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Pathology of Glomerular Disease II Dr. Álvaro Barboza Quintana. Clinico-pathologic Classification in Renal Syndromes H = High frequency among patients with the syndrome L = Low frequency among patients with the syndrome 1. •Nephrotic Syndrome (NS) •Primary Nephrotic Syndrome •Minimal change disease - H •Focal segmental glomerulosclerosis - H •Membranous glomerulopathy - L •Systemic Nephrotic Syndrome •Diabetes mellitus - H •Amyloidosis - L •Systemic lupus erythematosus (WHO Class V) 2A . Nephritic Syndrome - Low Serum Complement Primary Nephritic Syndrome •Post-infectious glomerulonephritis (GN) •Membranoproliferative GN - L Systemic Nephritic Syndrome •Systemic lupus erythematosus (WHO Class III, WHO Class IV) - H •Infectious endocarditis •HCV-associated cryoglobulinemia 2B. Nephritic Syndrome - Normal Serum Complement Primary Nephritic Syndrome •IgA Nephropathy •Hereditary Nephritis (Alport syndrome) - L •Rapidly progressive GN (RPGN), ANCA associated, pauciimmune Systemic Nephritic Syndrome •Lupus nephritis (WHO Class II) - H •Anti-basement membrane disease (Goodpasture's Syndrome) - L •Systemic vasculitis: •Polyarteritis nodosa •microscopic polyarteritis •Wegener's granulomatosis •Henoch Schoenlein Purpura •Thrombotic thrombocytopenic purpura / Hemolytic uremic syndrome 3 Acute Renal Failure . •Pre Renal - Decreased renal perfusion •Renal •Rapidly progressive GN (RPGN) •Pauci-immune RPGN, ANCA-associated •Anti-glomerular basement membrane disease (Goodpasture) - L •Immune complex mediated RPGN:Systemic lupus erythematosus, IgANephropathy, etc. •Acute tubulointerstitial diseases: •Acute tubular necrosis (ATN) - H •Acute interstitial nephritis (AIN) - H •Post Renal - Obstruction 4 Chronic renal failure . Glomerular diseases that run with nephrotic syndrome. Minimal Change Disease (Lipoid Nephrosis) Most frequent cause of nephrotic syndrome in children (2 – 6 years of age). Follows a respiratory infection or routine prophylactic immunization. “Its most characteristic feature is its usually dramatic response to corticosteroid therapy” Etiology: It’s not known, in most cases is idophathic. – Interstitial nephritis by medical treatment – HIV, heroin – Hodgkin disease Morphology MCD By light microscopy the glomeruli are normal. By electron microscopy, the basement membrane appears normal. Principal lesion: visceral epithelial cells show a uniform, and diffuse effacement of foot processes, – “Fusion” of foot processes, represents simplification of the epithelial cell architecture with flatening, retraction and swelling of foot processes. Glomeruli are normal by light microscopy in minimal change disease, as shown in this biopsy. The glomerular basement membrane is thin and delicate, and mesangial cellularity and matrix are within normal limits. (Jones' silver stain, X200). In this electron micrograph, overlying epithelial cell foot processes are effaced (giving the appearance of fusion) and run together. Morphology MCD This changes are reversible after corticosteroid therapy and remission of the proteinuria. The cells of the proximal tubules are often laden with lipid, reflecting tubular reabsorotion of lipoproteins passing through diseased glomeruli: Lipoid nephrosis. Immunofluorescence studies show no immunoglobulin or complement deposits. Clinical Course Nephrotic syndrome: – Proteinuria (albumin) > 3.5 g/day. – Hipoalbuminemia – Edema – Hyperlipidemia – Lipiduria – Thromboembolic events – Slow decrease of the glomerular filtrate Membranoproliferative Glomerulonephritis (Mesangiocapillary glomerulonephritis) 5% to 10% of cases of idiopathic nephrotic sd. In children and young adults (< 30 years). Associated with other systemic disorders and known etiologic agents (secundary MPGN) or may be primary, without known cause (idiopathic) in the kidney. Primary MPGN – Type I: Inmune complexes and activation of alternative and classic pathways of complement – Type II:Alternative pathway of complement. Autoantibodies IgG (Nephritic factor C3) which joins with C3 convertase and inactivate C3. Morphology MPGN By light microscopy, both types are similar. – The glomeruli are large and hipercelular (by proliferation of cells in the mesangium). – The glomeruli have an “hyperlobular” appearance accentuated by the proliferating mesangial cells and increased mesangial matrix. – The GBM is thickened in the peripheral capillary loops. – The glomerular capillary wall aften shows a “double-contour” or “tram-track” appearance (silver or PAS stains). As seen here, the glomerulus has increased overall cellularity, mainly mesangial. Extensive double contours of the glomerular basement