Presentation on theme: "Pathology of Glomerular Disease II"— Presentation transcript:
1 Pathology of Glomerular Disease II Dr. Álvaro Barboza Quintana.
2 Return to Renal Learning Module Clinico-pathologic Classificationin Renal SyndromesH = High frequency among patients with the syndromeL = Low frequency among patients with the syndrome1.Nephrotic Syndrome (NS)Primary Nephrotic SyndromeMinimal change disease - HFocal segmental glomerulosclerosis - HMembranous glomerulopathy - LSystemic Nephrotic SyndromeDiabetes mellitus - HAmyloidosis - LSystemic lupus erythematosus (WHO Class V)
3 Membranoproliferative GN - L Nephritic Syndrome - Low Serum ComplementPrimary Nephritic SyndromePost-infectious glomerulonephritis (GN)Membranoproliferative GN - LSystemic Nephritic SyndromeSystemic lupus erythematosus (WHO Class III, WHO Class IV) - HInfectious endocarditisHCV-associated cryoglobulinemia
6 Glomerular diseases that run with nephrotic syndrome.
7 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 treatmentHIV, heroinHodgkin disease
8 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.
9 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).
11 In this electron micrograph, overlying epithelial cell foot processes are effaced (giving the appearance of fusion) and run together.
12 Morphology MCDThis 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.
13 Clinical Course Nephrotic syndrome: Proteinuria (albumin) > 3.5 g/day.HipoalbuminemiaEdemaHyperlipidemiaLipiduriaThromboembolic eventsSlow decrease of the glomerular filtrate
14 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 MPGNType I: Inmune complexes and activation of alternative and classic pathways of complementType II:Alternative pathway of complement. Autoantibodies IgG (Nephritic factor C3) which joins with C3 convertase and inactivate C3.
15 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).
16 As seen here, the glomerulus has increased overall cellularity, mainly mesangial.
17 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).
18 Type I MPGN2/3 of cases“Subendothelial electrodense deposits” under transmission electronic mycroscopy.ImmnunofluorescenceC3 in a granular patternIgGEarly complement components (C1q and C4).
19 Membranoproliferative glomerulonephritis type 1 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
20 Segmental, coarsely granular-to-globular or elongated capillary wall IgG deposits in membranoproliferative glomerulonephritis type 1 (immunofluorescence with anti-IgG; origina magnification, x200).
21 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.
22 Type I Type II Clinical Course: Massive proteinuria, Nephrotic sd. Treatment: Elimination of the infection.Prognosis: Good, 70 – 85% without clinical alterations.Type IIClinical Course: Nephrotic and Nephritic sd.Prognosis: Most patients progress to end-stage renal disease within 10 years.In both types: Hipocomplementemia, cause of the comsumption in the glomeruli.
23 Membranous Glomerulonephritis Membranous NephropathyEpimembranous GNSpikes GN
24 Membranous GN Most common cause of nephrotic syndrome in adults. Characterized by:Diffuse thickening of glomerular capillary wallAccumulation of electron-dense, deposits of immunoglobulin.Along the subepithelial side of the basement membrane
25 Membranous GN Idiopathic – 85% of cases Secondary to: Drugs: penicillamine, captopril, gold, NSAIDsUnderlying malignant tumors: carcinoma of lung, colon and melanoma.Systemic Lupus: Most common type.Infections: chronic hepatitis B/C, syphilis, schistosomiasis, malaria.DM, thyroiditis.
30 IMMUNOFLUORESCENCE: Deposits of immunoglobulines (G or M) and complement.
31 Electron microscopy: thickening by irregular dense deposits between BM and podocites (subepithelial). Podocites have lost their foot processes.
32 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.
33 Prognosis and Treatment 60% recovers with persistent proteinuria10% die or progress to renal insufficiency.Spontaneous remission and better prognosis in women with non-nephrotic proteinuria.Treatment:NON
35 AmyloidosisA 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, adrenals, thyroid, pituitary and tongue.Associated with:multiple myeloma, chronic inflammatory conditions, chronic renal failure, Alzheimer’s disease, type 2 diabetes.
