms b) Non-immune mechanisms

Glomerular lesions
Unspecific mechanisms Scars Tubulo-interstitial lesions Chronic renal failure

Resolution

19

Glomerulonephritis
a) GN with nephritic syndrome b) GN with nephrotic syndrome c) GN with urinary abnormalities
35

Patterns of glomerular injury

Subendothelial pattern Mechanism Consequences

b) Clinical
Activation within the capillary: Proteases, complement, coagulation/fibrinolysis, kinines Proliferation and exsudation Nephritic syndrome GFR reduction Post-infectious GN Anti-GBM nephritis 36 SLE (III, IV)

a) Histopathological Severe inflammatory reaction

Clinical conditions

Nephritic syndrome
An association of clinical and laboratory findings characterized by:
Oedema Moderate systolo-dyastolic arterial high blood pressure Oliguria Macroscopic/microscopic haematuria with dysmorphic erythrocytes Erythrocyte casts, granular casts Leucocyturia, always inferior to haematuria Variable, non-selective proteinuria, usualy <3.5g/day Renal failure -/+ and glomerular proliferative lesions

Nephritic urinary sediment

Dysmorphic eryhtocytes

Erythrocyte casts
38

Acute diffuse glomerulonephritis

39

Aetiology - determinant factors [1]

A. Infections
1. Post-streptococcal acute diffuse GN (60-68%)
Streptococcus group A, type 4 (epidemics) i type 12 (sporadic)

2. Non-streptococcal acute infectious GN (32-40%)

Bacterial infections Infective endocarditis (staphylococci), septicaemia, shunt nephritis, pneumococcal pneumonia, visceral abscesses, osteomyelitis, syphilis, typhoid fever, meningococcal meningitis, leprosy, brucellosis, leptospirosis Viral infections
hepatitis B, CMV, MI, Coxsackie or ECHO measles, mumps

Protozoal: malaria, toxoplasmosis, schistosomiasis, filariasis 40 Other: Rickettsial, fungal infections

Aetiology determinant factors [2]

B. Systemic diseases
Systemic lupus erythematosus Vasculitis Goodpasture syndrome Thrombotic microangiopathies

C. Primary glomerular nephropathies

membrano-proliferative GN GN with mesangial deposits of IgA

D. Various
Guillain-Barr syndrome Serum sickness DTP vaccination
41

Aetiology - favoring factors

Age
Maxim incidence 15-20 years (rare < 4 years)

Gender
M=2F

Climate
cold, wet (autumn, winter)

Diet
malnutrition, vitamin deficiencies

Genetic factors
more common associated with HLA DR4, DR38, DR37 no familial aggregation
42

Post-strept. AcDGN pathogenesis

Streptococcal infection Streptococcal Ag

1) 2) 3) 4)

planted in glomerulus - unchanged planted in glomerulus - incomplete (haptene) antigen mimicry - renal structural Ag deposition of circulating immune complexes

Ab-Ag
Glomerular inflammation

43

Histopathology (LM)

LM DIFFUSE ENDOCAPILLARY PROLIFERATION

mesangial, endothelial cells inflammatory infiltrate (PMN, Mo)

reduction of capillary lumen

+
44

Histopathology (LM)

LM DIFFUSE ENDOCAPILLARY PROLIFERATION

mesangial, endothelial cells inflammatory infiltrate (PMN, Mo)

reduction of capillary lumen

+
45

Histopathology (IF)

Garlands deposits of Ig (Ig G) and complement

46

Histopathology (EM)

Dense deposits on external side (humps, chapeau rouge)

47

Clinical features

A) Causative infections
Most frequent: streptococcal pharyngitis Rare: skin streptococcal infections (impetigo, ectima, erizipelas)
48

Clinical features
B) Latentcy period (10-14 days) C) Acute nephritic syndrome
1. oedematous syndrome (2/3 of cases) 2. urinary syndrome
oliguria dark-red turbidurine (meat wash, Coca cola) increased urinary density (osmolarity) proteinuria 1-3g/day (50%<0.5g/day; 20% nephrotic domain) reduced urinary excretion of Na, nitrogen compounds haematuria initially macroscopic, subsequent microscopic with dismorphic erythrocyte leucocyturia less than haematuria erythrocyte, granular casts
49

Clinical features
3. Renal insufficiency syndrome 4. Cardio-vascular syndrome
Arterial hypertension (70-80%) - moderate, systolo-dyastolic (hypervolaemia) Acute pulmonary oedema (12%) Nephritogen eclampsia Volhard

5. Infectious syndrome (subfever, malaise etc)

50

Laboratory data
1. Immunological profile
Markers of causative infection:
increased ASLO (in evolution) 75% Anti DN-aza B 90% Anti hialuronidase (skin infections)

Transient hypocomplementaemia (8 weeks) Cryoglobulinaemia Presence of CIC

2. Normal/ renal size (plain radiograph, ultrasound) 3. Renal biopsy - usualy, not necessary
51

Differential diagnosis
1. Acute focal and segmental glomerul[onephr]itis
exclusively urinary abnormalities