membranes, stained by silver, in membranoproliferative glomerulonephritis type 1, caused by mesangial interposition and new basement membrane formation in response to subendothelial immune complex deposits. The deposits are PAS positive and globular-to-sausage shaped (Jones' silver stain; original magnification, x400). Type I MPGN 2/3 of cases “Subendothelial electrodense deposits” under transmission electronic mycroscopy. Immnunofluorescence – C3 in a granular pattern – IgG – Early complement components (C1q and C4). Membranoproliferative glomerulonephritis type 1. The marked endocapillary proliferation (proliferating endothelial and mesangial cells) appears to occlude the capillary lumen. Numerous large subendothelial and occasional mesangial-dense immune complex-type deposits (bottom middle) are present (transmission electron microscopy; original magnification, x4,700 Segmental, coarsely granular-to-globular or elongated capillary wall IgG deposits in membranoproliferative glomerulonephritis type 1 (immunofluorescence with anti-IgG; origina magnification, x200). This electron micrograph demonstrates the dense deposits in the basement membrane of MPGN type II. There are dark electron dense deposits within the basement membrane that often coalesce to form a ribbon-like mass of deposits. Type I Clinical Course: Massive proteinuria, Nephrotic sd. Treatment: Elimination of the infection. Prognosis: Good, 70 – 85% without clinical alterations. Type II • Clinical Course: Nephrotic and Nephritic sd. • Prognosis: Most patients progress to endstage renal disease within 10 years. In both types: Hipocomplementemia, cause of the comsumption in the glomeruli. Membranous Glomerulonephritis Membranous Nephropathy Epimembranous GN Spikes GN Membranous GN Most common cause of nephrotic syndrome in adults. Characterized by: – Diffuse thickening of glomerular capillary wall – Accumulation of electron-dense, deposits of immunoglobulin. – Along the subepithelial side of the basement membrane Membranous GN Idiopathic – 85% of cases Secondary to: – Drugs: penicillamine, captopril, gold, NSAIDs – Underlying malignant tumors: carcinoma of lung, colon and melanoma. – Systemic Lupus: Most common type. – Infections: chronic hepatitis B/C, syphilis, schistosomiasis, malaria. – DM, thyroiditis. •Early Stage: Glomeruli appear normal or exhibit uniform, diffuse thickening of glomerular capillary wall. •BM material is laid down between the deposits, appearing as irregular spikes protruding from the GBM (silver stain is the best) IMMUNOFLUORESCENCE: Deposits of immunoglobulines (G or M) and complement. Electron microscopy: thickening by irregular dense deposits between BM and podocites (subepithelial). Podocites have lost their foot processes. Clinical Course Nephrotic syndrome or non-selective proteinuria. Common symptoms: hematuria, hypertension, and symptoms of secondary causes. Course: irregular, indolent. As the glomeruli sclerosis progresses: BUN elevated, hypertension and reduction in severity of proteinuria. Prognosis and Treatment Prognosis: – 60% recovers with persistent proteinuria – 10% die or progress to renal insufficiency. – Spontaneous remission and better prognosis in women with non-nephrotic proteinuria. Treatment: – NON Renal Amyloidosis Amyloidosis A systemic immune disease characterized by deposition of amyloid (may be localized) Amyloid is a pathologic proteinaceous substance, deposited between cells in various organs and tissues with a wide variety of clinical settings. Tipically involves: – Kidneys, spleen, liver, myocardium, thyroid, pituitary and tongue. adrenals, Associated with:multiple myeloma, chronic inflammatory conditions, chronic renal failure, Alzheimer’s disease, type 2 diabetes. Amyloidosis Amyloid is formed by fibril proteins in 95% and by glycloproteins (P component) in 5%. There are 15 biochemically distinct forms of amyloid proteins: – – – – Amyloid Light Chain Amyloid –associated protein Ab amyloid in Alzheimer’s disease All produce the same consequences and give the same pattern in microscopy. Renal amyloidosis is the most common and potentially the most serious form of organ involvevement. Gross Pathology Kidneys may be either : (1)Enlarged, firm with a waxy appearance (2)Shrunken and contracted owing to vascular stenosis. E A R L Y S T A G E Amyloid is deposited in the glomeruli, interstitium, arteries and arterioles. Appear as irregular thickenings of mesangium and capillary basement membranes. Congo Red Stain - Polarizing microscopy Show diffuse amyloid deposition (green birefringence) in glomerular tufts and mesangial regions. END STAGE: Glomerular tufts are flooded and replaced by