6.Glomerular disorders.Dr.Thilak Jayalath_Renal Lectures
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6.Glomerular disorders.Dr.Thilak Jayalath_Renal Lectures






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6.Glomerular disorders.Dr.Thilak Jayalath_Renal Lectures 6.Glomerular disorders.Dr.Thilak Jayalath_Renal Lectures Document Transcript

  • 1 Glomerular disorders Glomerular disorders  Glomerulonephritis  Glomerulopathy Glomerulonephritis • Inflammation of the glomeruli as primary disease or as part of a systemic illness • The aetiological description refers to primary (aetiology unknown, generally thought to be a manifestation of autoimmunity) • The aetiological description refers to secondary, associated with • Autoimmune • Infectious • Malignant • Metabolic Normal Glomerulus • Hereditary • Any age group may be affected though some types are particularly common in children • Many cases of glomerulonephritis result in mild, asymptomatic illness and remains undiagnosed • Glomerulonephritis is recognised as the second commonest cause of end-stage renal failure worldwide • Glomerulonephritis is more common in the male than in the female population • The pathogenesis of glomerulonephritis is complex and remains incompletely understood • Inflammation is immunologically mediated • Kidneys are involved symmetrically • Secondary mechanisms of glomerular injury occur following an initial immune insult • Complement activation • Fibrin deposition • Platelet aggregation • Activation of kinin systems • Inflammation with neutrophil dependent mechanisms • Renal interstitial damage is a regular accompaniment Immune mechanisms in glomerularnephritis  Antibody can also be deposited from circulation as a component of immune complexes or cryoglobulins, thus triggering a type III immune response within the glomerulus • Subacute bacterial endocarditis • Lupus nephritis • Hepatitis-C-related cryoglobulinaemia Dr.Thilak Jayalath MBBS MD FRCP FRCPE FISN Senior Lecturer in Medicine & Consultant Physician Department of Medicine, Peradeniya
  • 2  Deposition of antobodies against antigens in glomeruli, causing type II immune response within the glomerulus E.g. Goodpasture's disease  Accumulation of isotype-specific, though not antigen-specific, antibody within mesangial cells E.g. IgA nephropathy Glomerulonephritis Understanding Terms • Focal: some but not all the glomeruli contain the lesion • Diffuse (global): most of the glomeruli (> 75%) contain the lesion • Segmental: only a part of the glomerulus is affected (most focal lesions are also segmental, e.g. focal segmental glomerulosclerosis) • Proliferative: an increase in cell number due to hyperplasia of one or more of the resident glomerular cells with or without inflammation • Exudative : Neutrophil accumulation • Membrane alterations: capillary wall thickening due to deposition of immune deposits or alterations in basement membrane • Crescent formation: epithelial cell proliferation with mononuclear cell infiltration in Bowman's space. • Necrotising : Cell necrosis visible by light microscopy • Hyalinosis : Matrix accumulation Sub types of glomerulonephritis • Proliferative  Diffuse  Focal segmental • Membranous Glomerulonephritis • Minimal change nephropathy • IgA Nephropathy • Focal Glomerulosclerosis Clinical presentation of Glomerulonephritis Asymptomatic urinary abnormalities  Subnephrotic-range proteinuria, and/or microscopic haematuria, not accompanied by renal impairment, oedema, or hypertension Nephritic syndrome  Recent onset of haematuria and proteinuria  Renal impairment  Salt and water retention, causing hypertension Nephrotic syndrome  Nephrotic-range proteinuria (more than 3·5 g per 1·73 m2 in 24 h) hypoalbuminaemia  hyperlipidaemia  oedema  With cresent formation  Mesangiocapillary
  • 3 Rapidly progressive glomerulonephritis  Progression to renal failure over days to weeks, in most cases in the context of a nephritic presentation Chronic glomerulonephritis  Persistent proteinuria with or without haematuria and slowly progressive impairment of renal function Interrelationship of pathologic and clinical manifestations of Glomerular injury Minimal change Glomerulopathy Nephrotic Syndrome Membranous Glomerulopathy Focal Segmental Glomerulosclerosis Mesangioproliferative Glomerulopathy Membranoproliferative Glomerulonephrits Proliferative Glomerulonephrits Acute Diffuse Proliferative Glomerulonephrits Crescentic Glomerulonephrits Nephritic Syndrome Correlation between the histological type and the clinical picture Minimal change nephropathy  Light microscopy - normal  Electron microscopy - fusion of foot processes of podocytes  Most common in children and males  Highly selective proteinuria is typical 25% adult nephrotic syndrome due to minimal change nephropathy  In adults commonly seen after 40 years  Steroid resistance is common in adults Diffuse proliferative GN Acute nephritic syndrome Focal segmental GN Haematuria / proteinuria Rapidly progressive GN Progressive renal failure Mesangiocapillary GN Haematuria / proteinuria Acute nephritic syndrome Nephrotic syndrome Membranous GN Nephrotic syndrome Minimal change nephropathy Nephrotic syndrome IgA Nephropathy Asymptomatic haematuria Focal glomerulosclerosis Proteinuria or nephrotic syndrome
