Glomerulonephritis BPT 2012

Report
Glomerulonephritis
Renal BPT Lecture Series
Concord-Nepean Network
Dr Shaundeep Sen
15th May 2012
Glomerulonephritis
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Incidence
Presentation
Investigation
Classification
Pathophysiology
Management
Outcomes
Incidence
• Limited data on incidence or prevalence of
disease
– Definition/Investigation Issues
• Rates of ~0.2-2.5/100,000 person years
(McGrogan 2011 NDT)
• 21% of those commencing KRT in 2010 in
Australia had a diagnosis of GN (ANZDATA
Report 2011)
– ¼ were IgA mesangiocapillary GN
**Biopsy Underutilised for Diagnosis**
Classification?
Over 50 Different Classification Systems
• Histologic
– Location/Aetiology of Damage
• Clinical Presentation
• Primary vs Secondary
Harrison’s, Kumar, UpToDate
Glomerular Disorders - Primary
•IgA nephropathy
•Acute proliferative glomerulonephritis
–Post-infectious
–Other
•Rapidly progressive (crescentic) glomerulonephritis
•Minimal-change disease
•Focal segmental glomerulosclerosis
•Membranous glomerulopathy
•Membranoproliferative glomerulonephritis
•Chronic glomerulonephritis
Glomerular Disorders - Secondary
•Systemic lupus erythematosus
•Diabetes mellitus
•Deposition Diseases
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Amyloidosis
Light Chain Deposition Disease
•Goodpasture syndrome
•Microscopic polyarteritis/polyangiitis
•Wegener granulomatosis
•(Henoch-Schonlein purpura)
•Bacterial endocarditis
•Cryoglobulinaemia
•Thrombotic microangiopathies
•Malignancies:
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Hodgkin's lymphoma
lung and colorectal cancer
Glomerular Disorders - Hereditary
• Alport Syndrome
• Thin Basement Membrane Disorder
• Fabry Disease
Nephritic Syndrome
• Manifestations:
– Hematuria, azotemia, variable proteinuria, oliguria, edema, and
hypertension
• Conditions:
– IgA nephropathy
• Episodic, <5/7 post URTI
– Postinfectious GN
• Abrupt onset, 1-3/52 post-infection
– Rapidly progressive GN
• Vasculitis
• Anti-GBM GN
Nephrotic Syndrome
• Manifestations:
– >3.5 gm/day proteinuria, hypoalbuminemia (<30g/L),
hyperlipidemia (with low HDL), lipiduria
– Thrombo-embolic events (esp if Albumin <20g/L, with loss of
anti-thrombin III and antiplasmins in urine)
• Conditions:
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Deposition diseases
Minimal change disease
Focal and segmental glomerulosclerosis
Membranous nephropathy
Membranoproliferative GN
Rapidly Progressive GN
• Manifestations:
– Abrupt Onset, HT, haematuria, variable proteinuria
• Conditions:
– Type I (Anti-GBM Ab):
• Renal-limited, Goodpasture’s
– Type II (Immune Complex):
• Idiopathic, IgA/HSP, PIGN, Other
– Type III (Pauci-Immune):
• ANCA, Idiopathic, Wegener’s, Microscopic Polyangiitis
Aetiology
• Autoimmune
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Goodpasture’s
IgA
Lupus
Hereditary nephritis – Alport’s Syndrome
Membraneous GN
• Infection-Related
– PIGN
– HIV
– Infective Endocarditis
• Sclerotic
– MCD – FSGS
– Diabetic Nephropathy
Histologic Changes
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Hypercellularity
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Mesangial or Endothelial Cells
Leucocytes
Crescents
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Basement Membrane Thickening
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Deposition immune complexes, amyloid, cryoglobulins, fibrin, fibrils
Increased GBM production, eg DM
Podocyte Changes
Hyalinosis
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?Fibrin, TNF-alpha, Tissue Factor, IFN-gamma
Parietal epithelial cells and leukocytes infiltrate
Homogenous, eosinophilic (LM), extracellular (EM), obliterates capillaries – end-pathology of
disease, FSGS
Sclerosis
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Accummulation extra-cellular collagenous matrix
In mesangium only (DM), or capillaries also
DIFFUSE vs FOCAL
GLOBAL vs SEGMENTAL
IgA Nephropathy
• Most common GN diagnosed by Biopsy
• Deposition of IgA1-IgA1 or IgA1-IgG complex in
mesangium
• Present ?>20% of general population on
autopsy studies, majority with no evidence of
renal disease
• Variable presentation:
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Incidental finding on UA, HT (30%)
Episodic with URTI (60%)
RPGN / Nephritic / Nephrotic