masses or ribbons of amyloid. Glomerular diseases that run with Nephrytitc Syndrome Poststreptococcal Glomerulonephritis (Postinfectious Acute Glomerulonephritis) Pathogenesis Secondary to a pharyngeal infección with varying latent period Nephritic syndrome – Group A (1,2,3,4,12,18,25,49,55,57,60) Low complement levels, and high titles of streptococcal products. Glomeruli – Granular immune deposits – Endostreptsin and cationic antigens in afected áreas Macro Macroscopic hematuria with a rusty or smokey hue. Micro Glomeruli: bloodless, hypercelular and enlarged. Proliferating mesangial and endothelial cells oclude the capillary lumina – PMN and monocyte infiltration. Exudative and difuse (will affect all the lobules) Interstitium: edema Electron Microscopy Dome-shaped deposits projecting outward from epithelial side of basement membreane. – Epithelial cell slit pores – Separated from the basement membrane by cearl zone continuos with the lamina rara externa. PMN and monocytes Clinical Features Spontaneous nefritic syndrome – Fever, nausea, gross hematuria, oliguria after recovery from pharyngitis. Note: adults have a less spontaneous start with HTA. During epidemics, symptoms may be rare. 1% of children develop intense oliguria and progresive glomerulonephritis. Outcome in adults is less favorable. During sporadic cases, 60% have an early recovery. 1 or more weeks. Glomeruli show diffuse hypercellularity due to mesangial and endothelial cell increase and a large number of polymorphonuclear neutrophils (PMNs). H&E Diffuse proliferative acute postinfectious glomerulonephritis with numerous PMNs with PAS-positive cytoplasm and endocapillary proliferation. PAS The garland pattern of immune complexes due to large subepithelial deposits in acute postinfectious glomerulonephritis is shown (immunofluorescence Hump-shaped deposits in acute postinfectious glomerulonephritis with extensive foot process effacement and endocapillary proliferation Rapidly Progressive Glomerulonephritis Rapidly Progressive Glomerulonephritis General Info Very uncommon – 2 % of all cases presenting with GN Predominates in men (2:1) – Young to middle aged Rapidly Progressive Glomerulonephritis Classification 1.- Post-infectious (Post-Streptococcal) 2.- Associated to Systemic Diseases Lupus, Goodpasture syndrome, vasculitis, Wegener 3.- Primary or idiopathic In all cases the basic pathogenic mechanism is immunogenic Rapidly Progressive Glomerulonephritis Pathogenesis The presence of fibrin in Bowman’s space promotes the epithelial proliferation and formation of crescents Extravasation due to capillary damage Production stimulated by factors liberated by Monocytes GLOMERULUS Fibrin Fibrin Rapidly Progressive Glomerulonephritis Microscopic and Macroscopic Aspect MACRO: pale hipertrophic kidneys with petechial hemorrages on the cortical surface MICRO: proliferation of glomerular epithelial cells and mononuclear infiltrate forming crescents in the urinary space (Neutrophils and linfocytes may also be found) Crescents: complex mixture of proliferating epithelial cells and infiltrating monocytes forming concentric layers around the capillary tufts (which are compressed) This is a case of RPGN due to Lupus The implication of a cellular crescent is that the glomerulus has sustained acute intense injury. IDIOPATHIC RPGN Rapidly Progressive Glomerulonephritis Pathogenesis of symptoms Glomerular tufts adhere to Bowman’s capsule Cicatrization of capillaries Renal Failure OLIGURIA POST-GLOMERULAR ISCHEMIA TUBULAR ATROPHY AND INTERSTITIAL FIBROSIS Electron Microscopy: damage to basal membrane with ruptures but no evidence of immune complex deposition. •The urinary space in the top of the photograph shows portion of a crescent with the dark strands representing fibrin (arrow). Immunofluorescence: positivity with antibody to fibrinogen. With a rapidly progressive GN, the glomerular damage is so severe that fibrinogen leaks into Bowman's space, leading to proliferation of the epithelial cells and formation of a crescent. Rapidly Progressive Glomerulonephritis Clinical features Extremely rapid deterioration of renal function, within weeks or up to 2 months – Acute nephritis (Nephritic Sd.) with acute renal failure – Hypertension and edema – Hematuria, proteinuria, pyuria (nephrotic sd.) – Oliguria or anuria The patient may refer a viral syndrome or respiratory infection weeks before onset of renal failure Goodpasture’s Syndrome (Anti-Basement Membrane Disease) Goodpasture’s Syndrome General Info Acute and necrotizing RPGN associated to pulmonary hemorraging and hemoptysis Uncommon disease affecting primarily men (4:1) between 20-30 years of age. Autoimmune disease