2. Chronic glomerulonephritis (acute phase)

lack of the latent period pharyngitis - onset reduced urinary density reduced kidney size

3. Subacute glomerulonephritis
clinical presentation is dominated by renal failure subacute evolution (weeks) renal biopsy needed for diagnosis 52

Outcome. Complications
Outcome
1. Healing 50-70% (6-12 months - 3 years)
diuresis increases after 7 days, normalization of GFR after 3-6 weeks haematuria disappears in 3-6 months proteinuria persists >6 months

2. Death 0.5-2% (APE, stroke, ARF) 3. Chronic evolution 10-20%

Complications
ARF Heart failure (APE) Eclampsia Infections

53

Prophylaxis
1. 2. 3. of the disease correct treatment of the streptococcal infections (PENICILLIN G) of the complications early and correct treatment of the relapses eradication of chronic infection sites after the acute episode

54

Therapy (post-streptococcal GN)

Diet:
bed rest until disappearance of oedema hypertension and haematuria diet: fluid intake depending on diuresis, hyposodate, normocaloric, hypoproteic (0,6g/kg)

Anti-infectious:
Pencillin G, 400.000UI im every 6 hours, 14 days Bezantinpenicillin 1.400.000UI every 14 days, 1-2 years Macrolides (erythromicin 2g/d)

Infection sites eradication after 3 months

55

Therapy (post-streptococcal GN)

Pathogenic treatment - no demonstrated usefulness Treatment of complications
Hypertension Acute pulmonary oedema Eclampsia ARF

hyposodate diet diuretics antihypertensive drugs

hemodialysis

56

Subacute glomerulonephritis
Crescentic glomerulonephritis Extracapillary (proliferative) glomerulonephritis Rapidly progressive glomerulonephritis Malignant glomerulonephritis

57

General characteristics
1) GN with intense extracapillary proliferation Crescents formation in >60% glomeruli
2) Nephritic syndrome - features
absent/moderate oedema Arterial hypertension is not frecquent RF (GFR reduction with > 50%) in weeks-months (<3 months)

3) Without therapy, leads constantly to ESRD and death in 6 months - 2 years

58

Renal histopathology (LM)

Crescent formation in the urinary space

59

Crescents formation
1) Various injuries GBM attack (PMN, C5b-9, Mo etc) 2) Glomerular capillary wall breaks Coagulation Fibrinogen in urinary space activation 3) Fibrin in urinary space Mo, L chemoattraction Proliferation of the epithelial cells from Bowmans capsule 4) Crescent formation Breaked Bowmans capsule Intact Bowmans capsule Cellular crescents GBM, collagen IV synthesis CRESCENT Fibro-cellular crescents DISAPPEARANCE Fibrous crescents GLOMERULAR FIBROSIS
60

Classification - IF
1) with granular deposits (immune complexes) - 40%
Post-infectious GN Systemic diseases (SLE) Henoch-Schnlein purpura superimposed on certain primary glomerular nephropathies (IgA N; MN; MPGN; FSGS)

2) with linear deposits (anti-GBM Ab) - 10-20%

with pulmonary haemorrhage - Goodpasture syndrome without pulmonary haemorrhage

3) without immune deposits or with few deposits (pauciimmune), 10-20%, but with Anti-Neutrophil Cytoplasmic Antibodies (ANCA) [+]
Small vessel vasculitis: SYSTEMIC microscopic polyangeitis Wegeners granulomatosis Churg-Strauss syndrome RENAL LOCALIZATION

61

Symptoms
A) Onset B) Clinical period C) Laboratory data
62

A) Onset
1. Acute onset Anti GBM Ab / Pauciimmune
Oliguria + H-urie macroscopic + oedema Flu-like syndrom
(fever, malaise, headaches, arthralgia, odinophagya)

2. Onset ~ Rheumatoid purpura

Purpura Arthritis Abdominal pains, melena

Pauciimmune/ICx

3. Insidious onset: H-uria, P-uria, randomly discovered RF 4. Onset in two steps ICx (superimposed CGN)
initially, P-urie, subsequent, rapidly progressive RF
63

B) Clinical features
1. 2. 3. 4. Haematuria (macroscopic) + oliguria Oedema - mild/moderate +/- HBP +/- Systemic signs: purpura, acute pneumopathy,
haemorrhagic alveolitis, unexplained anemia, arthritis, polyneuropathy, fever etc

64

C) Laboratory data
1. Urine examination
oliguria anuria proteinuria (<3,5g/24h, non-selective) Reduced excretion of nitrogen compounds/electrolytes sediment: H-uria (dysmorphic + non-dysmorphic), erythrocyte, granular casts

2. Rapidly progressive azotaemia 3. Immunology lab data useful for differential diagnosis 4. Renal biopsy mandatory for diagnosis 5. Imaging examinations - normal/ kidney size
65