Association with CLD (poor clearance Abs)
Antibodies
IgA Nephropathy
Clinical Risk Factors for Progression:
• Proteinuria
• Hypertension
• Reduced eGFR at time of diagnosis
• Elderly, male
• DD genotype for ACE gene
• Serum IgA level not diagnostic
– Cf IgA1 level
NOT macroscopic haematuria
Prognosis: ESKD 20-40% @ 5-35 years
IgA Nephropathy
Oxford Histological Classification of IgA:
• Mesangial cellularity score
• %gloms with segmental adhesion or
sclerosis
• %gloms with endocapillary hypercellularity
• % interstit fibrosis / tubular atrophy
Associated with reduction in eGFR,
proteinuria
KI (2009). 76. 534-45, 546-56
IgA Nephropathy
Primary Abnormality:
•Galactose-deficient hinge region O-glycans
IgA1 production
IgA Nephropathy
Controversial:
Fish Oil – limited benefit
Tonsillectomy
Alcohol
Anti-Platelet Therapy
IgA Nephropathy
Immunosuppression
• eGFR > 50ml/min, proteinuria >1gm:
– Corticosteroids 6 months
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MMF – limited data
Combination therapy – not recommended
eGFR < 50ml/min – supportive therapy only
RPGN – treat with combination therapy
Nephrotic – oral corticosteroids 6 months
Secondary IgA (Liver ) – supportive only
Transplant Recurrence – supportive only
Post-Infectious GN (1)
• Decreasing incidence in the Western world
• In children and the elderly with EtOH or IVDU
• Due to Group A (or C) Strep infection (throat/skin),
producing nephritogenic Ag’s that activate the alternate
complement pathway, via plasmin:
– Nephritis-associated plasmin receptor (NAPlr, glyceraldehyde-3phosphate dehydrogenase)
• Present early in the mesangium in kidney biopsies
– Streptococcal pyrogenic exotoxin B (SPEB) – a cationic cysteine
proteinase generated by proteolysis of a zymogen precursor
(zSPEB)
• Present later in sub-epithelial humps (diagnostic)
Rodriguez-Iturbe 2008 JASN
Post-Infectious GN (2)
• Presentation – Nephritic Syndrome 1-3 weeks
post infection
– Rust-coloured urine
• ~10-20% Pharyngitis due to Strep
– Clin risk factors: <14yoa, no cough, tender LNs, fever
>38, tonsillar swelling or exudate
• DDx
– IgA (temporal)
– TBMD
– Hereditary Nephritis
Post-Infectious GN (3)
• Investigations:
• Bloods – electrolytes, C3/C4 (↓ for up to 8
weeks only), Antistreptolysin O titre, AntiDNase B Ab
• Urine – Micro, RBCs, Proteinuria
• Renal Biopsy - diagnostic
H+E of glom showing increased mesangium, PMNs, endocapillary prolif
IgG and C3 on IF (IgG shown) irregularly lining the capillaries
Epithelial “humps” (IgG, C3), can also get other less-organised deposits
Post-Infectious GN (4)
Management
• Hypertension – in up to 75% of children
– Aetiology unclear (Na/H2O retention)
• Antibiotics – no renal benefit once immune
activation occurred; TREAT EARLY
Prognosis
• Children – 1-2% CKD
• Elderly – up to 50% CKD
RPGN
• Clinical and Histologic Diagnosis:
– Rapid loss GFR over days to weeks with
evidence glomerular disease (active urine)
– Crescents on biopsy:
RPGN
Classification
• Primary:
– TYPE I: Anti-GBM Ab Disease
– TYPE II: Granular Immune Complex Assoc (IgA, PIGN)
– TYPE III: Pauci-Immune
• Secondary:
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Superimposed
Post-infectious
Vasculitic
Polyarteritis nodosa
Goodpasture’s Syndrome
Carcinoma
Allopurinol / Penicillamine
Anti-GBM
• Ab predominantly to NC1 domain of α3
chain of type IV collagen
– Found in GBM and alveolar BM (+retina,
choroid plexus)
– Normally in hexamer with α4 and α5
• α3 only “available” if exposed after other
insult, eg
– exposure to hydrocarbons, smoking, infection,
lithotripsy, degradation by reactive oxygen
species or BM disruption due to other GN
Anti-GBM
• Ab is IgG1 > IgG3
• Also role for autoreactive T-Cells
• HLA DRB1*1501 confers 3x RR (but
present 30% caucasian population)
NOTE: Alport’s recurrence in Kidney
Transplants is due to formation of Ab to α5
chain, even if in hexamer
Anti-GBM
Investigations
• Urine: active sediment
• Serum:
– EUC
– C3
– pANCA/MPO: 30% dual +ve (relapse)
– Anti-GBM Ab
• Kidney Biopsy
Anti-GBM: IgG and C3 deposition (IgG shown) in linear pattern along GBM
Anti-GBM
Treatment:
If mild/moderate kidney failure
• Pulse Prednisolone
• Cyclophosphamide
• Plasmapheresis/exchange
• ?Rituximab
If dialysis-dependent with poor Bx findings
• Supportive
Pauci-Immune GN
• Chapel Hill Classification of Vasculitis based on
