glomerulonephritis renal bpt lecture series concord-nepean network dr shaundeep sen 15 th may 2012
TRANSCRIPT
GlomerulonephritisRenal BPT Lecture Series
Concord-Nepean Network
Dr Shaundeep Sen
15th May 2012
Glomerulonephritis
• 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
– Amyloidosis– Light Chain Deposition Disease
•Goodpasture syndrome•Microscopic polyarteritis/polyangiitis•Wegener granulomatosis•(Henoch-Schonlein purpura)•Bacterial endocarditis•Cryoglobulinaemia •Thrombotic microangiopathies •Malignancies:
– 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:– 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
– Goodpasture’s– IgA– Lupus– Hereditary nephritis – Alport’s Syndrome– Membraneous GN
• Infection-Related– PIGN– HIV– Infective Endocarditis
• Sclerotic– MCD – FSGS– Diabetic Nephropathy
Histologic Changes• Hypercellularity
– Mesangial or Endothelial Cells– Leucocytes– Crescents
• ?Fibrin, TNF-alpha, Tissue Factor, IFN-gamma• Parietal epithelial cells and leukocytes infiltrate
• Basement Membrane Thickening– Deposition immune complexes, amyloid, cryoglobulins, fibrin, fibrils– Increased GBM production, eg DM– Podocyte Changes
• Hyalinosis– Homogenous, eosinophilic (LM), extracellular (EM), obliterates capillaries – end-pathology
of disease, FSGS• Sclerosis
– 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:– 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 levelNOT macroscopic haematuriaPrognosis: ESKD 20-40% @ 5-35 years
IgA NephropathyOxford 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• 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-3-
phosphate 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, Anti-DNase 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:
RPGNClassification• Primary:
– TYPE I: Anti-GBM Ab Disease– TYPE II: Granular Immune Complex Assoc (IgA, PIGN)– TYPE III: Pauci-Immune
• Secondary:– 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 GNInvestigations:
– Normal complement levels– WG: cANCA/PR3 +ve 80-95%– MPA: pANCA/MPO +ve 40-80%
• Kidney Biopsy:• 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 sclerosisNOT: 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, 211-220)
Pauci-Immune GN
• 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, D-penicillamine, 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
• Treatment:• Supportive – Na restrict, diuretics• Steroids• +/- cyclophosphamide/CyA• Relapses common, resistance to pred
common in younger age groups• Prognosis:• Good unless steroid resistant, then 30-
50% ESKD in 5 years
Focal and Segmental Glomerulosclerosis
• 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
FSGS2+ hits to podocytes
FSGS
• 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 proteinturia20-40% 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 NephropathyAetiology 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 NephropathySecondary 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
• 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:• Male• >10gm/24hr proteinuria• HT• Azotemia• Tubulo-interstit fibrosis and glomerulosclerosis
Membranous NephropathyManagement:• Supportive
– 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 sub-endothelial “Tram tracks” and sub-epithelial “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.