Biological presentation
Laboratory data
Anti MBG Ab Anti-DNA, anti-Sm Ab Cryoglobulins C3NeF ASLO, anti B DN-ase, anti-hialuronidase ANCA C4, normal C3 C4, C3 Complement normal C3, C4 IgG, IgM IgE IgA Goodpasture syndrome SLE Cryoglobulinaemia MPGN type II Post-streptococcal GN Vasculitis Cryoglobulinaemia SLE Post-infectious GN MPGN type I LE, vasculitis, infectious GN Churg-Strauss syndrome IgA nephropathy Henoch-Schnlein purpura
66

Immunoglobulins

Biological presentation
Laboratory data
Acute phase proteins Albumin decrease Neutrophils, thrombocytosis Eozinophils Leucopenia, thrombopenia Severe anaemia CRP + ESR N CRP + ESR Vasculitis SLE Vasculitis Vasculitis Churg-Strauss syndrome SLE Goodpasture syndrome Endocarditis, infected cerebral shunt
67

Haematologic

Positive blood cultures

Diagnosis
Nephritic syndrome with:
HTA -/+ Oedema -/+ Rapidly progressive RF (weeks, months) Characteristic serology (high ESR, ANCA, low C, anti-GBM Ab)

Renal biopsy:
Crescent formation >60% glomeruli
68

Differential diagnosis
ADGN Thrombotic microangiopathies
TTP, HUS post-partum ARF scleroderma malignant arterial hypertension

Allergic acute interstitial nephropathy Renal athero-embolism CRF (other causes)

69

SUBACUTE GLOMERULONEPHRITIS

1. SAGN with anti-GBM antibodies 2. Pauciimmune SAGN 3. SAGN with ICx

70

1 - Goodpasture syndrome (10%)

1. <1-2 cases/1 million inhabitants, per year 2. PATHOGENETIC antibodies:
anti-GBM (AlvBM) against alfa3 chain of the type IV collagen linear disposition at IF

3. RPGN haemorrhagic alveolitis 4. Evolution: rare relapses

Ernst Goodpasture, American pathologist

71

Epidemiology
Rare disease
incidence 0,5-2 cases/1 million inhabitants year 1% from all glomerulonephritis 10% from SAGN

Incidence with bimodal distribution

III-rd decade VI-th, VII-th decade

Environmental factors
Viral infections Exposure to hydrocarbons Extracorporal lithotripsy Cigarette smoking (pulmonary haemorrhage)

Disease associations
Idiopathic MN ANCA + vasculitis (10-20%)
72

Goodpasture antigen

type IV collagen network

73

Humoral immunity role

Anti-GBM Ab are involved in the pathogenesis:
1. Ab eluated from kidneys of patients could cause pathological glomerular changes in animals (pasive transfer of the disease) (Lerne, 1967) 2. Correlation between Ab titre and the activity of disease (Saxen, 1989) 3. Strong association between renal prognosis and the ability of Ab to bind NCI (Hellmark, 1999) 4. Reduction of Ab titre by plasma exchanges is followed by clinical remission (Pusey, 2000)
74

Cell-mediated immunity
T lymphocytes:
1. are constantly present in renal lesions; 2. show proliferative response to alfa3(IV)NCI; 3. autoreactive TL are more frequent in patients compared to controls; 4. the percent of autoreactive TL decreases in remission.

75

Histopathology (LM)

Mesangial expansion + hypercellularity Focal and segmental GN Segmental necrosis of the capillary loop Crescent formation Lesions are at the same stage of evolution

76

Histopathology (IF)

linear deposits of Ig (IgG, IgM, IgA)

77

Clinical features
1. Systemic features
lesser than in vasculitis more common than in SAGN with ICx

78

Clinical features
2. Haemorrhagic alveolitis:
precedes, coexists, follows GN or is absent favored by:
smoking infections uraemia fluid overload

variable in intensity imprevisible outcome (frequent cause of death)

79

Clinical features
3. Renal features
Oliguria Haematuria (macroscopic) Proteinuria <3.5g/day Extremely rapid progressive renal failure

80

Diagnosis
Rapidly evolutive pneumo-renal syndrome
pulmonary haemorrhage (70%) RPGN

+
Identification of anti-GBM Ab
circulating (ELISA - 5% false positive) fixed on GBM (indirect IF - 40% false positive)

+
Renal biopsy
Crescent formation (the same evolutive stage of lesions) IF anti-GBM Ab, linear staining
81

Differential diagnosis
1. Severe heart failure with pulmonary oedema 2. RF of any cause complicated with pulmonary oedema 3. Vasculitis with immune complexes:
SLE Henoch-Schnlein purpura Cryoglobulinaemia Drugs: penicillamine, hydralazine

4. Pauciimmune vasculitis
Wegeners granulomatosis PAN

5. Infectious diseases Legionellosis, Leptospirosis 6. Renal venous thrombosis with pulmonary thrombembolism
82

Natural history. Prognosis

Natural history - rare relapses
n Creat <5mg/dL Creat >5mg/dL Dialysis Total
Levy et al, 2001