in which there is production of Anti-Basement Membrane Antibodies (ABM) that deposit on alveoli and glomeruli Goodpasture’s Syndrome Pathogenesis The Goodpasture antigen resides in the noncollagen portion of the 3-alpha chain of type IV collagen Precipitation factor is unknown, may be: – – – – – Virus Hydrocarbonated solvents Tobacco smoke (permissive role) Drugs Cancer Genetic predisposition: DRW15/DQW6 The lesion consists of deposits of ABM antibody and complement on the basement membrane of glomeruli and alveoli causing their destruction Goodpasture’s Syndrome Macroscopic and Microscopic Aspect MACRO: same aspect as RPGN MICRO: crescents composed of epithelial cells and monocytes surrounding capillary tufts in the urinary space – Methenamine silver stain – Electron Microscopy: does not show deposits, only architectural damage and epithelial proliferation – Immunofluorescence The lungs show alveolar hemorrage, hemosiderinfilled macrophages and thickening of alveolar septi. The BM shows immune deposits Silver stain Immunofluorescence: shows positivity with antibody to IgG has a smooth, diffuse, linear pattern that is PATOGNOMONIC Goodpasture’s Syndrome Clinical features Typically begins as flu-like illness with evidence of pulmonary compromise Pulmonary hemorrages HEMOPTYSIS Progressive dyspnea Nephritis (Nephritic Sd.) and acute renal failure The disease progresses rapidly with renal failure ocurring within weeks or months Treatment and Prognosis High doses of steroids, with or without cytotoxic agents. Plasmapheresis removes ABM-antibodies Better prognosis than other diseases causing RPGN Glomerulonephritis IgA or Of Berger Classification This form of glomerulonephritis is characterized by the presence of prominent IgA deposits in the mesangial regions. Primary glomerular disease Frequent cause of recurrent hematuria Most common Present in children and young adults. Pathogenesis Genetic or acquired abnormality of inmune regulation leading to increased mucosal IgA synthesis in response to respiratory or GI exposure to environmental agents. IgA1 and IgA1complexes are entrapped in the mesanguim. They activate the alternative complement pathway and initiate glomerular injury. MICRO/ H&E Mesangial widening or proliferation (arrow) Segmental proliferation Overt crescentic glomerulonephritis (rare) Sclerosis (healing of focal proliferative lesion). MICRO/ Electron Mic. Mesangial electron dense deposits and increased mesangial matrix and cellularity in IgA nephropathy (transmission electron microscopy, original magnification x8,500). MICRO/ Immunofluorescence Mesangial deposition of IgA Clinical Course Gross hematuria after GI or respiratory infection. 5-10% develop a typical acute nephritic syndrome. Hematuria lasts several days and then subsides, only to return every few months. Sistemic Lupus Erithematous Diffuse Proliverative Glomerulonephritis Introduction SLE- Classic prototype of the multisystem disease of autoimmune origin, characterized by a bewildering array of autoantibodies, particulary antinuclear antibodies (ANAs). Acute or insidious in its onset, it is a chronic, remitting and relapsing, often febrile illness characterized principally by injury to the skin, joints, kidney, and serosal membranes. Classification Lupus Glomerulonephritis Kidney appears to be involved in 60 to 70% of cases. According to the WHO (morphologic class.) Class I: Normal by light, electron, and imunofluorescent microscopy Class II: Mesangial lupus glomerulonephritis Class III: focal proliferative glomerulonephritis Class IV: Diffuse proliferative glomerulonephritis Class V: Membranous glomerulonephritis MICRO/ H&E Proliferation of mesangial cells and endothelial cells, along with infiltrating mononuclear and polymorphonuclear leukocytes afecting more than 50% of the glomerular area. Extensive peripheral capillary wall subendothelial immune deposition (wire loop), and extracapillary proliferation in the form of crescents. Fibrinoid necrosis, leukocyte infiltration, wireloop deposits, hyaline thrombi, and hematoxylin bodies MICRO/ Others Half of the tuft is distorted by marked endocapillary proliferation with occasional infiltrating cells. Segmental areas of basement membrane splitting and eosinophilic subendothelial deposits and mesangial eosinophilic deposits are visualized (Jones' silver stain; original magnification x400). Clinical Course Typically have: – high anti-DNA antibody titers – low serum complement levels – Very active urinary sediment with: erythrocytes other casts present on urinalysis – Proteinuria – Half of the patients will have nephrotic syndrome – Hypertension ¡ X FIN ¡ Gracias... [email protected] MMI