glomerulonephritis renal bpt lecture series concord-nepean network dr shaundeep sen 15 th may 2012

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.