size of vessel affected:
• Large – Giant Cell Arteritis, Takayasu
• Medium – Kawasaki Disease (nil renal), Polyarteritis
Nodosa (may involve renal arteries)
• Small
– Wegener’s Granulomatosis (small arts and veins,
GN + Pul)
– Churg Strauss (EΦ)
– Microscopic Polyangiitis (GN + pul capillaritis)
– HSP (renal, skin gut)
– Cryoglobulinaemic (Skin + GN)
– Cutaneous leukocytoclastic (isolated to skin only)
80-90% Pauci Immune GN are ANCA Positive
WG and MPA
• Age 60-80yoa
• Systemic symptoms over weeks
– Fever, malaise, myalgia, arthralgia, weight
loss
• Renal involvement – oliguria, h’aturia,
p’uria, RBC casts, rapid decline eGFR
• Diffuse alveolar haemorrhage
• Palpable purpuric skin lesions, esp LLs
• WG: sinusitis, rhinitis, otitis, ocular
inflammation
Pauci-Immune GN
Investigations:
– Normal complement levels
– WG: cANCA/PR3 +ve 80-95%
– MPA: pANCA/MPO +ve 40-80%
• Kidney Biopsy:
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Vasculitic changes in arterioles and venules
Mesangio-prolif
Segmental necrotising
Crescents
No IF staining
EM: no deposits
Pauci-Immune GN
Negative Prognostic Markers:
• Increased creatinine
• African-American race
• Arterial sclerosis
NOT: pul disease, crescents/necrosis on Bx,
age
Pathogenesis unclear:
?cross-reactive Abs in response to fimbriated bacterial infection, against
lysosomal membrane protein-3. LMP-3 colocalised to MPO and PR3 in
vesicle…
Pauci-Immune GN
• Management – WG/MPA
• Steroids
– Pulsed if RPGN, pulmonary haemorrhage
• Cyclophosphamide
– ?advantage of iv over oral
• Azathioprine
– For maintenance
• Rituximab (anti-CD20, B-cell depleting)
– No benefit over cyclophos (NEJM 363;3, 211220)
Pauci-Immune GN
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Prognosis WG/MPA:
70% get renal involvement
70-90% respond to Cyclophos Mx
1 year mortality 15%
– Active infection
– Vasculitis
Podocyte Function & Disease
Minimal Change Disease
• 20-30% adults who present nephrotic
• Normal light microscopy with podocyte
foot effacement on EM
• ?presence of as yet unidentified
glomerular permeability factor
• Role of T- and B-Cell dysfunction
Minimal Change Disease
• Primary vs
• Secondary:
– NSAIDs, COX Iii, Li, amp/rifamp/cephs, Dpenicillamine, pamidronate, sulfasalazine,
trimethadione, immunisations, gamma-IFN
– Malignancy (Hodgkin, NHL, leukaemia)
– Infection (syphilis, TB, mycobact, HIV…)
– Allergy
– Other glom diseases (IgA, SLE, DM, PKD)
Minimal Change Disease
• Complications
– VTE
– T-Cell dysfunction leading to infection with
encapsulated organisms:
• S pneumoniae
• E coli
• H influenzae
Minimal Change Disease
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Treatment:
Supportive – Na restrict, diuretics
Steroids
+/- cyclophosphamide/CyA
Relapses common, resistance to pred
common in younger age groups
• Prognosis:
• Good unless steroid resistant, then 3050% ESKD in 5 years
Focal and Segmental Glomerulosclerosis
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40% of Nephrotic presentations
Incidence 7 per million
>50% of cases present nephrotic
80% idiopathic/primary
Secondary causes:
– Genetic: ?APOL1 G1 and G2
– Virus: HIV 1, Parvo B19, SV40, CMV, EBV
– Drugs: heroin, IFN, Li, Pamidronate, mTORi,
CNI
– Adaptive: in response to reduced renal mass
or inadequate mass
2+ hits to
podocytes
FSGS
FSGS
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Worse Prognosis:
African American
Increased proteinuria
Poor kidney function
IF/TA, collapsing variant on Bx
Partial or no remission on treatment
• ?role soluble urokinase receptor
50% ESKD @ 10yrs if
nephrotic range
proteinturia
20-40% recurrence
risk in KTx
Membranous Nephropathy
• 1 case per 100,000 person years
• Most common adult diagnosis for
nephrotic syndrome (increasing frequency
with age for idiopathic form)
• 80-95% >50yoa at diagnosis
• Incidence male=female, but male worse
outcome RR~3
• Primary/idiopathic vs secondary (~30%)
Membranous Nephropathy
Aetiology for Idiopathic MN:
• Antigens:
– Neutral endopeptidase in neonates whose
mother is deficient
– M-type phospholipase A2 receptor (PLA2R1)
• Antibodies to:
– Aldo-keto-reductase family 1, member 1
(AKR1B1)
– Mitochondrial superoxide dismutase 2 (SOD2)
• HLA-DQA1 allele on chromo 6p21
Membranous Nephropathy
Secondary Causes:
• Infections – HBV, HCV, Malaria, ….