19 13 39 71

Patient survival (%) 100 83 65 77

Kidney survival (%) 95 82 8 63

Serum creatinine >5mg/dL >75% crescents + fibrosis

poor prognosis
83

Treatment
Aim: rapid reduction of anti-GBM Ab titre Plasmapheresis
60mL/kg (Mx 4L) 14 days or until anti-GBM negative

Prednisolone
1mg/kg day (max 60mg) 7 days initially reduction with 5mg per week discontinuation at 6 months

Cyclophosphamide
2-3mg/kg day (2mg/kg over 50 years) discontinuation at 3 months
84

SUBACUTE GLOMERULONEPHRITIS

1. SAGN with anti-GBM Ab 2. Pauciimmune SAGN 3. SAGN with ICx

85

General characteristics
Incidence 10-15 cases/1 million inhabitants Clinical
SAGN frequent associated with Systemic features

Pathology
GN with crescent formation and immune deposits few/absent small vessel vasculitis

Immunological
ANCA (+) Absence of: CIC, anti-GBM Ab and cryoglobulins Normal serum complement

Evolution frequent relapses/recurrences

86

The main causes

Necrotizing angeitis of small vessel a) Without granulomas
1. Angeitis localized exclusively in the kidney 2. Systemic microscopic angeitis 36,2% 32,8% 20,7% 10,3%

b) With granulomas
1. Wegeners granulomatosis 2. Other angeitis (Churg-Strauss etc)

87

Histopathology (LM)

Initially, segmental necrotizing glomerulonephritis

88

Histopathology (LM)

Subsequent, crescent formation Lesions in different stages usualy coexist.

89

Histopathology (LM)

Breaks in the capillary basement membrane. Lack of deposits.

90

Histopathology (LM)

Necrotizing arteritis
91

Antineutrophil cytoplasmic antibodies - ANCA

Davies (1982) showed Ab reacting with neutrophil cytoplasma, in patients with necrotizing GN de Wounde (1985) association cANCA Wegeners granulomatosis Falk i Jennette (1990) ANCA could activated cANCA the leucocytes

pANCA (cytoplasmic: anti- (perinuclear: antiproteinase 3) myeloperoxidase)

92

ANCA assays
Indirect immunofluorescence using ethanol-fixed neutrophils
Ab anti-PR3 (cANCA) Ab anti-MPO (pANCA)

ELISA Association of tests:

increases specificity 70% increases sensibility 90%
93

Are ANCA involved in pathogenesis?

Viral/bacterial infection Cytokines (TNFalfa, IL-1)

ANCA

Expression of MPO/PR3 on neutrophil surface Endothelial adhesion (beta integrines) Neutrophil activation (ROS, lytic enzymes)

Endothelial injury
94

Clinical features
Onset usualy insidious Constitutional symptoms frequent
fever/subfever sweat malaise weight loss

95

Clinical features
Systemic features (useful for diagnosis) Microscopic GW Churg-Strauss angeitis Cutaneous 40 40 60 Musculoskeletal 60 60 50 Neurological 30 50 70 Gastrointestinal 50 50 50 Respiratory airways 35 90 70 Pulmonary 50 90 70 Renal 90 80 45
96

Clinical features
Renal features
nephritic syndrome rapidly progressive renal insufficiency seldom, hydronephrosis

97

Are ANCA useful for diagnosis ?

100% 80% 60% 60% 40% 20% 0% Pauciimmune Anti-MBG ICx
Falk, RJ, Am Soc of Nephrol, 2000 98

28%

21%

cANCA pANCA Negative

ANCA in pauciimmune SAGN

anti-PR3 (cANCA) GW 85% Microscopic angeitis 45% Churg-Strauss 10% anti-MPO (pANCA) 10% 45% 60%

99

Diagnosis
1. Suggestive clinical aspects
SAGN + Constitutional symptoms + Systemic features ANCA + ICx, absent cryoglobulins, normal complement

2. Characteristic serological markers 3. Renal biopsy

100

Natural history. Prognosis

Natural history
frequent relapses 17-30% cases mean duration until relapse 2,2 years (40 days 15 years)

Prognosis at 2 years
ESRD 21% Death 26%
101

Treatment INDUCTION (sCr <5mg/dL)

Prednisolone
1mg/kg, with weekly reduction until 20mg/kg iv (puls) 0,5-1g/m2 po 3mg/kg

Cyclophosphamide 3 months

+/- (severe cases)

Plasmapheresis 4L daily, 7-10 days or Metilprednisolone
10-15mg/kg day, 3 days

102

Treatment MAINTENANCE
2 years
Prednisolone 20mg/day, gradual reduction Azathioprine 1-2mg/day

103

Can ANCA predict the outcome ?

