An Approach to Glomerular Disease PDF

An Approach to Glomerular Disease Prof Malcolm Davies Consultant Nephrologist, HJH [email protected]  Definition Glomerular Disease = any abnormality of the glomerulus Broadly speaking there are 3 categories of glomerular disease: 1. Pod...

An Approach to Glomerular Disease Prof Malcolm Davies Consultant Nephrologist, HJH [email protected]  Definition Glomerular Disease = any abnormality of the glomerulus Broadly speaking there are 3 categories of glomerular disease: 1. Podocytopathy (disease specifically of the podocyte) 2. Glomerulonephritis (inflammation of the glomerulus) 3. Structural abnormalities of the GBM... although combinations of these may co-exist  Key concepts “Syndrome” ≠ “Diagnosis” “Syndrome” = Clinical presentation Clinical presentation depends on nature of glomerular insult (≈ histology) Nature of glomerular insult depends on underlying disease pathophysiology Treatment and prognosis depends on underlying disease, nature of glomerular insult, and clinical presentation Structure and function of the glomerulus 1. Filtration 2. Protein “sieving” Clinical presentation depends on histology Nature of injury is determined by functional anatomy Small filtration pores relatively impermeable to immune complexes Antigens (and Ics) hidden from circulating WC Favours non-inflammatory injury Large fenestrae permeable to immune complexes In-situ antigens exposed to circulating WC Favours inflammatory injury  Types of glomerular disease Primary Glomerular Disease Disorders in which the glomeruli are the sole or predominant tissue involved. May be idiopathic or with described pathophysiology Secondary Glomerular Disease Glomerular injury is a feature of a systemic disease involving multiple organs or systems  Structural abnormality of the GBM The GBM is an important size barrier and prevents erythrocytes straying into Bowman’s space Abnormalities of the GBM result in glomerular (dysmorphic) haematuria No inflammatory response occurs as these are STRUCTURAL lesions There is therefore NO nephritic syndrome The haematuria is therefore ASYMPTOMATIC (Alports may develop CKD)  Glomerulonepritis In order to stimulate an inflammatory response, complexes must be deposited at sites where they are exposed to circulating leukocytes present in the capillary lumen, ie: – On the endothelium – Between the endothelium and the GBM (“subendothelially”) – On the GBM – In the mesangium The relatively large size of immune complexes usually (but not always, see later) prevents deposition between the GBM and the podocyte (“subepithelially”) Podocyte injury (podocytopathy) Mechanisms of injury: – Immune (antibodies) IgG2/IgG4 conformation favours translocation through endothelial / GBM barriers – Infection of podocyte HIV, PB19, vaccines – Drugs IFN – Ischaemia HT, DM, ACEI, heroin – Inherited defects of structure NEPH1 ,APOL1/MYH9 mutations Functional anatomy determines presentation Podocytopathy Proteinuria Nephrotic syndrome Structural abnormality of GBM Asymptomatic haematuria Endothelial injury (Glomerulonephritis) Leukocyturia, haematuria Nephritic syndrome  Clinical presentation depends on histology Podocyte Endothelium (visceral epithelium) Parietal Capillary lumen epithelium GBM Mesangium Bowman’s space Mesangial cell Clinical presentation depends on histology: the podocytopathies “Podocytopathy” = pathology of the podocyte Not necessarily immunological / inflammatory injury Includes genetic defects in structure and function, acquired podocyte injury from non-immune causes (drugs, toxins, infections…)  Clinical presentation depends on histology The podocyte filtration barrier prevents loss of large molecules (proteins) to urine Does not prevent filtration of smaller molecules (electrolytes, urea, creatinine) Damage to or dysfunction of barrier will therefore cause proteinuria as primary clinical feature Proteinuria will be of variable severity depending on severity of podocyte injury  Extra-glomerular proteinuria No INTRINSIC INJURY / DEFECT in