36 AmyloidosisAmyloid 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 ChainAmyloid –associated proteinAb amyloid in Alzheimer’s diseaseAll produce the same consequences and give the same pattern in microscopy.
37 Renal amyloidosis is the most common and potentially the most serious form of organ involvevement.
38 Gross Pathology Kidneys may be either : (1)Enlarged, firm with a waxy appearance(2)Shrunken and contracted owing to vascular stenosis.
39 E A R L YS T AG EAmyloid is deposited in the glomeruli, interstitium, arteries and arterioles. Appear as irregular thickenings of mesangium and capillary basement membranes.
40 Congo Red Stain - Polarizing microscopy Show diffuse amyloid deposition (green birefringence) in glomerular tufts and mesangial regions.
41 END STAGE: Glomerular tufts are flooded and replaced by masses or ribbons of amyloid.
42 Glomerular diseases that run with Nephrytitc Syndrome
44 PathogenesisSecondary to a pharyngeal infección with varying latent periodNephritic syndromeGroup A (1,2,3,4,12,18,25,49,55,57,60)Low complement levels, and high titles of streptococcal products.GlomeruliGranular immune depositsEndostreptsin and cationic antigens in afected áreas
45 Macro Micro Macroscopic hematuria with a rusty or smokey hue. Glomeruli: bloodless, hypercelular and enlarged.Proliferating mesangial and endothelial cells oclude the capillary luminaPMN and monocyte infiltration.Exudative and difuse (will affect all the lobules)Interstitium: edema
46 Electron MicroscopyDome-shaped deposits projecting outward from epithelial side of basement membreane.Epithelial cell slit poresSeparated from the basement membrane by cearl zone continuos with the lamina rara externa.PMN and monocytes
47 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.
48 Glomeruli show diffuse hypercellularity due to mesangial and endothelial cell increase and a large number of polymorphonuclear neutrophils (PMNs). H&E
49 Diffuse proliferative acute postinfectious glomerulonephritis with numerous PMNs with PAS-positive cytoplasm and endocapillary proliferation. PAS
50 The garland pattern of immune complexes due to large subepithelial deposits in acute postinfectious glomerulonephritis is shown (immunofluorescence
51 Hump-shaped deposits in acute postinfectious glomerulonephritiswith extensive foot processeffacement and endocapillaryproliferation
53 Rapidly Progressive Glomerulonephritis General InfoVery uncommon2 % of all cases presenting with GNPredominates in men (2:1)Young to middle aged
54 In all cases the basic pathogenic mechanism is immunogenic Rapidly Progressive GlomerulonephritisClassification1.- Post-infectious (Post-Streptococcal)2.- Associated to Systemic DiseasesLupus, Goodpasture syndrome, vasculitis, Wegener3.- Primary or idiopathicIn all cases the basic pathogenic mechanism is immunogenic
55 Rapidly Progressive Glomerulonephritis PathogenesisThe presence of fibrin in Bowman’s space promotes the epithelial proliferation and formation of crescentsGLOMERULUSExtravasation due to capillary damageFibrinProduction stimulated by factors liberatedby MonocytesFibrin
56 Microscopic and Macroscopic Aspect Rapidly Progressive GlomerulonephritisMicroscopic and Macroscopic AspectMACRO: pale hipertrophic kidneys with petechial hemorrages on the cortical surfaceMICRO: proliferation of glomerular epithelial cells and mononuclear infiltrate forming crescents in the urinary space (Neutrophils and linfocytes may also be found)
57 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
58 The implication of a cellular crescent is that the glomerulus has sustained acute intense injury. IDIOPATHICRPGN
59 Pathogenesis of symptoms Rapidly Progressive GlomerulonephritisPathogenesis of symptomsGlomerular tufts adhere toBowman’s capsuleOLIGURIAPOST-GLOMERULARISCHEMIACicatrization of capillariesRenal FailureTUBULAR ATROPHYAND INTERSTITIALFIBROSIS
60 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).