• Autoimmune – SLE, RA, Sarcoid….
• Malignancies – Lung, colon, breast, stomach,
oesoph; melanoma; leukaemia; NHL
• Meds – gold, D-penicillamine, Hg, captopril,
probenecid, trimethadione, NSAIDs
• Genetic – sickle cell, Fanconi’s, ?DM
• Other
MUST RULE THESE OUT
Membranous Nephropathy
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Investigations:
“Nephrosis” screen (50% also have h’aturia)
Normal serum complement
Renal Biopsy:
– Grading I-IV of sub-epithelial “spike” deposits of IgG
and C3
– Thickened GBM
– IF/TA
– EM: deposits with podocyte foot effacement and new
GBM growth
• Endothelial cell tubulo-reticular structures = Lupus
• Mesangial deposits = HBV, Lupus
Membranous Nephropathy
Membranous Nephropathy
Membranous Nephropathy
Progression
• 20-40% complete remission
• 20-35% partial remission
• 10-30% to ESKD over 10-20 years
– Risk factors:
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Male
>10gm/24hr proteinuria
HT
Azotemia
Tubulo-interstit fibrosis and glomerulosclerosis
Membranous Nephropathy
Management:
• Supportive
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ACEi / ARB
Lipids
Diuretics
?anti-platelet/-coagulant
• Immunosuppression
– Moderate Risk (if prot > 4gm/24hr after 6/12)
• Steroids + Cyclophosphamide
• Steroids + CNI
– High Risk (prot >8gm for >3/12, dec eGFR)
• As above, but CNI ?first
– Resistant – RITUXIMAB (if eGFR >75ml/min)
Membranoproliferative GN
• 3rd-4th most common primary GN cause of
ESKD
• Present any age, and any renal condition,
ie rapid/chronic, nephritic (20%)/nephrotic
(50%), RPGN, asyptomatic proteinuria
(30%)
• Primary (unknown aetiology ? Low C3
levels) vs Secondary
• Diagnosis by biopsy
MPGN
• Three Types; all have classic Histo finding
of mesangial expansion and thickening of
glom capillary walls
– Thickening due to immune and mesangial
matrix deposits causing double contour of
GBM (“tram tracks”)
MPGN
• Type I – immune complex
– Bx: nodular sub-endothelial/mesangial
deposits, with IgG/C3
– Serum: all complement components reduced
(classical pathway activation)
MPGN
• Type II – Dense Deposit Disease
– C3 deposits only, in ribbon-like fashion on
GBM with nodular mesangial deposits
– C3 only low in serum: ?alternative pathway
MPGN
• Type III – C3/IgG with mixed subendothelial “Tram tracks” and subepithelial “spikes”
• Low C3 and C5, normal C4
MPGN
• Secondary Causes:
• Infection: HBV, HCV+cryo, IEndo, EBV,
HIV…
• Autoimmune: SLE, RA, SS, Sarcoid…
• Chronic Liver Disease
• Thombotic microangiopathy
• Malignancy
• Genetic
• Dysproteinaemia
MPGN
Treatment:
• Underlying disorders
• General Supportive
• ACEi
• ?anti-platelet
• Alte die glucocorticoids
• ?eculizimab (anti-C5 mAb)
Prognosis:
• ? Up to 60% renal survival at 20 years
Summary
• Rare condition with potentially catastrophic
consequences
• Early diagnosis critical
• Multiple classifications systems
– Clinical presentation
– Histologic
– Pathogenic
• Pathophysiology not known for all conditions
• Supportive/General Measures for all
Summary
• Investigate for and treat underlying
conditions
• Judicious use of immunosuppressives
– Natural history of the disease
– Patient factors
– ?salvageable renal tissue
• More RCTs needed, cf anti-CD20 esp.

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