podocyte barrier EXTRA-RENAL factors cause barrier DYSFUNCTION, hence mild (< 1g/24hr) proteinuria Mainly caused by glomerular hypertension Examples: pregnancy, sepsis (pyrexia), anaemia, cardiac failure (cardio-renal syndrome type 1)  Glomerular proteinuria INTRINSIC (intra-glomerular) INJURY / DEFECT in podocyte barrier results in significant proteinuria, i.e.: NEPHROTIC SYNDROME Podocytes respond to injury in a predictable manner The mechanism of injury therefore determines histological response and hence clinical presentation All podocytopathies share EM features of podocyte injury  Clinical consequences of proteinuria: development of nephrotic syndrome Proteinuria Altered turnover of Loss of proteins immunoglobulin, carrying reduced cellular hormones, Albuminuria immunity metals, vitamins Altered coagulation factors Malnutrition ↑ infection Thrombosis/ embolism Hypoalbuminaemia Tubular ↑ tubular Oedema dysfunction reabsorption Clinical presentation depends on histology Podocytopathy Proliferative endocapillary Crescentic GN glomerulonephritis Membranoproliferative GN Mesangioproliferative GN  Clinical presentation depends on histology: GN YY Y Overview of immune system activation Antigen Y Antibody Cytotoxicity (cell injury) Complement activation Inflammatory cell recruitment  An immune response may be elucidated against: – Glomerulus-specific antigens – Systemic antigens also expressed in the glomerulus – Antigens deposited in the glomerulus In these cases antibody-antigen (immune) complexes form in the glomerulus (in-situ formation) – Preformed antigen-antibody complexes deposited in the glomerulus The immune response damages glomerular cells which respond by undergoing apoptosis and/or proliferation (“proliferative GN”) Infiltrating leukocytes breach the urinary space – Producing an active urinary sediment Red cells can pass through the damaged barriers – Dysmorphic haematuria Proliferating endothelial, epithelial (and mesangial) cells reduce filtration – Renal dysfunction – Fluid retention – causing oedema and hypertension  Proliferative Glomerular Diseases Glomerular cellular proliferation is largely related to deposition of complexes in the mesangial sub- endothelium. The degree of complement activation also seems to play a role. Patients with hypocomplementemia almost always have a proliferative GN BUT not all proliferative GN is hypocomplementemic  Glomerular Diseases associated with Low Complement Levels Post infectious GN SLE Membranoproliferative GN (MPGN) Cryoglobulinemia associated GN Atheroembolic disease  Glomerular cell responses to injury: Crescentic glomerulonephritis DEFINITION: rapid loss of renal function, (usually a 50% decline in kidney function within 3 months); with: glomerular crescent formation seen in at least 50% of glomeruli Rupture of filtration barrier allowing translocation of ICs / antibodies into Bowman’s space, injuring Bowman (parietal) epithelium Injured epithelium proliferates in response forming crescent May occur as a complication of ANY severe enough GN  The nature of the underlying disease determines the glomerular injury Endothelium / Mesangium GBM subendothelium IgA nephropathy AntiGBM disease Post infectious GN SLE class I (Goodpasture’s) Cryogloblinaemia SLE class II ANCA vasculitis Amyloidosis SLE class III TMA SLE class IV HBV, HCV TMA Idiopathic MPGN  Classification of glomerulonephritis Pauci-immune Immune ANCA vasculitides AntiGBM disease All others Injury, histology and presentation: MPGN  Factors modifying mechanism of injury Black African origin Caucasoid origin MYH9 / APOL1 Abnormalities of mutation HIV infection T/B cell regulation Abnormality of cytoskeletal Autoimmunity structure Proliferative Podocyte apoptosis inflammatory response HIVAN HIVICKD NEPHROTIC NEPHRITIC  History and Examination Swelling of extremities especially periorbital in the morning Foamy or bubbly urine Dark urine Decreased urine output, fatigue and weakness Ankle and leg oedema in the morning, if excessive systemic fluid retention occurs