  • 4 Causes • Primary • Secondary Drugs - Gold, Lithium ,NSAIDS Infections - Syphilis Neoplasia Hodgkin’s and Non Hodgkin’s , carcinoma of kidney , pancreas, colon and prostate Management  Over 90% respond to high dose corticosteroids  50 % Remain steroid dependent o Other drugs o Cyclophospamide o Chlorambucil o Cyclosporin o Levimasole Membranous glomerulonephritis  Immune complex deposition leads to thickening of basement membrane  Progress to increased matrix deposition and glomerulosclerosis  Granular deposits of IgG along the basement membrane in a subepithelial pattern, is typical  Most common cause of nephrotic syndrome in adults  Two peaks of disease in adults Mid 20 s and 60-70 years  Usually idiopathic  Strong association with HLA DR3  Renal vein thrombosis in 5 % of patients  Recurs frequently in renal transplants  One-third remit spontaneously, one-third remain in a nephrotic state, and one-third show progressive loss of renal function Secondary causes Malignancy Bronchus , Stomach , Colon , Non Hodgkin’s lymphoma, CLL Connective tissue disease SLE , Rheumatoid Arthritis Sjogren ’syndrome Chronic Infection Hepatitis B , Malaria , Syphilis Drugs Gold , Penicillamine , Captopril Minimal change glomerulonephritis Light microscopy Minimal change glomerulonephritis Electron microscopy
  • 5 Membranous glomerulonephritis Treatment  Severe nephrotic syndrome, Impaired renal function  Immunosuppressive treatment indicated  Combination of prednisolone and chlorambucil given in alternating monthly cycles for 6 months  Ace inhibitors reduce proteinuria and may slow the progression of renal insufficiency  Anticoagulants are indicated Mesangiocapillary Glomerulonephritis Other names: • Membranoproliferative Glomerulonephritis • Hypocomplementemic Glomerulonephritis • Lobular Glomerulonephritis  Primary form is common from late childhood to young adulthood  Usual clinical presentation is nephrotic syndrome complicated by acute nephritis with haematuria and hypertension  Most common pattern found in association with subacute bacterial infection Primary – Type I, Type II, Type III Secondary Autoimmune- Rheumatoid arthritis, Sjogren’s syndrome, SLE Infections – Bacterial Infective endocarditis Leprosy, Visceral abscess, Infected shunts Viral Hepatitis B and C , Cryoglobulinemia Protozoal Malaria, Schistosomiasis Type 1  Deposition of circulating immune complexes or 'planted' antigens  Subendothelial deposits seen  Commonest pattern seen in secondary types  Activation of classical pathway is a feature Type II  Commonly idiopathic  Also called “dense deposit disease ”  Intramembranous dense deposits  Associated with complement consumption caused by auto antibodies
  • 6  C3 nephritic factor and partial lipodystrophy  Type II MCGN recurs in virtually 100% of renal transplant patients but recurrence is less common in type I (25%)  Idiopathic MCGN with normal renal function, non-nephrotic range proteinuria, no specific therapy is required  Close follow up with specific attention to blood pressure control is recommended  In adults with the nephritic syndrome and/or renal impairment, aspirin (300 mg) or dipyridamole (75-100 mg) or a combination of the two, should be given for 6-12 months  If no benefits are seen, the treatment should be stopped. Treatment to slow the rate of progression of renal failure is instituted IgA Nephropathy Most commonly recognised type of glomerulonephritis and can present in many ways Haematuria is almost universal, proteinuria usual, and hypertension very common A particular hallmark in some individuals is acute exacerbations, often with gross haematuria, in association with minor respiratory infections. Characteristically, the latency from clinical infection to nephritis is short: a few days or less. Most common cause of asymptomatic microscopic haematuria Partial lipodystrophy
  • 7 Commonly occur in children and young adults 5 % develop nephrotic syndrome IgA nephropathy and henoch- schonlein has similar pathological features Focal and segmental proliferative glomerulonephritis with mesangial deposits of polymeric IgA1 The disease may be a result of an exaggerated bone marrow and tonsillar IgA1 immune response to viral or other antigens Up to 50% of patients exhibit elevated serum IgA (polyclonal) concentration The risk of eventual development of end-stage renal failure is about 25% in those with • Proteinuria of more than 1 g per day • Elevated serum creatinine • Hypertension • ACE gene polymorphism (DD isoform) • Tubulointerstitial fibrosis on renal biopsy Patients with proteinuria over 1-3 g/day, mild glomerular changes only and preserved renal function should be treated with steroids All patients, with or without hypertension and proteinuria, should receive a combination of ACE inhibitor and angiotensin II receptor antagonist Mesangiocapillary Glomerulonephritis IgA Nephropathy