61 Immunofluorescence: positivity with antibody to fibrinogen 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.
62 Rapidly Progressive Glomerulonephritis Clinical featuresExtremely rapid deterioration of renal function, within weeks or up to 2 monthsAcute nephritis (Nephritic Sd.) with acute renal failureHypertension and edemaHematuria, proteinuria, pyuria (nephrotic sd.)Oliguria or anuriaThe patient may refer a viral syndrome or respiratory infection weeks before onset of renal failure
64 Goodpasture’s Syndrome General InfoAcute and necrotizing RPGN associated to pulmonary hemorraging and hemoptysisUncommon disease affecting primarily men (4:1) between years of age.Autoimmune disease in which there is production of Anti-Basement Membrane Antibodies (ABM) that deposit on alveoli and glomeruli
65 Goodpasture’s Syndrome PathogenesisThe Goodpasture antigen resides in the non-collagen portion of the 3-alpha chain of type IV collagenPrecipitation factor is unknown, may be:VirusHydrocarbonated solventsTobacco smoke (permissive role)DrugsCancerGenetic predisposition: DRW15/DQW6The lesion consists of deposits of ABM antibody and complement on the basement membrane of glomeruli and alveoli causing their destruction
66 Macroscopic and Microscopic Aspect Goodpasture’s SyndromeMacroscopic and Microscopic AspectMACRO: same aspect as RPGNMICRO: crescents composed of epithelial cells and monocytes surrounding capillary tufts in the urinary spaceMethenamine silver stainElectron Microscopy: does not show deposits, only architectural damage and epithelial proliferationImmunofluorescenceThe lungs show alveolar hemorrage, hemosiderin-filled macrophages and thickening of alveolar septi. The BM shows immune deposits
68 Immunofluorescence: shows positivity with antibody to IgG has a smooth, diffuse, linear pattern that is PATOGNOMONIC
69 Treatment and Prognosis Goodpasture’s SyndromeClinical featuresTypically begins as flu-like illness with evidence of pulmonary compromisePulmonary hemorrages HEMOPTYSISProgressive dyspneaNephritis (Nephritic Sd.) and acute renal failureThe disease progresses rapidly with renal failure ocurring within weeks or monthsTreatment and PrognosisHigh doses of steroids, with or without cytotoxic agents.Plasmapheresis removes ABM-antibodiesBetter prognosis than other diseases causing RPGN
71 ClassificationThis form of glomerulonephritis is characterized by the presence of prominent IgA deposits in the mesangial regions.Primary glomerular diseaseFrequent cause of recurrent hematuriaMost commonPresent in children and young adults.
72 PathogenesisGenetic 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.
73 MICRO/ H&E Mesangial widening or proliferation (arrow) Segmental proliferationOvert crescentic glomerulonephritis (rare)Sclerosis (healing of focal proliferative lesion).
74 MICRO/ Electron Mic.Mesangial electron dense deposits and increased mesangial matrix and cellularity in IgA nephropathy (transmission electron microscopy, original magnification x8,500).
75 MICRO/ Immunofluorescence Mesangial deposition of IgA
76 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.
78 IntroductionSLE-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.
79 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 microscopyClass II: Mesangial lupus glomerulonephritisClass III: focal proliferative glomerulonephritisClass IV: Diffuse proliferative glomerulonephritisClass V: Membranous glomerulonephritis
81 MICRO/ H&EProliferation 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, wire- loop deposits, hyaline thrombi, and hematoxylin bodies
82 MICRO/ OthersHalf 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).
83 Clinical Course Typically have: high anti-DNA antibody titers low serum complement levelsVery active urinary sediment with:erythrocytesother casts present on urinalysisProteinuriaHalf of the patients will have nephrotic syndromeHypertension
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