104

35 30 25 20 15 10 5 0 '9-10 '7-8 '5-6 4 Abs

105

29

7 4

8 7 6 5 4 3 2 1 0 '9-10 '7-8 4 6

'5-6

4
106

Subacute glomerulonephritis
1. SAGN with anti-GBM Ab 2. Pauciimmune SAGN 3. SAGN with immune complexes
107

Etio-pathogenesis
Frequency
20-30% from SAGN (cumultive data in the world) 15% from SAGN (Romania)

Aetiology
Frequent, secondary to:
Post-infectious acute diffuse GN IgAN/ Henoch-Schnlein purpura Membrano-proliferative glomerulonephritis Membranous nephropathy SLE nephropathy Cryoglobulinaemia

Rare, primary

Pathogenesis
Deposition/formation of immune complexes
108

Clinical features
Renal or systemic pre-existing disease Systemic features: lesser than in all other SAGN Renal features:
nephritic syndrome rapidly progressive renal failure more common than in all other SAGN:
nephrotic syndrome arterial hypertension

Immunological characteristics:
Presence of CIC, cryoglobulins Decreased serum complement lack of ANCA
109

Renal biopsy
LM
Crescent formation Characteristics lesions for pre-existing nephropathy

IF
granular deposits of Ig (Complement)

EM
identifies the location of deposits
subepithelial acute diffuse GN subendothelial SLE mesangial - IgAN
110

Diagnosis
Pre-existing nephropathy + SAGN + Renal biopsy with granular deposits (IF)

111

Treatment
Induction, depending on underlying disease
Corticotherapy
Metilprednisolone 7-15mg/kg day, 3 days Prednison 60mg/zi, 7 days, subsequent reduction

Cyclophosphamide
3 mg/kg day, 8-12 weeks

Plasmapheresis (?)

Maintenance, depending on underlying disease

Prednisolone 40mg/day, slow reduction Azathioprine 1-2mg/day
112

The main GN types

a) GN with nephritic syndrome b) GN with nephrotic syndrome c) GN with urinary abnormalities
113

Nephrotic syndrome
A complex of clinical and laboratory findings characterized by:
proteinuria >3.5g/day (2.5mg/min or >3 g protein/g creatinine in urine) its consequences:
hypoalbuminaemia oedema hyperlipidaemia, lipiduria enhanced coagulability infections

as a result of abnormal glomerular basement membrane permeability

114

Glomerular filtration barrier

1) Endothelium (lamina fenestrata) 2) Glomerular basement membrane:

Lamina rara interna Lamina densa Lamina rara externa

3) Visceral epithelium
Slit pore membrane (slit diaphragms)
115

Mechanisms of the barrier function

1) Size selectivity (< 150kD)
GBM Epithelial filtre (slit pore membrane)

2) Molecular shape selectivity

GBM

3) Charge selectivity (70-150kD)

Endothelium GBM (polyanionic glycoproteins) Epithelium

116

Nephrotic syndrome associated GN

1. 2. 3. 4. 5. 6. Minimal change disease Membranous nephropathy Focal and segmental glomerulosclerosis Membrano-proliferative glomerulonephritis Diabetic nephropathy Amyloid nephropathy

117

Minimal change disease

Lipoid nephrosis

80% from nephrotic sd. in children 20% from nephrotic sd. in adults
118

Aetiology
Primary (80%) Secondary (20%)
Respiratory tract infections Allergy (atopy) (HLA-B12) Hodgkins disease, other lymphoproliferative diseases Drugs (NSAID, rifampicin, IFN) Heroin iv Dextran iron HIV
119

Histopathology (1)
LM normal glomeruli

IF absence of immune deposits

120

Histopathology (2)

EM

no parietal deposits podocyte foot-process fusion (effacement) microvillus formation 121

Clinical features (1)

Oedema - anasarca Normal blood pressure Urine examination
oliguria increased urinary density

122

Clinical features (2)

massive proteinuria (>3.5g/day; 50mg/kg-day), selective

>85% albumin selectivity index (IgG Cl / transferrin Cl) <0,1

enzymuria glycosuria +/-

123

Clinical features (3)

Urinary sediment
H absent L +/Transudation casts (hyaline) Fat bodies

Renal function = normal Blood chemistry:

Hypoproteinaemia
Hypoalbuminaemia Hyper alfa2, beta Hypo gamma

Hyperlipoproteinaemia Increased fibrinogen Increased ESR Microcytic hypocromic anaemia Deficiency of ATIII, C, S proteins

124

Pathogenic treatment

Corticosteroids
adults then children then 1-1.5mg/kg day 4 weeks 1mg/kg every other day, 4 weeks 60mg/mp day (<80mg), 4 weeks 40mg/mp every other day, 4 weeks
125

Pathogenic treatment
Alkylating agents
Cyclophosphamide 2-3mg/kg day, 8-12 weeks or chlorambucil 0,1-0,2mg/kg day, 8-12 weeks

Cyclosporin (5-8mg/kg day, 8-12 months)