then anasarca, ascites, pleural effusions Urinalysis  Examination of the renal system IS NOT complete WITHOUT urinalysis Urinalysis confirms the presence of RENAL (kidney) pathological processes and can indicate aetiology Dipstix is a screening test ONLY – semi quantifiable Therefore needs formal quantification with urine protein : creatinine ratio and microscopy Caveats: Ensure adequate sample has been collected Meatus to be cleaned with saline Fresh catch midstream specimen Analyze timeously Ensure adequate dipstix Check use-by date Check container: keep closed, cool environment as specified by manufacturer  Syndrome = clinical presentation Nephrotic Syndrome Nephritic Syndrome Caused by podocytopathy Caused by glomerulonephritis Peripheral oedema Peripheral oedema Proteinuria > 3.5g / 24 hours Variable proteinuria Dyslipidaemia No dyslipidaemia Usually normal urine output Oligo-anuric Variably hypertensive Always hypertensive Variable renal function Always renal dysfunction Variable haematuria Always haematuria Inactive / bland urinary sediment “Active” urinary sediment  Syndrome Asymptomatic nephrotic range = clinical presentation proteinuria Asymptomatic Nephrotic Asymptomatic nephrotic range subnephrotic proteinuria Syndrome range Nephrotic / proteinuria Nephritic Nephritic Syndrome Asymptomatic haematuria  Injury determines treatment in glomerulonepritis 1. Must remove the source of antigen – Antibiotics in post-strep GN – Antivirals in HBV / HCV 2. Must remove the antibody – Plasmapheresis (plasma exchange) – High dose steroids (solumedrol) – Cyclophosphamide – MMF, AZA, rituximab… Prognosis will depend on the disease (post-strep = good, ANCA vasculitis = bad) and how severe the glomerular injury is (focal proliferative > diffuse proliferative > RPGN)  Injury determines treatment in nephrotic syndrome Symptomatic treatment: – ACE Inhibitors Reverse engineer the podocyte cytoskeleton to fix the filtration – Statins barrier → reduce proteinuria Specific treatment: – Treat the underlying cause if secondary – Primary – MCN, FSGS: prednisone (possible immune cause); CNI (synaptopodin on cytoskeleton) MPGN: turn off complement activation (eculizimab) MN: reduce antibody – cyclophophamide + prednisone Histology determines clinical presentation Nephrotic Syndrome Renal function Histological injury  Genetic abnormalities of: Podocyte structure Auto-immune diseases GBM structure Infections Complement regulation Drugs/ toxins Immune regulation Site and mechanism of Primary glomerular injury Secondary disorder disorder Histological pattern of injury Endothelium Podocytopathy and / or mesangium Podocyte and mesangium and / or endothelium MCN | MN | FSGS | MPGN | Focal/Diffuse Proliferative GN Nephritic Syndrome Nephrotic Syndrome  Conclusions The glomerulus is vulnerable to injury because: – High volume of blood flow → large volume of immune complex / toxin delivered / large exposure to blood- borne infections (viruses) – Nature of the ultrafilter (good at retaining proteins) → immune complexes extensively deposited – Extensive glomerular surface area → vulnerable to inflammatory injury from circulating leukocytes – High glomerular pressure → podocytes already under strain, vulnerable to increased intraglomerular pressure under conditions of hyperdynamic circulation  Conclusions The underlying disease process (disease-related factors) and modifying patient-related factors determine how the glomerulus is injured A single disease process can therefore produce multiple histological forms of injury – e.g.: HIV and HIVAN (collapsing FSGS) / HIVICK (MPGN) A similar histological pattern can be produced by different disease processes – e.g.: MN can be produced by SLE, HIV, cancer… The histological pattern determines the clinical presentation  Conclusions Asymptomatic proteinuria / Nephrotic Sydrome / Mixed nephrotic – nephritic / Nephritic Syndrome / Asymptomatic haematuria Confirm with formal urinalysis Basic investigations Refer to Nephrologist Definitive diagnosis Specific therapy