  • 8 In patients with progressive disease (creatinine clearance less than 70 mL/min), fish oil or prednisolone with cyclophosphamide for 3 months followed by maintenance with prednisolone and azathioprine Focal Segmental Glomerulosclerosis Disease of unknown aetiology All age groups are affected A circulating permeability factor (with serine protease activity) causes the increased protein leak Presents typicaly with nephrotic syndrome Associated with • Hypertension • Microscopic haematuria • Impaired renal function tests • Impaired renal function tests Segmental scars in some glomeruli No acute inflammation Podocyte foot process fusion seen in primary FSGS with nephrotic syndrome Prednisolone 0.5-2 mg/kg/day is used in most patients and continued for 6 months before declaring the patient resistant to therapy;. The use of ciclosporin at doses to maintain serum trough levels at 150-300 ng/mL may be effective in reducing or stopping urinary protein excretion. Cyclophosphamide, chlorambucil or azathioprine is used for second-line therapy in adults. In FSGS patients with mesangial hypercellularity and tip lesion, use of cyclophosphamide 1-1.5 mg/kg/day with 60 mg of prednisolone for 3-6 months followed by prednisolone and azathioprine as maintenance therapy has found some success. About 50% of patients progress to end-stage renal failure within 10 years of diagnosis, particularly those who are resistant to therapy Focal Segmental Glomerulosclerosis Rapidly progressive Glomerulonephritis (RPGN) RPGN is a syndrome with glomerular haematuria, rapidly developing acute renal failure over weeks to months and focal glomerular necrosis with or without glomerular crescent development on renal biopsy
  • 9 • Goodpasture's disease • Small-vessel vasculitides • Systemic Lupus Erythematosus • IgA and other nephropathies • Post-infectious GN • Mesangiocapillary GN (type II > type I) • IgA nephropathy Acute post-infectious Glomerulonephritis Most common following infection with certain strains of streptococcus and therefore is often called post-streptococcal nephritis, but it can occur following other infections Much more common in children than adults Latency is usually about 10 days after a throat infection or longer after skin infection, suggesting an immune mechanism rather than direct infection All glomeruli are affected All cell types are proliferative Granular deposits of immunoglobulins and C3 An acute nephritis of varying severity occurs • Sodium retention • Hypertension • Oedema • reduction of GFR • Proteinuria • Haematuria • Reduced urine volume • Urine a red or smoky appearance • Low serum concentrations of C3 and C4 • Evidence of streptococcal infection Treatment of patients with poststreptococcal GN should be directed at:  Eradicating the infection (a 10-day course of penicillin or erythromycin is advised even if the original infection appears to have resolved)  Providing symptomatic relief of the consequences of the acute nephritis:  Aggressive treatment of hypertension, salt, and water restriction with or without diuretics for oedema; and dialysis if necessary  Recovery is the rule, although haematuria and proteinuria may persist and some have a risk of chronic renal failure
  • 10 Acute post-infectious Glomerulonephritis Acute post-infectious Glomerulonephritis Rapidly progressive Glomerulonephritis (RPGN)  RPGN is a syndrome with glomerular haematuria, rapidly developing acute renal failure over weeks to months and focal glomerular necrosis with or without glomerular crescent development on renal biopsy Clinical presentation - acute nephritic syndrome Cresents = Aggregate of macrophages and epithelial cells in bowman’s space • Goodpasture's disease • Small-vessel vasculitides • Systemic Lupus Erythematosus • IgA and other nephropathies • Post-infectious GN • Mesangiocapillary GN (type II > type I) • IgA nephropathy Antiglomerular basement membrane disease  Antiglomerular basement membrane disease is an autoimmune disease in which patients develop pathogenic autoantibodies against the glomerular basement membrane (GBM) RPGN
  • 11  The triad of anti-GBM antibodies, rapidly progressive glomerulonephritis (RPGN), and pulmonary haemorrhage is referred to as Goodpasture's disease  Goodpasture's syndrome describes patients with RPGN and pulmonary haemorrhage of various aetiologies.  Most patients present with RPGN or lung haemorrhage, or both.  Some patients have isolated lung haemorrhage and never develop renal failure (although most of these have haematuria and proteinuria)  Autoimmunity to α3 chain of type IV collagen  HLA-DR15 (previously known as DR2)  Linear IgG along GBM  Serological testing for anti-GBM antibodies and ANCA is crucial for confirming the diagnosis, and a renal biopsy is almost always indicated  Treatment with plasma exchange, cyclophosphamide, and corticosteroids, together with dialysis when required, can allow up to 90 per cent of patients to survive, but only around 40 per cent of survivors will recover renal function Antiglomerular basement membrane disease