126

Membranous nephropathy - MN
extramembranous glomerulonephritis epimembranous glomerulonephritis membranous glomerulonephritis

20% from nephrotic sd. in adults

127

Aetiology
Idiopathic MN 75% Secondary MN 25%
Infections (Hep B, Hep C, syphilis, malaria, schistosomiasis) Solid malignancies (10%) Systemic diseases (SLE, RP, SD, DM, sarcoidosis) Drugs (captopril, NSAID, organic gold compounds, D-penicillamine) Renal transplantation (de novo/recurrence)
128

Pathogenesis
Disease with immune complexes located subepithelial
a) In situ formed:
Circulating Ab glomerular structural Ag (idiopathic MN) - podocytes surface (gp330 megaline) - lamina rara externa Circulating Ab exogenous cationic Ag planted in glomerulus (secondary MN : SLE, tumours, infections)

b) Formed in the circulation and deposited in glomeruli (secondary MN : VHB, malaria, neoplasia)

Consequent complement activation (C5b-C9) ROS Podocyte lesions Growth factors

129

Histopathology (LM)

Irregular GBM thickening

130

Histopathology (LM)

GBM thickening + spikes formation

131

Histopathology (IF)

granular deposits of IgG along the capillary walls

132

Histopathology (EM)

1. dense deposits on the external side of GBM 2. spikes formation 3. podocyte foot-processes effacement

133

Histopathology

Stage I Stage II spike subepithelial formation osmiophilic deposits with no GBM projections

Stage III deposits incorporation by the adjacent spikes

Stage IV vacuolated appearance

MN stages at EM

134

Clinical features
Nephrotic syndrome
30% asymptomatic non-selective proteinuria - 80%

Urinary sediment
microscopic haematuria (20-55%) hyaline casts fat bodies

Hypertension - rare at onset (10-20%) Renal insufficiency - rare at onset (10%)

135

Complications
A. Renal vein thrombosis (5-35%) B. Accelerated atherosclerosis increased CV risk C. Sudden deterioration in renal function:
1) ARF
a) functional, pre-renal, due to hypovolaemia diuretics b) renal (ischaemic tubular necrosis), due to prolonged hypovolaemia + interstitial oedema

2) Renal vein thrombosis 3) Drug-related interstitial nephritis (diuretics, antibiotics) 4) Superimposed crescentic GN

136

Natural history
1) 1/3 Slowly progressive
Remissions and relapses of the nephrotic syndrome

2) 1/3 Spontaneous remission

child >50% adult
complete 25% partial 25-30%

3) 1/3 - CRF
onset at 2 years after Dg uraemia 10-20 years after Dg
137

Prognostic factors
Good prognosis
1. 2. 3. 4. 5. Children Women Asymptomatic sub-nephrotic proteinuria Normal renal function at 3 years after onset Complete remission, spontaneously or posttherapeutically

138

Prognostic classification
1. Low risk
Normal renal function proteinuria <4g/day

(Cattran et al)

6/12 months

2. Moderate risk
Normal renal function persistent proteinuria 6/12 months 4-8g/day
6/12 months

3. High risk
Abormal renal function and/or proteinuria >8g/day

139

Pathogenic treatment
Recommended to patients with
poor prognosis serum creatinine <4mg/dL

Association corticosteroids Alkylating agents

Corticotherapy (months 1, 3, 5)
Metilprednisolone 1g/day IV, 3 days, followed by Prednisolone po 0.5mg/kg day, 27 days

Alkylating agents (months 2, 4, 6)

Chlorambucil 0.2mg/kg day, 30 days or Cyclophosphamide po 2-3mg/kg day, 30 days

Association corticosteroids - cyclosporin

CsA 4-6mg/kg/day Prednisolone 1-2mg/kg alternate-day schedule
140

General therapeutic measures

1. Diet
hyposodate + diuretics hypoprotidic hypolipidic + statins

2. Non-specific anti-proteinuric methods

ACEI or/and AT 1 RB Indometacin 100-150mg/day

3. Blood pressure control (<130/80mmHg) 4. Platelet antiaggregant drugs (aspirin)

141

Focal and segmental glomerulosclerosis

15-20-30% from nephrotic sd. in adults 7-15% from nephrotic sd. in children
142

Aetiology (1)
Idiopathic FSGS (primary) Secondary FSGS
a) Glomerular diseases
HIV nephropathy Heroin-associated GN Diabetic nephropathy Berger's disease Neoplasia-associated GN Congenital nephrotic sd. Alport's Sd. Preeclampsia

b) Tubulo-int./vascular diseases:
Reflux nephropathy Radiation nephropathy Analgesic nephropathy Sickle-cell disease Unilaterally renal agenesia Renal hypoplasia Oligomeganephronia Obesity Elderly 143

c) Other

Aetiology (2)
c) Renal transplantation
Allograft recurrent FSGS Allograft de novo FSGS Chronic vascular rejection Remnant kidney of the graft donor

144

Pathogenesis
IDIOPATHIC Unidentified factor (cytokine ?)

SECONDARY Stretch
Hyperfiltration

Podocyte lesion Increased permeability of glomerular barrier Proteins accumulation (albumin, Ig, Complement) Subendothelial deposits of hyaline material

Inflammation GN Vasculitis

145

Histopathology (LM)

Segmental non-proliferative capillary sclerosis Hyaline subendothelial deposits Matriceal matrix increase Flocculo-capsular adherences
146

Histopathology (LM)

Non-proliferative capillary sclerosis Hyaline subendothelial deposits Matriceal matrix increase Flocculo-capsular adherences
147

Histopathology (IF)

Segmental deposition of anti-C3 Ab

148

Clinical features
Child Male gender Proteinuria
nephrotic range subnephrotic 54% 88% 12%

Adult
62% 76% 33% 43%

Arterial hypertension 26% Haematuria (dysmorphic H) 50% RF (sCr >1.3mg/dL) 19% Initially non-conclusive RB Frequent evolution to:
Corticoresistance CRF

40%
34%

149

Poor prognosis factors

1. Proteinuria severity
nephrotic syndrome 45% survival at 10 years subnephrotic proteinuria 90% survival at 10 years

2. Serum creatinine >2mg/dL at the diagnosis 3. Interstitial fibrosis (>20%) 4. Tip lesions"/collapsing forms 5. Response to corticosteroids treatment
Progression to CRF Follow up Complete Partial No (years) remission remission response Adults 5,5 1,7% 13% 54% Children 7,0 14% 0% 37% Total 6% 11% 46% Treatment response stable renal function Lack of response 30-60% end-stage CRF
150

Treatment
1. Corticosteroids
0.5-2mg/kg day, 6 months (eventually reduced only after at least 3 months, maintaining doses >60mg/kg)
5mg/kg could reduce proteinuria frequent relapses after discontinuation of CsA low dose CsA could prevent the relapses the second therapy line
151

2. CsA

3. Alkylating agents

Membranoproliferative GN
Mesangiocapillary GN Mesangioproliferative GN Lobular GN
The most rare cause of nephrotic syndrome in adults (<7%)
152

Aetiology - classification
A) Idiopathic (Primary)
Type I
subendothelial and mesangial deposits (frequent association with infections - VHC, VHB)

Type II
GBM dense deposits (electron-dense transformation), with reduced content of Ig associated with C3Nef

Type III
GBM changes + subendothelial and subepithelial dense deposits
153

Aetiology - classification
B) Secondary
Diseases with immune complexes: SLE, mixed cryoglobulinaemia, Sjgrens syndrome Neoplasia: leukaemias, lymphoma, solide tumours Infectious diseases: B/C Hep, HIV, endocarditis, infected ventriculo-atrial shunt, visceral abscesses Chronic active hepatitis and cirrhosis Other: partial lipodystrophy, heroin, sarcoidosis, congenital deficiencies of complement etc

154

Histopathology type I (LM)

lobular aspect of the glomerulus areas of mesangial hypercellularity mesangial expansion capillary wall thickening

155

Histopathology type I (LM)

lobular aspect of the glomerulus areas of mesangial hypercellularity mesangial expansion capillary wall thickening

156

Histopathology type I (IF)

granular deposits of Ig (IgG) on the inner side and in the mesangium, outlining the capillary
157

Histopathology type I (EM)

subendothelial dense deposits mesangial cells interposition reduction of the capillary lumen

158

Histopathology type II (LM)

accentuation of the glomerulus lobularity GBM thickening, with ribbon aspect mesangial expansion and interposition
159

Histopathology type II (LM)

accentuation of the glomerulus lobularity GBM thickening, with ribbon aspect mesangial expansion and interposition
160

Histopathology type II (EM)

ribbon aspect of GBM with subendothelial dense deposits capillary lumen reduction by mesangial interposition
161

Pathogenesis
Persistent hypocomplementaemia type I + type III
immune complexes (classic activation way)

type II
C3 nephritic factor: Auto Ab (IgG) anti-C3 convertase
(protects the covertase against degradation, allowing continuous splitting of C3 and alternate way of activation). C3c have affinity to GBM where it is deposited. 162

Clinical features
Onset
1. Nephrotic syndrome with insidious onset (50%) 2. Urinary syndrome (20-30%) randomly discovered (sub-nephrotic proteinuria + microscopic haematuria) 3. Acute nephritic syndrome ~ AcDGN (20-30%) 4. Recurrent macroscopic haematuria ~ IgAN

Clinical period
1. 2. 3. 4. Nephrotic syndrome with non-selective proteinuria Persistent hypocomplementaemia (>2 months) Arterial hypertension 33-50% Renal insufficiency 50%
163

Natural history
Primary MPGN (type I < type II)
50% (-60%) - CRF (10-15 years) 25% (-40%) - maintain stable renal function 10% - spontaneous remission

Secondary MPGN
remission depending on the efficacity of causative condition therapy
164

Poor prognosis factors

1. 2. 3. 4. 5. Arterial hypertension Nephrotic sd. (degree of proteinuria) Increased serum creatinine at the onset Type II Extracapillary proliferation

165

Pathogenic treatment
1. proteinuria <3.5g/day
Children
Corticosteroids 1mg/kg alternate-day schedule, 3 months follow-up + non-specific anti-proteinuric measures

Adults

2. proteinuria >3.5g/day
Children
Corticosteroids 40mg/mp alternate-day schedule, 6-12 months
Non-specific anti-proteinuric measures Aspirin 325mg/day Dipiridamol 350mg/day, 6-12 months

Adults

166

The main GN types

Chronic nephritic syndrome (urinary abnormalities)

167

Minor urinary abnormalities

Association of:
Urinary signs:
Reduced urine density Proteinuria (frequent sub-nephrotic) Microscopic haematuria Casts excretion (granular casts)

more frequent arterial hypertension with higher values CRF variable frequency
168

IgA nephropathy

Berger's disease
The most frequent primary glomerulonephritis in adults
169

Aetiology
Idiopathic
Exclusively renal disease Henoch-Schnlein purpura

Secondary
Liver diseases after billiary disorders Gastrointestinal diseases: coeliac d., Crohns d., adenocarcinoma Respiratory diseases: PIF, obstructive bronchiolitis, adenocarcinoma Cutaneous diseases: herpetiform dermitis, mycosis fungoides, leprosy Ocular diseases: episcleritis, anterior uveitis Other: ankylosing spondylitis, polychondritis, 170 Sjgrens sd. etc

Histopathology (LM)

mesangial expansion: matrix increase cell proliferation

171

Histopathology (LM)

mesangial expansion: matrix increase cell proliferation

172

Histopathology (IF)

mesangial deposits of Ig A (IgG, C3)

173

Histopathology (LM)

dense mesangial deposits

174

Pathogenesis
1 - Immunity deficiency of mucosas (?) Migration deficiency of T cells (?)

Exposure to environmental ubiquitar Ag Stimulation of B cells (pl IgA1)

2 - Galactosidation deficiency of pl IgA1 in B cells (beta-1,3 galactosil-transferase deficiency) 175

Pathogenesis
Excessive synthesis of Ig A1-GD IgA1-GD increase in circulation AutoAb anti IgA1-GD (anti-glican, -peptide) Circulating immune complexes (IgG - IgA1-GC/IgA - IgA1-GD)
176

Pathogenesis
Clearance deficiency at Kupffer cells level IgA1-GD deposition in mesangium (immune complexes, IgA1-GD aggregates, affinity for mesangial structures)

Activation/induction C3, cytokines, chemokines, GF

Inflammation, proliferation, apoptosis, fibrosis

177

Pathogenesis
Mesangial injury Glomerular capillary hypertension Permeability alteration Glomerulosclerosis Tubulo-interstitial injury

178

Clinical features
1. Recurrent macroscopic haematuria sin-pharingitic 2. Microscopic haematuria + sub-nephrotic proteinuria (50%) 3. Nephrotic proteinuria (10%), following upper respiratory tract infections 4. Acute nephritic syndrome (10%) 5. Random discovery (hypertension, RF)

179

Clinical features
Haematuria characteristics:
1) macroscopic in the acute episode and microscopic between them; 2) recurrent (occcurs after every episode of upper respiratory tract infection); 3) never disappearing (persisting microhaematuria between acute episodes); 4) associated with moderate proteinuria.
180

Diagnosis
Positive
distinct clinical features renal biopsy is indicated in case of rapid decline in renal function

Differential
macroscopic haematuria + negative family history IgAN persistent microscopic haematuria + family history of haematuria, but not CRF - Thin basement membrane disease persistent microscopic haematuria + family history of CRF/deafness - Alports syndrome
181

Natural history
GN with the slowest progression to CRF Arterial hypertension 33% CRF <25% after 20 years from diagnosis Poor prognosis factors
age proteinuria >2g/day arterial hypertension sCr >3mg/dL interstitial lesions crescents HLA-B35

182

Natural history
Rapid decline in renal function:
Acute tubular necrosis (secondary to massive glomerular haematuria) Severe glomerular lesions with crescent formation Severe tubulo-interstitial lesions

183

Treatment
Tonsillectomy (for patients with frequent episodes)
reduces haematuria, proteinuria

Nephrotic proteinuria
normal renal function (Cr Cl >70mL/min) Corticosteroids 1mg/kg zi (8 months) +/- Cytotoxic agents

impaired renal function (Cr Cl <70mL/min) Fish oil (1.2-1.8g/day)

Slowly progessive renal function decline

Fish oil (1.2-1.8g/day)

Contraindicated
Cyclophosphamide, CsA, warfarin, dipiridamol

Without effect
azathioprine, corticosteroids
184

185